Cystic Fibrosis Exercise

I. Introduction

Cystic fibrosis (CF) is an inherited disorder that impacts multiple body systems, although primarily the pulmonary and digestive systems are affected.[1],[2] These implications are due to a defect in the cystic fibrosis transmembrane conductance regulator gene,[3],[4],[5] resulting in a decreased life expectancy.[2] The benefits of exercise for those with CF have been shown at the functional level including improved pulmonary function,[6] increased sputum expectoration,[7] and significantly lower risk of death.[8] Although still in its infancy stages, this page will address the emerging evidence of proposed cellular mechanisms that supports exercise as medicine for people with CF [9],[10] and the limited available exercise recommendations for this population.

II. Ion Regulation in the Lungs During Exercise

A. Nasal Transepithelial Potential Difference

1. Determining Nasal Potential Difference During Exercise

Ions, such as sodium (Na⁺) and chloride (Cl^-), moving into and out of the cell create a nasal transepithelial potential difference (TPD) in the airway lining and the lumen and this potential difference can show the abundance of either Na⁺ or Cl^- within the lumen.[11] Researchers measure the nasal TPD by placing electrodes in the nasal cavity of the individual.[11] The nose lining is then exposed to a variety of solutions.[11][12] When the solutions are added, they can predictably change the TPD in the airway lining, making it possible for researchers to determine the effects of various ion exposure to the epithelial membrane in both normal subjects and subjects with CF.[11]

Figure 1: Nasal Potential Difference Testing in Normal Ion Regulation
Images taken from: http://www.hopkinscf.org/main/whatiscf/diag_testnasal.html

Normal ion regulation	Amiloride added	Cl- free solution added	Isproterenol added
The nasal TPD in a healthy person's airway lumen is more positive (less negative) than that of a patient with CF because the Na+ reabsorption is better controlled and Na+ remains outside the cell to balance the Cl- concentration.[11] There is adequate ion regulation of both Na+ and Cl- into and out of the cell during homeostasis.[11]	In a normal ASL lumen, the addition of amiloride, which blocks Na+ transport into the cell, causes the lumen of the lung to become more positive.[11]. The inhibition of Na+ causes a decrease in the Cl- absorption into the cell to compensate for this increase in positive charge in the lumen (outside the cell).[11] This decreases the TPD with the cell membrane potential becoming less negative in response to the increase in Na+ ions in the lumen.[11][12]	In normal subjects, when a Cl--free solution (isotonic) is added to the lumen, the cells increase the secretion of Cl- into the lumen via the CFTR channels that stimulate the efflux of Cl- out of the cell.[11] This increases the salt (NaCl) concentration in the lumen, which improves the airway surface liquid (ASL) volume because water follows NaCl.[11]	In the next stage, isoproterentol is added to the lumen. Isoproterentol stimulates Cl- secretion via the c-AMP K-dependent pathway that activates CFTR.[11] Isoproterentol is a synthetic catecholamine that stimulates the beta 1 and beta 2 adrenergic receptors to eventually activate CFTR.[11][13] The increase in Cl- efflux and secretion into the lumen makes the nasal TPD more negative as Cl- ions are secreted into the lumen.[11]

Figure 2: Nasal Potential Difference Testing in CF
Images taken from: http://www.hopkinscf.org/main/whatiscf/diag_testnasal.html

CF Ion Regulation	Amiloride Added	Cl- free solution added	Isproterenol added
Baseline nasal potential for individuals with CF, the nasal TPD is typically much lower (more negative) than healthy subjects due to the uninhibited Na+ reabsorption.[11]	When amiloride is added to the lumen, there is a rapid increase in the Na+ present in the lumen due to the inhibition of the Na+ transport back into the cell.[11] This decreases the TPD as the lumen becomes more positive.[11] Because CFTR is defective, there is only minimal transport of Cl- via other channels.[11] As a result of Na+ reabsorption inhibition, there is an increase in the NaCl content of the lumen. Because water follows solutes, there is an increased ASL volume.[11]	Addition of the Cl--free solution causes little change in the TPD as there is very little Cl- that can be secreted out of the cell into the lumen secondary to a defective CFTR.[11]	Once again, the addition of a synthetic catecholamine (isproterenol), which would usually trigger a Cl- efflux via the c-AMP-mediated pathway, is blocked and there is minimal secretion of Cl- out of the cell into the lumen hence very little change in the TPD.[11][13]

By comparing nasal TPD testing in normal and CF patients during homeostasis, researchers can determine the channels, proteins, and other components influenced during exercise and the effect of different exercise types on the nasal TPD.

2. Effects of Exercise on the Transepithelial Potential Difference

Study 1

Reference:Hebestreit et al., 2001[12]
Type of Study:Controlled Clinical Trial
Subjects: 9 healthy subjects (controls aged 15-33 years old) 9 subjects with CF (aged 10-31 years old)[12]
Exercise Intervention: Subjects were tested during 2 sessions with less than 14 days between sessions[12]

1. Maximum power cycling: One session included cycling to volitional fatigue on a cycle ergometer while supine with the head elevated 30 degrees. Power was raised every 2 minutes with subjects being instructed to pedal for at least 8 minutes. This session was only used to determine moderate-intensity exercise for each participant. No nasal TPD readings were taken at this visit.[12]
2. Cycling at 85% of Ventilatory anaerobic threshold (VT): The second session involved subjects cycling on a cycle ergometer semi-supine with the head elevated 30 degrees. The subjects pedaled for at least 10 minutes at 85% of their ventilatory thresholds[12]

Outcomes and Results:

1. Transepithelial nasal potential difference ΔPD at rest and with exercise.[12]
   • At rest, the TPD was more negative in the control group than the group with CF.[12]
   • After 10 minutes of exercise at 85%, the TPD decreased (became less negative) in subjects with CF as compared to rest. Exercise changes with regards to difference in TPD were significantly larger than the control group (p<0.001).[12]
   • No significant difference in nasal TPD between healthy controls and patients with CF after 10 minutes of exercise.[12]
2. Change in potential difference with the addition of amiloride (ΔPD_amil) at rest and during exercise[12]
   • ΔPD_amil was significantly less with exercise than at rest in both CF and healthy subjects.[12]
3. Change in potential difference with addition of Cl^- solution and isoprotenerol (ΔPD_{low Cl/iso}) at rest and during exercise[12]
   • There was little change in ΔPD_{low Cl/iso} during exercise and rest in both the CF and healthy control group.[12]

Study 2

Reference:Schmitt et al., 2011[13]
Type of Study: Controlled clinical trial
Subjects:11 healthy subjects, 9 subjects with exercised induce asthma (EIA), 10 subjects with CF[13]
Exercise Intervention:Intervention included 2 sessions of exercise with at least 7 days in between each session[13]

1. Maximum exercise test: One session of cycling until volitional fatigue on a cycle ergometer lying down with the head elevated 30 degrees initially at 50 W; power was increased by 25 W every 3 minutes. Nasal TPD was measured before exercise, immediately after exercise and 20 minutes later.[13]
2. Submaximal exercise: One session of cycling for 20 minutes on a cycle ergometer supine with the head elevated 30 degrees at a workload rate determined from the maximum exercise test and below anaerobic threshold. Nasal TPD was measured before exercise, 15 minutes into exercise, and 20 minutes after exercise.[13]

Outcomes and Results: Nasal TPD readings taken at rest, 15 minutes into exercise, immediately after exercise, and 20 minutes after exercise[13]

1. Nasal potential total (NP_total)[13]
   • In patients with CF, the NP_total was more negative than the control and EIA group at rest.[13]
   • There was a decrease (became less negative) in NP_total (~10mV) in patients with CF during BOTH maximal and submaximal exercise which was significantly larger than the EIA or control group.[13]
   • Slight decrease was found with NP_total in the control group with maximal exercise but not with submaximal exercise.[13]
   • After the 20-minute recovery each group’s NP_total returned to their baseline values[13]
   • There was no change in the NP_total in the EIA group in either maximal or submaximal exercise.[13]
2. Nasal potential after amiloride solution (NP_Δamil)[13]
   • There was a decreased NP_Δamil in patients with CF after maximal exercise (~10mV) but not in either the control or EIA group[13]
   • There was no significant change in NP_Δamil during submaximal exercise in any groups.[13]
3. Nasal potential after low chloride plus isoproterenol (NP_ΔCl-)[13]
   • There was a lower NP_ΔCl^- in the CF group in all exercise conditions as compared to both controls and EIA[13]
4. Catecholamines (epinephrine and norepinephrine) and glucocorticoids (cortisol) in blood at rest, 15 minutes into exercise, and immediately after maximal exercise[13]
   • Epinephrine was lower in CF after maximal exercise likely due to the decreased exercise intensity. No change between groups with submaximal exercise.[13]
   • Norepinephrine was significantly lower in patients with CF and EIA compared to controls during maximal exercise, while there was no change during submaximal exercise.[13]
   • Cortisol levels did not change between groups during any exercise conditions.[13]

Hebestreit et al. concluded that exercise may partially block Na⁺ reabsorption into cell with moderately intense exercise.[12] With exercise, the change in nasal TPD in subjects with CF decreased, eluding to a more positively charged lumen (more Na⁺ present outside the cell).[12] Additionally, the change in nasal TPD with addition of amiloride at rest and with exercise in subjects with CF was less than the healthy controls, indicating that Na⁺ reabsorption was being inhibited prior to the addition of the amiloride in the healthy subjects but not the subjects with CF.[12] To further prove that the Na⁺ channels were inhibited, there was no change in the nasal TPD at rest and with exercise in subjects with CF after the addition of a solution low in Cl^- and with isoprotenerol.[12] This shows that the Cl^- was still present in the lumen and the addition of the solutions did not alter the ion regulation in the lung epithelial tissue. One possible mechanism for this was that exercise and mechanical stress via increase in ventilation rate can trigger the release of ATP which has been previously shown and speculated to inhibit Na⁺ channels.[12]

In the study by Schmitt et al., because there was no change in the nasal TPD or NP_amil until after maximum exercise in the healthy controls, one can speculate that nasal TPD may depend on exercise intensity.[13] In patients with CF, the changes in the nasal TPD were smaller than those reported by Hebestreit et al. after submaximal exercise; however, there was still a decrease in the TPD (lumen became more positive). Larger changes in the nasal TPD for subjects with CF occurred only at a submaximal exercise intensity; whereas in the healthy controls, there was no change until after maximal exercise.[13] Therefore, the inhibition of Na⁺ reabsorption may depend on exercise intensity with Na⁺ reabsorption still being inhibited with submaximal exercise in patients with CF.[13] Additionally, catecholamine levels were not affected by exercise.[13]

Implications

It is important to understand the limitations with both of these studies. One limitation includes that subjects in both studies performed only short exercise bouts for 2 sessions. Therefore, the effects of chronic exercise on the nasal TPD are unknown at this time. One can speculate that while the nasal TPD is positively affected with exercise, the effects may not be sustained as nasal TPD levels returned close to baseline after 20 minutes of rest in the Schmitt et al. study.[13] Consequently, exercise’s ability to inhibit Na⁺ reabsorption and promote Cl^- secretion may be only a transient change. Additionally, the only exercise intervention studied was cycling in a semi-supine position so other exercise interventions should be considered. Areas for further research include the use of animal models to test the effects of chronic exercise at varying intensities to determine if there is a long term effect on the nasal TPD.

Recommendations

In patients with CF, while the aforementioned studies had limitations, the results have large implications on the effects of exercise. Patients with CF can perform submaximal exercise and actually change the TPD in their airway lumen in a beneficial way. Because exercising, specifically cycling, at a submaximal level decreased Na⁺ reabsorption, it is recommended that this type of activity be performed by patients with CF to increase their ASL volume and decrease the chance of infection.

B. P₂Y₂

Two reviews suggest that exercise is beneficial in CF at the cellular level through the activation of the purinergic (P₂Y₂) pathways that help control the ion channels in sweat glands and epithelial cells in the airways.[9],[10] As stated in the cell biology section, P₂Y₂ is activated by ATP and its metabolite adenosine (ADO).[9] The activation of P₂Y₂, receptors by ATP and ADO cause a depletion in phosphatidylinositol 4, 5-biphospate (PIP₂).[9] This indirectly inhibits ENaC (and thus, Na⁺ reabsorption) because PIP₂ is needed for activation of ENaC by protein kinase C.[9] The depletion in PIP₂ results in the formation of inositol triphosphate (IP3) and diacylglycerol (DAG) with IP₃ going on to mediate the release of Ca²⁺ from the endoplasmic reticulum.[9] This Ca²⁺ can then activate the calcium dependent chloride channels (CaCC), allowing for the secretion of Cl^-.[14] The inhibition of ENaC and the activation of CaCC promotes an increase in ASL by blocking Na⁺ reabsorption and increasing Cl^- secretion.[14]

ATP has been shown to be released with the exposure to physical forces from several factors, including mechanical deformation,[15],[16],[17],[18] stretch,[19],[20] shear stress from fluid,[21],[22],[23],[24] and osmotic shock.[25],[26][27] Mechanical deformation is the most important mechanism of ATP release for the exercise section because ventilation imparts a phasic shear stress in the airway, influencing the activation and inhibition of mechanosensitive channels that regulate ions within the cells.[27] Possible mechanisms that activate these channels in response to mechanical stress include changes in the shape of the lipid bilayer, phosphorylation or dephosphorylation of signaling proteins, and changes in the strain of the cytosol; however, the exact mechanism is unknown.[27] Because of the increase in tidal volume and respiratory rate that occur with exercise, exercise may improve pulmonary function in individuals with CF through ATP release and subsequent P₂Y₂ activation and improved ion regulation.[10] Thus, the inhibition of Na⁺ in the nasal passage reported by Hebestreit et al.[12] may be the result of the increase in ATP released from increased ventilation during exercise. Although Hebestreit et al.[12] did not link the increased ATP to activation of P₂Y₂, a study by Tarran et al.[24] performed a few years later provides in vitro evidence regarding this relationship to pericilliary layer (PCL) volume. Before discussing the influence of ATP on PCL volume, it is important to note that Donaldson et al.[28] found a similar concentration and release rate of ATP in both normal and CF airway epithelial cells in vivo. Consequently, it is important to review the literature in regards to the effects of mechanical stress on ATP and ion regulation.

As mentioned in the cell biology section, maintaining ASL hydration is important for pulmonary function.[29] In normal cells, ASL is maintained by adequate Cl^- secretion and Na⁺ reabsorption to regulate the PCL.[24] However, in CF, the PCL isn't properly regulated because of lack of CFTR.[24] Therefore, because P₂Y₂ participates in ion regulation through an increase in Cl^- secretion and decrease in Na⁺ reabsorption, its influence on ASL height has been studied.[24] This is important when assessing the effects of exercise in CF because improvement in ASL height, specifically the PCL, is beneficial for the innate immune system of the lungs.[27]

Tarran et al. conducted several in vitro experiments to determine the effect of mechanical shear stress, specifically phasic shear stress, on the volume of the PCL in normal and CF epithelial cells.[24] The authors cultured airway epithelial cells from the bronchial specimens of 15 normal subjects (6 females and 9 males) and 21 subjects with CF (9 females and 12 males).[24] A new incubator was developed to create a phasic shear stress to simulate the shear stress induced by breathing in humans with the frequency and magnitude of the shear stress and motion being controlled by a series of devices.[24]

The authors experiments and results are summarized below:

• In response to phasic shear stress, the authors found that both normal and CF airway epithelial cells responded similarly by reaching a "normal" height (7 micrometers) for PCL volume.[24] This is a very important finding demonstrating that motion can trigger signals that cause PCL volume to reach an effective height for the cilia to beat and clear bacteria from the mucus layer.[24]

• When looking at the effect of ATP concentration on PCL homeostasis, the authors first analyzed if there was a positive relationship between the amount of shear stress and ATP released to provide a corresponding increase in PCL volume.[24] They found that PCL volume in a static environment was indeed related to the amount of shear force.[24] Additionally, the authors found that the increase in PCL volume in CF airway epithelial cells in response to phasic shear stress was regulated solely by ATP, which differed from the PCL volume in normal airway cells that was also influenced by adenosine.[24]

• The authors were then interested in the link between ion transport and the release of ATP from phasic shear stress.[24] The CF cultures were put in a chamber that measured intracellular Ca²⁺ and Cl^- secretion, a measure found to assess the ATP signaling pathway in the epithelial cells of airways,[30] while phasic shearing forces were intermittently applied.[24] The phasic shearing increased Cl^- secretion (leading to increased TPD) and Ca²⁺ concentration.[24] Amylase, an enzyme that degrades ATP to AMP, was then added to differentiate the pathway involved in the Cl^- secretion.[24] Because the effect of the phasic shear stress on Cl^- and Ca²⁺ disappeared with application of this enzyme, the authors considered this strong evidence that changes in phasic shear stress activate ATP release that specifically influence P₂Y₂ receptors.[24]

• The final inquiry the authors addressed was the increased incidence of chronic lung infections in patients with CF despite normal tidal volume influencing the release of ATP to appropriately regulate the PCL.[24] It was found that the CF cultures infected with respiratory syncitial virus (RSV) and exposed to phasic shear stress (equivalent to normal tidal breathing in vivo) resulted in a reduction in PCL to ~4.5 micrometers, which is inadequate to provide mucus transport.[24] Additionally, the authors previously found that inflammation causes an increase in extraceullar ATPase, which lowers ATP concentration in PCL.[24] Therefore, normal tidal breathing is unable to maintain the PCL volume in infected CF airways.[24] The data in this experiment showed that the upregulation in enzymes that degrade ATP was the result of the actual RSV versus the release of cytokines to fight the infection because CF cultures were able to maintain PCL height with cytokine exposure but not RSV.[24]

Figure 2: ASL Height in CF and Normal Airway Epithelial Cells[24]
http://www.jbc.org/content/280/42/35751/F7.large.jpg

Implications

These in vitro results provide evidence of the possible mechanisms behind improved lung function that has been associated with exercise.[6],[31],[32],[33],[34],[35] This study suggests that the increased ventilation with exercise may provide the mechanical stimulus (phasic shear stress) to release ATP. This ATP goes on to activate P₂Y₂ which promotes Cl^- secretion and Na⁺ reabsorption to increase PCL height, aiding in the ciliary function to keep the lungs free of infection.[24] The effects of phasic shear stress on PCL volume in normal and CF airway epithelial cells are summarized in Figure 2 above by Tarran et al.[24] The results of this in vitro study need to be analyzed in animal models to assess the effects of exercise on ATP release, P₂Y₂ activation, ASL volume, and pulmonary function. Specifically, the effects of increased ventilation during exercise on PCL volume in animal models infected with pulmonary diseases, like RSV, should be investigated to determine if the increased phasic shear stress can maintain PCL volume despite the decrease in ATP found with this virus. It is crucial that these effects of exercise begin to be studied in animal models as a starting point in determining the specific benefits and detrimental effects that occur as the result of aerobic exercise. These findings can then be applied to humans to determine the ideal frequency, intensity, and duration to optimize the positive benefits of aerobic exercise in individuals with CF.

C. Atrial Natriuretic Peptide

This critical analysis of atrial natriuretic peptide (ANP), a polypeptide hormone, is reserved for the exercise page because ANP is secreted by the heart in response to atrial stretch from increased blood pressure and volume,[36],[37],[38] which occurs during exercise.[10] A recent review by Cholewa et al. suggests that the increased release of ANP during exercise may be another benefit of exercise in individuals with CF.[10] This theory is based on studies that have shown an inhibition of Na⁺ reabsorption in respiratory epithelial cells of murines and rats without CF following circulation of ANP in the lungs.[39],[40]. Like Cholewa et al., Hebestreit et al. theorized that ANP may be partially responsible for the observed decrease in Na⁺ reabsorption in the airway epithelial cells after exercise, resulting in a decreased TPD.[12] Once again, a decreased TPD has been associated with increased Cl^- secretion and improved ASL hydration.[10] Although the study by Hebestreit et al. [12] analyzed TPD in subjects with CF, the effects of ANP have not been analyzed in CF tissues. Therefore, the proposed benefits of ANP on CF tissue is based on the cell mechanisms observed in normal tissue and the underlying pathophysiology observed in CF.

ANP synthesis and activity has been found in the heart,[41] brain,[42],[43] lung,[44] and pulmonary and systemic vasculature.[41],[45] When secreted, ANP binds to a natriuretic peptide receptor (NPR) like NPR-A, a protein included in the membrane guanylyl cyclase family.[41][46] ANP binding to NPR-A activates cyclic guanosine 3',5' monophosphate (cGMP).[41],[47],[48]. Cyclic GMP has been shown to inhibit Na⁺ channels[39] While the evidence for inhibition of Na⁺ reabsorption is well documented after ANP perfusion,[24],[36],[39],[40] there are gaps in the literature related to the exact mechanism of ANP-induced inhibition of Na⁺ reabsorption. One study by Novaira et al.[36] demonstrated increased mRNA coding CFTR expression in the proximal colon of rats after exposure to ANP, suggesting that ANP contributes to the amount of CFTR expressed in the epithelial cells of the intestines.[36] Moreover, these authors refer to the possibility that ANP inhibits Na⁺ reabsorption through cGMP-dependent protein kinase G signaling cascades [49] that activate CFTR,[50], inducing Cl^- secretion and Na⁺ inhibition.[36] Although the study by Novaira et al. provides evidence for the influence of ANP on CFTR, it does not analyze the effects of ANP on other mechanism that influence Na⁺ regulation. In regards to additional methods of inhibition of Na⁺ reabsorption, a study by Campbell et al. found that ANP decreased the Na⁺/K⁺ ATPase pump in vitro in alveolar epithelial cells of rats.[51] Cholewa et al. infers that inhibition of this pump will lead to a decrease in the electrochemical force driving Na⁺ into the cell,[10] providing an alternate method for decreased Na⁺ reabsorption that is much more applicable to CF tissue in which Na⁺ reabsorption cannot be inhibited by CFTR activation.

Exercise has been found to mediate a neuroendocrine response in an intensity-dependent relationship with the majority of hormones increasing with an increase in exercise intensity.[52] The hypothalamic-pituitary-adrenal-axis is activated during exercise with the pituitary gland releasing peptide hormones and the adrenal glands secreting catecholamines and corticosteroids.[10] In addition to secretion by the pituitary gland, ANP has been found to be released by the heart during an increase in blood volume or blood pressure, which occurs during exercise.[53] Furthermore, ANP has been reported to increase during short-term, high-intensity exercise and prolonged aerobic exercise.[53],[54],[55],[56] A study by Mandroukas et al., with a repeated measures design, found that ANP increased significantly after submaximal and maximal cycling in 10 healthy females with the average age of 20.5 years.[55] The exercise protocol included submaximal cycling at 100 W (40-50% maximal heart rate) for 20 minutes followed by a period of maximal exercise achieved by an increase of 25 W each minute until the individual reached exhaustion.[55] ANP levels were positively correlated to exercise intensity and duration with an increase from an average of 49 pg/ml at rest to an average peak level of 95.7 pg/ml during maximal exercise.[55] The authors also found that the ANP levels were significantly reduced (average of 80 pg/ml) after 10 minutes of rest, suggesting that the heart stops secreting ANP during rest.[55]

A later study by Mandroukas et al., with a cross-over, repeated measures design, confirmed these results in males by testing the influence of four different exercise running protocols (maximal test, continuous running for 32 minutes at 12 km/hr, alternating every 4 minutes between running at 12 km/hr to 8 km/hr for 32 minutes, and alternating every 4 minutes between running at 12 k/hr and resting) on ANP in 15 healthy, moderately-trained trained men with an average age of 22.3 years.[56] The authors found the greatest increase in ANP occurred during the bout of maximal exercise with an improvement from an average of 44.8 pg/ml at rest to an average of 102.3 pg/ml during maximal exercise.[56] Continuous running also resulted in an increase in ANP from an average of 44.8 pg/ml to an average of 63.3 pg/ml after 32 minutes.[56] The authors reported a decrease in ANP from baseline during the running protocols that required only intermittent running at 12 km/hr.[56] ANP levels returned to near baseline after all four exercise protocols.[56] The authors concluded that the intensity of exercise is more important than the duration to increase ANP release, with short-term high intensity exercise having the greatest effect.[56] Weaknesses in these studies include lack of a control group, long-term outcome measures, and of the use of both male and female subjects. Additionally, these studies only analyzed ANP after a single bout of exercise and the subjects were moderately-trained. Therefore, it is difficult to make generalizations to other populations, including individuals with CF. However, one can hypothesize that the secretion of this hormone would be similar because CFTR dysfunction does not appear to affect hormones released from the heart.

Implications

Although the influence of ANP on the inhibition of Na⁺ reabsorption has been researched in animal models without CF to determine the effects of ANP on Na⁺ regulation,[40],[51] it is difficult to translate these results to CF tissue because the exact mechanism of ANP-induced inhibition of Na⁺ inhibition is not known in non-CF tissue. Therefore, more studies are needed to determine the exact mechanism that allows ANP to provoke Na⁺ reabsorption in epithelial tissue. Specifically, the influence of cGMP on P₂Y₂ should be assessed to determine if this alternate pathway for inhibition of Na⁺ reabsorption, especially beneficial in CF, is activated. Moreover, studies are needed to determine the effects of ANP during exercise in vivo. Because there is too much Na⁺ reabsorption occurring in CF cells, increased ANP from exercise may assist to inhibit Na⁺ reabsorption, leading to a decrease in the TPD and an increase in the drive for Cl^- secretion.[10] Based on the limited studies by Mandroukas et al., short-term maximal intensity will have the greatest benefit in increasing the circulating levels of ANP.[56] More studies are warranted to determine the effects of ANP on CF tissue to assess if exercise induces benefits related to this hormone in patients with CF.

D. Arginine Vasopressin

Arginine Vasopressin (AVP) is a hormone produced by the posterior pituitary gland as well as bronchial epithelial cells.[57] AVP has been proposed to play a role in promoting airway hydration in patients with CF and exercise may contribute to greater production of this hormone.[10] However, stronger research is needed at this time in order to fully understand its implications in CF and to make exercise recommendations.

Multiple factors such as reductions in plasma volume and plasma osmolality from exercise contribute to increases in plasma AVP concentrations.[58] Besides plasma levels of AVP, exercise contributes to a pathway that raises bronchial epithelial cell production of AVP. Progressive exercise increases bradykinin and activates kallikrein. [57],[59],[60],[61] Plasma kallikrein then additionally increases bradykinin production which leads to AVP release from bronchial epithelial cells.[57],[59],[60],[61] A study on physically active subjects with an average age of 27 years discovered significant increases in bradykinin with 10-minute periods of dynamic plantar flexion contractions at different workloads and 10 minutes of rest between each bout; however, there was no conclusive evidence about the ideal workload level.[59]

AVP affects ion regulation which may in turn reduce water absorption of the lumen in airway epithelial cells, but more research on the effect of AVP on TPD in patients with CF is needed.[10] AVP binds to multiple receptors, and V_1b is one example of an apical membrane receptor located in the trachea and bronchi that is coupled with G-proteins.[10] After this AVP binding to V_1b, phospholipase C is activated and causes PIP2 cleavage.[10] PIP₂ cleavage results in less Na⁺ absorption through ENaC inhibition as well as increased Cl^- secretion through CaCC.[10] It has been suggested that CaCC can be used to bypass the defective CFTR channel,[9] and these findings demonstrate that increased AVP may be a potential mechanism for increased CaCC activation in patients with CF. Additional influences on increasing Cl^- secretion result from influx of ions through Na⁺-K⁺-ATPase pump and Na⁺/K⁺/2Cl^- cotransporter due to binding of AVP on basolateral V₂ receptors.[10] One study reported a reduction in TPD and 17% increase in water flux from basolateral to luminal membrane in epithelial tracheal cells in response to administration of AVP.[62] In addition to effects on TPD and Cl^- secretion, Tamaoki et al.[63] found a significant increase in cilia beat frequency that occurred three minutes after AVP administration and lasted for approximately 20 minutes in rabbit trachea epithelia. This increase in cilia beat frequency could contribute to improved mucous clearance for patients with CF.[10]

Implications

The findings discussed above suggest mechanisms caused by AVP, such as ENaC inhibition and CaCC activation, that contribute to reduced water absorption of the lumen.[10] This increased CaCC activation could also lead to a potential bypass system of dysfunctional CFTR in patients with CF. [9],[10] Additionally, AVP can contribute to improved mucous clearance due to increased cilia beat frequency. Although there is evidence linking progressive exercise to increased AVP release in typical bronchial epithelial cells,[57],[59],[60],[61], this has not yet been shown in patients with CF. There is also insufficient research regarding exercise and its implications to make an exercise prescription based on this cell mechanism for this patient population.

E. AMP-Activated Protein Kinase

It has been proposed that aerobic exercise promotes airway hydration, reduces oxidative stress, and reduces airway inflammation through 5’ adenosine monophasphate-activated protein kinase (AMPK).[10] AMPK is an intracellular kinase that is activated under metabolic stress conditions such as hypoxia or increased AMP:ATP ratios.[10] Actions of AMPK include pathway and transcriptional regulation.[64] Pathways that utilize ATP are down regulated and pathways that make ATP are up regulated by AMPK activation.[64] A restoration in the cell’s energy stores is the resulting net effect of AMPK.[65]

It has been found that total AMPK is greater in airway epithelial cells for people with CF compared to those without.[66] Additionally, increased stretch in airway epithelia is a proposed mechanism which may activate AMPK.[65] After 15 minutes of increased mechanical ventilation, one study demonstrated a significant increase in activation of AMPK in mice airway epithelial cells in vivo.[65] Cyclic stretch resulted in an almost 50% increase of AMPK activation in in vitro alveolar epithelial cells.[65] This specific investigation showed the controlling effects of dystroglycan, a scaffolding protein involved in mechanical deformation conduction,[67] on AMPK activation. When dystroglycan is inhibited, the activation of AMPK was absent in alveolar epithelial cells and there was an increase in mitochondrial production of reactive oxygen species.[65] Therefore, dystroglycan plays a role in AMPK activation through the laminin-dystroglycan-plectin complex.[10],[68] Mechanical deformation which may increase activation of AMPK is induced through an increased depth of breathing that can be caused by exercise.[10], [27]

AMPK has numerous effects on ion regulation, specifically Na⁺ absorption, that may reduce TPD resulting in better airway hydration in those with CF.[10] AMPK plays a role in inhibition of Na⁺-K⁺-ATPase through activation of protein kinase C.[69] Additionally, there is possible reduction of apical Na+ absorption and basolateral Na secretion through direct AMPK inhibition of the basolateral Ca²⁺-activated K⁺ channel, which decreases both the electrical and chemical gradients.[70] Reduced ENaC activity caused by inhibition of PIP₂ binding and decreased apical membrane ENaC quantity caused by diminished PIP₂ binding are two main effects of AMPK that may reduce the TPD and have positive effects on airway hydration in those with CF.[71] Although not yet shown in lung or airway epithelial cells, AMPK activation decreases radioactive oxygen species in cardiac, endothelial, and liver epithelial cells which reduces oxidative stress.[72],[73],[74] Research has also shown activation of AMPK causes an inhibition of specific pathways, such as factor kappaB, which in turn reduces cytokines and decreases inflammation in bronchial epithelial cells in people with CF.[66],[75]

Although there is evidence supporting proposed AMPK activation benefits, more research is needed that involves conclusive effects of AMPK activation in people with CF versus healthy epithelial tissue as well as a causal link between exercise interventions and AMPK activation. The implications of increased AMPK activation at the organ level are also important to consider because a study has suggested a negative consequence.[76]

Implications

AMPK may reduce TPD and promote airway hydration,[71], decreases ROS levels in specific healthy human tissues,[72],[73],[74], and has been shown to reduce bronchial epithelial cell inflammation in patients with CF.[66],[75] Increased depth of breathing achieved through exercise could activate AMPK through airway epithelia stretch [10],[27],[65] and patients with CF do have increased AMPK in airway epithelial cells.[66] However, there is limited research available for exercise-induced AMPK implications in patients with CF.

III. Ion Regulation in the Sweat Glands During Exercise

As previously described in the cell bio portion, ion dysregulation also occurs in the sweat glands in patients with CF with a high concentration of NaCl in the sweat. This gives way to the theory that both Na⁺ and Cl^- are not absorbed in the sweat duct in patients in with CF.[77] In the sweat ducts of healthy tissue, both CFTR and ENaC are on the apical membrane and have been proven to operate together to regulate ions in the sweat glands.[77]Therefore, a dysregulation of CFTR can inhibit Na⁺ reabsorption and cause both Na⁺ and Cl^- to be excreted out of the body, causing salty sweat.[77] The following studies address the effects of exercise on the sweat glands in healthy subjects, subjects with salty sweat, and subjects with CF.

Study 1

Reference:Brown et al., 2011[78]
Type of Study:Cross sectional research design
Subjects:6 normal sweaters, 6 very salty sweaters (SS), 6 subjects with CF
Exercise Intervention:Cycling in a heated environment at 50% of VO2 max; 20-minute bouts with 5-minute rest breaks; Cycling continued until subject lost 3% of body weight via sweating.
Outcome Measures and Results:

1. Basal ALDO (aldosterone) and AVP (Vasopressin concentration)
   • No significant differences with ALDO between all groups; Basal AVP was higher in the group of SS compared to the control group; CF group had no differences in basal AVP amongst all groups; higher Na⁺ concentration in sweat correlated to higher AVP in the blood in patients without CF
2. Amount of CFTR and ENaC in membrane
   • Decreased CFTR abundance in SS and CF as compared to controls; no significant difference in ENaC abundance across all groups
   • Decreased CFTR in duct correlated to increased concentrations of Na⁺ and Cl^- in sweat in healthy controls only; in patients with CF, the abundance of CFTR did not "significantly" affect the NaCl sweat concentration.
   • In patients with CF, there was a direct relationship between ENaC in lumen and concentration of Cl^- in the sweat

Study 2

Reference:Brown, Haack, et al., 2011[77]
Type of Study:Cross sectional research design
Subjects:8 very salty sweaters (SS), 8 typical sweaters, and 6 patients with CF
Exercise Intervention:Dehydration exercise: Cycling in heated environment at 50% of VO2 max; 20-minute bouts with 5-minute rest breaks. Cycling continued until subjectt lost 3% of body weight via sweating.
Outcome Measures and Results:

1. Rate of perceive Thirst
   • Thirst stimulus was not affected by high Na⁺ concentration in sweat; likely triggered by decreased serum osmolality and decreased plasma volume (hypovolemia)
2. Volume of fluid ingested after exercise
   • CF patients drank 40% less fluid after exercise than controls
3. Na⁺ and Cl^- concentrations in sweat
   • Increased concentrations of Na⁺ and Cl^- in the sweat in both SS and CF patients as compared to controls
4. Serum Osmolality, Free Water (FW), Plasma volume (PV)
   • SS and CF patients had decreased osmolality rise and more plasma volume (PV) loss with increased dehydration; The concentration of Na⁺ in the sweat was directly proportional to the plasma volume percent loss.

Two studies by Brown et al. addressed the impact exercise has on the sweat glands in patients with cystic fibrosis.[78],[77] In Study 1 by Brown et al., the authors concluded that the abundance of ENaC channels on the apical membrane in the sweat glands did not differ between groups, while CFTR was less present in the membranes of patients with CF.[78] Because both ENaC and CFTR are activated together in the sweat glands, ENaC is not regulated with malfunctioning CFTR, resulting in a higher NaCl concentration in sweat after exercise.[78] Additionally, the hormones aldosterone (ALDO) and vasopressin (AVP) have been shown to regulate Na⁺ and fluid, and, therefore, may have a potential effect on the sweat glands during exercise however the effect in CF is unknown[78] The authors found that in the SS group, there were higher levels of AVP as compared to the controls and subjects with CF.[78] They attributed this to potentially be a compensatory measure to regulate fluid levels in response to an increased Na⁺ sweat concentration.[78] There was no difference in the levels of ALDO amongst all groups after exercise.[78]

Study 2 by Brown et al. stressed the importance of hydration in individuals with CF. It is important to understand that during exercise, patients with CF must be careful as they are at risk for becoming dehydrated.[9],[77] The high concentration of NaCl in the sweat of individuals with CF decreases the serum osmolality due to less Na⁺ (solute) in the blood.[77] This causes the person to have decreased thirst, and subsequently, they do not consume enough water, leading to dehydration.[9],[79],[33] However, Brown et al. hypothesized that there is still is a thirst stimulus present by way of another mechanism.[77] The authors concluded that despite the increased concentrations of NaCl in the sweat and a decreased serum osmolality following exercise, a decreased plasma volume provided a thirst stimulus for patients with CF.[77] Though patients with CF consumed 40% less fluid than the control or SS group after exercise, this was likely attributed to the severe decrease in serum osmolality and the type of fluid provided at the end of the exercise which was hypotonic (low in solute concentration).[77] Had a more hypertonic (increased solutes) liquid been provided after exercise, the patients with CF may have consumed more because increasing the solute intake would increase the serum osmolality, creating a thirst stimulus. Had their serum osmolality been higher following exercise, the consumption of a hypotonic beverage may have been greater as the body wants to meet the increased number of solutes in the blood with a low osmotic solution such as water.[77] Without the increase in solutes in the blood after exercise, the stimulus to drink a hypotonic fluid is blunted.[77] Drinking fluids with a low osmolality such as water causes the blood serum osmolality to fall and decreases the thirst stimulus before a patient has drank enough liquid to replace loss of the solutes in the blood.[77]

Recommendations

Although the effects of exercise on the sweat glands are still being studied in patients with CF during exercise, it is imperative that these individuals maintain proper hydration to prevent dehydration despite having a thirst stimulus. Therefore, it is recommended that patients with CF drink a hypertonic solution (more salt) following exercise to replace the loss of solutes (salt) in the blood and continue to drink even after they no longer have a thirst stimulus. Additionally, in Study 1 by Brown et al., in non-CF patients who were salty sweaters, the baseline AVP was higher than the healthy controls, while there was no difference in subjects with CF.[77] Consequently, it is difficult to make exercise recommendations at this time without more research. However, it has been speculated that if an increase in sweat Na⁺ concentration increases AVP, AVP will increase plasma volume, which is important for diluting sweat and retaining serum electrolytes.[9][77]

IV. Exercise and Inflammatory Cytokines

The effects of exercise on inflammatory cytokines in healthy individuals have been well documented.[81] There is well over 1800 studies that have investigated the immune response to exercise.[82] Briefly, pro-and anti-inflammatory cytokines such as IL-6, TNF-α, and IL-10 increase in response to a bout of exercise.[81] Due to the fact that muscle activation releases IL-6,[81],[83],[84] it is unsurprising that exercise results in increased levels of this cytokine. The levels of IL-6 can rise significantly in an acute bout of exercise in a healthy individual.[81],[85] The degree to which these cytokines are increased, decreased, sustained, or suppressed is mediated by the duration, intensity, and type of exercise in healthy individuals.[81] Strenuous and eccentric exercise are two types of exercise that have been demonstrated to affect cytokines the greatest.[81],[86],[87],[88],[89],[90] Furthermore, it has been found that people who participate in extreme exercise (such as marathons) are at greater risk for infection due to a compromised immune system as a result of a depressed cytokine response from this high level of exercise.[81],[91] Conversely, the effects of acute bouts of exercise on inflammatory cytokines were found to be transient in nature regardless of the intensity level of exercise.[81] Interestingly, it has also been demonstrated that healthy individuals who chronically exercise have a lower resting level of inflammatory cytokines than those who do not regularly exercise.[81],[92] This finding implies that exercise may have a potential benefit on people with inflammatory diseases.[81],[85],[93] However, due to the nature of acute bouts of exercise increasing inflammatory cytokines, people with inflammatory diseases must proceed with caution and exercise at safe intensities and dosages so as not to exacerbate their disease.[81] Nonetheless, evidence is emerging to suggest that chronic exercise may attenuate the inflammatory response of a single acute bout of exercise.[81],[90],[94]

Exercise is generally believed to be an important component of rehabilitation for many chronic conditions.[81],[95] However, therapists must be aware of the potential harmful effects of exercise on conditions with inflammatory processes. It is known that people with CF have higher resting levels of inflammatory cytokines than in healthy individuals.[96],[97],[98],[99] It is not advantageous to increase levels of IL-6 or TNF-α in people with CF due to potential increases in muscle wasting and bone catabolism.[96],[97],[100],[101],[102],[103],[104],[105] Therefore, it is of interest to discover the effects of exercise on inflammatory cytokines in order to determine if exercise is safe in people with CF. If exercise is safe, it is important to determine the appropriate intensity and dosage at which exercise will yield the greatest benefit.

A. IL-6 & TNF-α

The evidence on the effects of exercise on IL-6 and TNF-α specifically in CF is emerging. Despite the fact that the response of these inflammatory cytokines to exercise has been well researched, the literature in CF is still in its infancy. To date, only four studies have looked at the relationship between exercise and inflammatory cytokines in CF.[96],[97],[104],[106] Additionally, experiments in animal models have not yet been studied. In a systematic review from 2009, the effects of exercise on inflammation in various inflammatory diseases (including CF) in children and adults were investigated.[81] Ploeger et al. concluded that, in children and adults, acute bouts of exercise will generally raise inflammatory cytokines in conditions such as CF.[81] Since this review’s publication, more research has been conducted to further elucidate the effects of exercise in people with CF. Refer to table 1 for the current evidence on the effects of exercise on inflammatory cytokines in CF.

The first study that was published on this topic was in 2001 by Tirakitsoontorn et al.[104] The major findings of this study, in terms inflammatory cytokines, were that an intense bout of acute exercise significantly increased IL-6 and TNF-α in children with CF compared to healthy controls and that children with CF on anti-inflammatory drugs (ibuprofen) had a smaller increase in these cytokines.[104] Interestingly, IL-6 levels peaked during the 90-minute post-exercise bout whereas TNF-α peaked immediately following exercise.[104] Additionally, this study also looked at the relationship of these cytokines to growth factors after exercise, which is described below. From the methodology of this study, it is difficult to determine if an intense bout of exercise was truly measured. The exercise protocol consisted of ten bouts of cycling for two minutes at 50% VO2peak with one minute rest breaks between bouts.[104] It could be argued that this protocol measured intermittent moderate-intensity bouts of exercise. A VO2peak of 50% would suggest moderate level effort, and thus, this study does not investigate intense level exercise. While these results provide important information about inflammatory factors in CF during exercise, this study has several limitations. Thus, the results of this study must be interpreted with caution. First, this was not a randomized controlled trial, but rather a two-group, non-random pre-test post-test design. Second, these results are based upon a very small sample size. It is also unknown if the children with CF were stable or in an exacerbation period. Furthermore, it is unknown as to whether or not the children were chronic exercisers or sedentary prior to this study. Finally, this study does not investigate the effects of an exercise program but rather just one episode of exercise and does not complete adequate follow-up. Therefore, from this study it is unknown what effects training may have on these cytokines or long-term effects of increased cytokine levels. This is important to understand when considering that people with CF already have a heightened baseline of inflammatory cytokines.[96],[97],[98],[99]

The second study published in 2006 by Ionescu et al. also looked at IL-6 and TNF-α in response to a bout of moderate-intensity exercise in adults (box stepping until exhaustion for a maximum of 20 minutes).[97] Growth factors were also investigated as described below. This study had similar findings to Tirakitsoontorn et al.[104] They found that in comparison to healthy controls, IL-6 and TNF-α levels were significantly greater post-exercise.[97] Additionally, similar to the study above, it was observed that IL-6 and TNF-α peaked immediately after exercise, but IL-6 concentrations remained elevated at 30 minutes and 120 minutes post-exercise.[97] The elevation of IL-6 for 2 hours was not observed in the healthy controls.[97] Though these findings support what was found by Tirakitsoontorn et al. in an adult population, this study also has several limitations. Namely, this study was limited by lack of randomization, small sample size, and lack of generalizability beyond one bout of exercise.

A third study was conducted by Moeller et al. in 2010.[106] This study took place in Switzerland where the cool temperatures are believed to be optimal for exercise in people with pulmonary conditions to prevent heat exhaustion.[106] Several cytokines were investigated in this study, which are found in table 1, including IL-6 and TNF-α during a three week inpatient rehabilitation program for children with a diversified exercise program.[106] However, no significant changes were noted in sputum cytokines. This study has numerous weaknesses. First, cytokines were analyzed from sputum production from each child as opposed to from blood or urine analysis.[106] Because of this, sputum could only be collected if the child produced it when they coughed and was only collected in the morning after chest physical therapy.[106] Therefore, cytokine levels were not assessed around physical activity. In this way, the cytokine measurements were not an accurate portrayal of exercise response. Furthermore, this study poorly describes the exercise interventions as duration, intensity, and exact types exercises are unknown. Finally, there was no randomization, no control group, and a small sample size.

Finally, Nguyen et al. compared the differences between continuous moderate-intensity exercise and intermittent high-intensity exercise on inflammatory cytokines and growth factors in children with CF.[96] As found in previous studies,[97],[98],[99],[107], the children had a significantly higher baseline concentration of IL-6 and TNF-α.[96] During the middle of exercise for both exercise conditions, no significant differences were noted. However, immediately after exercise, IL-6 was significantly higher in both the CF and healthy age-matched control groups that participated in continuous moderate-intensity cycling. Importantly, IL-6 levels were not significantly elevated in the CF group that participated in intermittent, high-intensity cycling. [96] For all groups, TNF-α was not significantly increased immediately after exercise.[96] In fact, TNF-α was not significantly different at any point during exercise or post-exercise.[96] This finding was surprising, as it contradicts the previous studies above which found that peak TNF-α levels in response to moderate level exercise were significantly increased immediately after exercise.[97],[104] At 30 minutes and 60 minutes post-exercise, IL-6 was significantly higher in both the CF and healthy age-matched control groups that participated in continuous moderate-intensity cycling but again were not elevated in the CF group that participated in intermittent, high-intensity cycling.[96] A strength of this study was that the control group was age-matched to the CF groups in each condition, which helps control for potential age differences especially in such a small sample. However, this study was not clear on if there was random assignment to each exercise condition or if all participants completed each condition in a cross-over design. Furthermore, this study is limited by a small sample size and potential lack of randomization.

B. Precursors to IL-6 and TNF-α

Briefly, two studies looked at monocytes in response to exercise in CF. Monocytes are precursors to macrophages, which produce IL-6 and TNF-α.[96],[108] Refer to table 2 for study descriptions and findings. Both studies were conducted by Boas et al.[107],[109] and investigated several immune mediators in response to exercise. For the purposes of this discussion, however, only the effects on monocytes will be reported. In summary, both studies revealed that an intense bout of exercise resulted in significant increases in total monocyte count in children with CF and in healthy controls immediately post-exercise, which effects were attenuated after 1 hour.[107],[109] Children with CF had higher baseline monocytes and a greater increase in monocytes post-exercise.[107],[109] The authors concluded that children with CF immune function responds in a similar manner to exercise as in healthy children.[107],[109] These studies were also limited by non-randomization and small sample size.

Table 1: Effects of Exercise on Inflammatory Cytokines

Study	Question	Level of Evidence	Subjects	Age Range	Intervention	Outcome Measures	Findings
Tirakitsoontorn et al., 2001[104]	Effect of brief bout of intense exercise on catabolic and anabolic mediators in children with CF	2 group nonrandom pretest-posttest	*14 children (8 female) with CF (9 taking ibuprofen, 5 no NSAIDs) *14 healthy children (7 female)	*CF group:7-17 years *Healthy group: 8-15 years	Both groups performed 2 minute bouts of exercise on cycle ergometer, at 50% of peak VO2, 10 times, with 1 minute rest between bouts	Serum and Urine cytokines: IL-6, TNF-α, IL-1β, IL-1ra	Significant increase in IL-6 in both groups (p<0.002). IL-6 increased greatest in children with CF not on ibuprofen and smallest in healthy controls.TNF-α significantly increased immediately after exercise with the greatest increase in children with CF not on ibuprofen and the smallest in healthy controls. No effect was observed for IL-1β, IL-1ra.
Ionescu et al., 2006[97]	Effect of moderate-intensity exercise on inflammatory mediators	2 group nonrandom pretest-posttest	*11 adults with CF (6 female) after 14 day inpatient treatment of acute exacerbation *12 healthy adults (7 female) not on a regular exercise program	*CF group: mean age 28.2 years *Healthy group: mean age 29.9 years	Box-stepped (20 cm), 15 steps/min until exhaustion for a maximum of 20 minutes	Serum cytokines: IL-6, TNF-α	Both pre-exercise and post-exercise serum concentrations of IL-6 (p<0.01) and TNF-α (p<0.05) were significantly greater in the CF group compared to the healthy controls. Peak IL-6 and TNF-α levels were observed at the end of exercise. IL-6 remained significantly elevated for 30 min (p<0.01) and 2 hours (p=0.016) post-exercise in the CF group, while IL-6 only remained elevated in healthy subjects for 30 min.
Moeller et al., 2010[106]	Effect of a 3 week intensive rehabilitation program on airway inflammation in children with stable CF	One group, pretest-posttest	18 children with stable CF	Median age 12.1 years	3-week inpatient rehabilitation program which consisted of chest PT 2x/day, gymnastic program in the morning (warm-up, cardiovascular endurance training exercises in conjunction with coordinative exercises and stretching, and a diversified physical activity program 1-2x/day (cycling, walking, hiking, climbing, swimming, and rollerblading	Cytokines in sputum: IL-1b, IL-6, IL-8, IL-10, IL-12, TNF-α	No significant change in sputum cytokines after 3 week program
Nguyen et al. 2011[96]	Effect of moderate-intensity, continuous exercise versus a high-intensity, intermittent exercise on inflammatory responses in children with CF	2 group nonrandom pretest-posttest	*12 children with CF (2 female) *12 healthy children (age-matched)	*CF group: 11.3-17.5 years *Healthy group: 10.5-17.5 years	Moderate-intensity continuous exercise (MICE) group: 2 x 30 min bout of cycling at 50% peak mechanical power with 6 minute rest break between bouts High-intensity intermittent exercise (HIIE) group: 6 series of 4x15 sec bouts of cycling at 100% peak mechanical power with 1 minute rest between bouts and a 6 minute rest between each series.	Plasma cytokines: IL-6, TNF-α	*Pre-exercise: Children with CF had significantly higher levels of cytokines *Mid-point of exercise: No significant differences *Immediately after exercise: IL-6 levels were significantly higher in CF MICE group and also in the age-matched MICE control compared to pre-exercise (p<0.05), but were not significantly elevated in the HIIE. No significant difference for TNF-α. *30 min post: IL-6 levels were significantly higher in CF MICE group and also in the age-matched MICE control compared to pre-exercise (p<0.001), but were not significantly elevated in the HIIE. No significant difference for TNF-α. *60 min post: IL-6 levels were significantly higher in CF MICE group and also in the age-matched MICE control compared to pre-exercise (p<0.01), but were not significantly elevated in the HIIE. No significant difference for TNF-α.

Table 2: Effects of Exercise on Precursors to Inflammatory Cytokines

Study	Question	Level of Evidence	Subjects	Age Range	Intervention	Outcome Measures	Findings
Boas, Danduran, McBride et al., 2000[109]	What are potential mediators of immune response during exercise in children with CF?	2 group nonrandom pretest-posttest	*12 children with stable CF *12 healthy children	*CF group: 8-17 years *Healthy group: 8-17 years	Graded maximal exercise test on cycle ergometer to exhaustion at rate of 60 revolutions/min and 90% max heart rate. Increase in power was incrementally (10, 15, or 20 watts) made based on subject height	Serum Leukocytes: Monocytes	Both the CF and healthy control group had a significant increase in monocyte count in response to exercise.
Boas, Danduran, McColley et al., 2000[107]	Does immune function in children with CF respond to exercise similarly to the response in healthy children?	2 group nonrandom pretest-posttest	*15 children with stable CF (8 female) *15 healthy children (6 female)	*CF group: 8-21 years *Healthy group: 8-18 years	Graded maximal exercise test on cycle ergometer to exhaustion at rate of 60 revolutions/min and 90% max heart rate. Increase in power was incrementally (10, 15, or 20 watts) made based on subject height	Serum Leukocytes: Monocytes	Serum monocytes were significantly greater for the CF group than the healthy control group at baseline. Both the CF and healthy control group had a significant increase in monocyte count 3 minutes post exercise, but no significant difference 1 hour after exercise. The CF group had a larger increase in monocytes than the control.

C. IL-10

Two studies have measured the effect of exercise on the anti-inflammatory cytokine IL-10 in people with CF.[106],[110] In their study, Moeller et al.[106] measured sputum IL-10 levels in addition to the pro-inflammatory cytokine levels described above. Consistent with the results of the pro-inflammatory cytokine measurement, they found no change in sputum IL-10 following the three-week rehabilitation program.[106] Another study by Sahlberg et al.[110] measured serum levels of pro-inflammatory and anti-inflammatory cytokines before and after a six-month exercise program in people with CF. The program consisted of three, weekly 30-45 minute exercise sessions with one group completing endurance training and the other group completing resistance training for three months.[110] The final three months of the program consisted of a mixed training program for both groups that followed the same training schedule.[110] The authors found no change in serum IL-10 levels in either the endurance training group or the resistance training group following the exercise intervention.[110] The limitations of this study included a small sample size, lack of randomization, lack of a control group, and differences in cytokine measurements between the groups at baseline.[110] Clearly, both studies have considerable limitations and provide unreliable information about the effect of exercise on IL-10 in people with CF. The lack of a control group in both studies prevents comparison between the effects of exercise versus no exercise on IL-10 level in people with CF. Therefore, more research is needed to determine how exercise truly affects IL-10 in people with CF.

Implications

Exercise is believed to be important for bone and muscle growth and development, which is diminished in CF.[96],[97],[112] It is therefore important to understand the inflammatory response to exercise in CF to attempt to diminish this effect. In general, the studies above show that IL-6, TNF-α, and monocytes significantly increase in response to exercise.[96],[97],[104] Though, this effect may be attenuated in children with CF on anti-inflammatory drugs.[104] There does not appear to be age or sex-related differences to inflammatory responses from exercise in people with CF based on the current evidence. Additionally, it appears that IL-6 remains elevated for a longer period of time than TNF-α.[97],[104] It is therefore important to target exercise intensities and durations that will prevent IL-6 from increasing in order to prevent the most damaging effects associated with this cytokine. Nguyen et al. found that high-intensity intermittent exercise does not result in a significant increase in IL-6 or TNFα.[96]

From these studies some contradictions did arise. First, Moeller et al. found no significant changes in inflammatory cytokines during a 3-week exercise program.[106] This was probably due to the fact that cytokines were not assessed directly after or around a bout of exercise. Furthermore, this was a poorly designed study and the validity of its results are uncertain. Second, Nguyen et al. did not find a significant increase in TNF-α to any exercise intensity or duration like previous reports have.[96] The reason for this is currently unknown and more research is needed to better understand the mechanisms involved.

The research on the effects of exercise on IL-10 in people with CF is weak but indicates that IL-10 does not change in response to exercise in this population.[106],[110] More research is needed because levels of IL-10 appear to be positively correlated with amount of weekly exercise in people without CF.[111] If exercise is actually able to increase or prevent decrease in IL-10 in people with CF, it could help to prevent the negative effects of inflammation in this population.

All these results are based on weak evidence with very few studies and therefore the findings cannot be generalized. In addition, the studies are difficult to compare as exercise protocols, methods of measurement, clinical status of participants, and cellular factors of interest varied. Future randomized controlled trials are needed to confirm these findings, specifically in animal models, to elucidate the cellular mechanisms. More controlled research with larger samples are also needed in humans to confirm these findings. Future studies will also need to investigate functional and quality of life related outcomes measures in addition to these cellular mechanisms to determine clinical relevance of these findings. Furthermore, in addition to looking at inflammatory factors during and after exercise, future studies need to investigate the cellular effects in the bone and muscle after exercise to confirm that catabolic changes are occuring as a result of increased inflammatory cytokines. In some instances, IL-6 is thought to act as an anti-inflmmatory cytokine rather than pro-inflammatory with muscle contraction.[96],[113] However, there is currently no evidence to support this notion in CF. This is an important question regarding exercise prescription. Additionally, no studies have adequately looked at the effects of chronic exercise in people with CF with respect to inflammatory mediators and catabolic versus anabolic effects on muscle and bone. This is a crucial question for this disease and should be a direction for future research.

Recommendations

Based on the current evidence, it appears that in order to avoid an inflammatory response, high-intensity intermittent exercise (6 series of 4x15 second bouts of 100% mechanical power with 1-minute rest between bouts and 6-minute rest between series) is best for people with CF.[96]

V. Exercise and Growth Factors

Growth Hormone (GH) and insulin-like growth factor 1 (IGF-1) are important for mediating the growth of bone and muscle in people with CF, thereby, preventing or diminishing muscle wasting and maintaining bone mineral density.[96],[97] It is known that TNF-α has the ability to reduce concentrations of growth hormone and that TNF-α and IL-6 are associated with protein catabolism.[96],[97],[112] The studies described above detailed how exercise can result in increases in inflammatory cytokines. While this is not advantageous, the studies described below detail how exercise can increase levels of growth factors, which have beneficial effects. The challenge is to find the balance between eliciting the negative effects of cytokines and the positive effects of growth factors with exercise prescription.

A. Growth Hormone & IGF-1

The studies by Tirakitsoontorn et al., Ionescu et al., and Nguyen et al. (which are described in detail above and in table 1 and table 3) investigated the effects of exercise on growth factors in children and adults with CF. In summary, exercise of any intensity had no effect on IGF-1 in people with CF.[96],[97],[104] However, growth hormone was found to significantly increase in response to exercise of both moderate and high intensities and to exercise that was continuous and intermittent in duration.[96],[104] Furthermore, it was found that growth hormone increased the most in response to continuous acute bouts of moderate-intensity exercise.[96] These results are, as with the findings above, based on a low level of evidence.

Table 3: Effects of Exercise on Growth Factors

Study	Question	Level of Evidence	Subjects	Age Range	Intervention	Outcome Measures	Findings
Tirakitsoontorn et al., 2001[104]	Effect of brief bout of intense exercise on catabolic and anabolic mediators in children with CF	2 group nonrandom pretest-posttest	*14 children (8 female) with CF (9 taking ibuprofen, 5 no NSAIDs) *14 healthy children (7 female)	*CF group:7-17 years *Healthy group: 8-15 years	Both groups performed 2 minute bouts of exercise on cycle ergometer, at 50% of peak VO2, 10 times, with 1 minute rest between bouts	Serum Growth Factors: GH, IGF-1	GH increased significantly in both groups (p<0.001), no significant difference between groups. Significant decrease in IGF-1 in both groups which was observed at 60 minutes post exercise (p<0.001), no significant difference between groups
Ionescu et al., 2006[97]	Effect of moderate-intensity exercise on inflammatory mediators	2 group nonrandom pretest-posttest	*11 adults with CF (6 female) after 14 day inpatient treatment of acute exacerbation *12 healthy adults (7 female) not on a regular exercise program	*CF group: mean age 28.2 years *Healthy group: mean age 29.9 years	Box-stepped (20 cm), 15 steps/min until exhaustion for a maximum of 20 minutes	Serum growth factors: IGF-1	No significant difference
Nguyen et al. 2011[96]	Effect of moderate-intensity, continuous exercise versus a high-intensity, intermittent exercise on growth factor response in children with CF	2 group nonrandom pretest-posttest	*12 children with CF (2 female) *12 healthy children (age-matched)	*CF group: 11.3-17.5 years *Healthy group: 10.5-17.5 years	Moderate-intensity continuous exercise (MICE) group: 2 x 30 min bout of cycling at 50% peak mechanical power with 6 minute rest break between bouts High-intensity intermittent exercise (HIIE) group: 6 series of 4x15 sec bouts of cycling at 100% peak mechanical power with 1 minute rest between bouts and a 6 minute rest between each series.	Plasma Growth Factors: GH, IGF-1	Pre-exercise: No significant differences between groups Mid-point of exercise: Significant increases (p<0.001) in GH for both MICE and HIIE groups compared to pre-exercise for both CF and age-matched controls. The largest increase in GH was observed in the MICE groups. No significant differences for IGF-1. Immediately after exercise: For the CF group, there was a significant increase (p<0.01) in GH for MICE only; no significant difference for HIIE compared to pre-exercise. In the age-matched controls, there was a significant difference in GH for both MICE (P<0.001) and HIIE (P<0.01) compared to pre-exercise. The largest increase in GH was observed in the MICE groups. No significant differences for IGF-1. 30 min post: No significant differences 60 min post: No significant differences

Implications

Although these results suggest that moderate-level, continuous exercise is optimal for production of growth hormone, IL-6 (which can stay circulating in the blood 2 hours post-exercise[97]) significantly increases at this level of intensity[96] and TNF-α may increase as well.[104] Due to the fact that growth hormone was found to increase with high-intensity intermittent exercise without an increase in inflammatory cytokines,[96] this prescription of exercise is more optimal for people with CF. However, the level of intensity may not matter in this instance. It may be that it is the intermittent nature of the exercise protocol that is important in mediating inflammatory factors, but there is currently no research to speak to this hypothesis. Future studies should compare the effects of moderate-intensity continuous, moderate-intensity intermittent, high-intensity continuous, and high-intensity intermittent exercise on growth factors and inflammatory cytokines in people with CF. Additionally, future studies need to investigate the effects at the level of the bone and muscle in conjunction with growth and inflammatory factors to determine at what level exercise creates greater anabolic than catabolic effects. Again, these results are based on a few, low level of evidence studies and, therefore, should be interpreted with caution. More controlled research and research in animal models is needed to confirm these results.

Recommendations

Based on the current evidence, in order to optimize the production of growth hormone without increasing inflammatory cytokines, it appears that high-intensity intermittent exercise (6 series of 4x15 second bouts of 100% mechanical power with 1-minute rest between bouts and 6-minute rest between series) is best for people with CF.[96]

VI. Exercise and Bone Mineral Density

With an increasing lifespan and 38% of young adults with CF having osteopenia and 23.5% having osteoporosis,[114] strategies to maintain bone mineral density (BMD) are essential in this population.[115] These include proper nutrition and supplementation to promote bone health, minimal use of glucocorticoids, aggressive treatment of pulmonary infections, and performance of exercise.[115] For the purpose of this page, only exercise will be discussed. The causes and implications of low BMD in CF are described in the musculoskeletal and inflammatory sections of the cell biology page. Two key concepts that contribute to BMD in CF include the relationship between the inflammatory factors (IL-6 and TNF-α) and growth hormone. As mentioned previously, IL-6 and TNF-α have been associated with low BMD[97],[103],[104] due to these cytokines’ influence on increasing osteoclast activity.[116], while growth hormone functions to improve bone growth.[96] Because of these influences, the above recommendation in regards to exercise and growth hormone is important in BMD maintenance. Based on the aforementioned current but weak evidence, high-intensity intermittent exercise is optimal for promoting growth hormone without increasing inflammatory cytokines[96] and should be the most advantageous for bone health.

Although there is some evidence in regards to the effect of exercise on levels of IL-6, TNF-α, and growth hormone, these studies did not consider the effect on BMD. Furthermore, while there have been several cross-sectional and retrospective studies that have found a positive correlation between level of physical activity and CF,[117],[118][119] there have been no intervention studies to analyze the effects of specific exercise on BMD in individuals with CF. Animal and human studies need to focus on determining the connection between exercise and the effects on cell factors (IL-6, TNF-α, and growth hormone) and BMD in subjects with CF. Randomized controlled trials need to be conducted in humans with CF to determine the most appropriate frequency, intensity, and duration of exercise for optimal bone health.

VII. Exercise and Oxidative Stress

As described in Cystic Fibrosis Cell Bio, the epithelial cells of people with CF have higher levels of reactive oxygen species (ROS) than those of people without CF, indicating the presence of oxidative stress within the cells.[120],[121],[122] The effect of exercise on oxidative stress in the cells of people with CF is unknown because no research has been completed in this area. Therefore, in order to form a hypothesis about the effects of exercise on oxidative stress in people with CF, it is necessary to look at the effects of exercise on people without CF.

In the general population, acute exercise increases oxidative stress by increasing the production of ROS in the electron transport chain, which then leak from the mitochondria.[123],[124] Activity of xanthine oxidase and NAD(P)H oxidase enzymes during exercise also increase ROS.[123],[124] Studies indicate that although ROS levels increase in response to acute exercise, there is an adaptation response to long-term, regular exercise.[123],[125],[126] A study by Falone et al.[125] compared oxidative stress in trained versus sedentary males. They found that the trained subjects had a higher antioxidant capacity and a reduced acute oxidative response to individual bouts of exercise compared to the sedentary subjects.[125] Based on these results, the authors concluded that moderate-intensity aerobic exercise can increase antioxidant defenses.[125]

The mechanism by which this adaptation response is believed to occur is through activation of the nuclear factor kappa B (NF-κB) transcription factor by the increased ROS within the cell following exercise.[126],[127],[128],[129] Once activated, NF-κB increases the transcription of antioxidant enzymes, including mitochondrial Mn-superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS).[126],[127],[128],[129] A study by Hollander et al.[127] found that an exhaustive bout of exercise led to increased binding of NF-κB in rat skeletal muscle and that the NF-κB binding remained increased for at least 48 hours following exercise. This study also found that an exhaustive exercise bout led to increased MnSOD mRNA but no increase in MnSOD protein levels in the rat deep vastus lateralis muscle for at least 48 hours following the exercise.[127] The authors stated that chronic exercise may be required in order to increase the level of MnSOD protein.[127] However, in the rat superficial vastus lateralis muscle, increased MnSOD protein levels were found following the exhaustive exercise bout.[127] This study demonstrated that exercise increases NF-κB binding, which then leads to increased antioxidant enzyme gene expression.[127] Radak et al.[130] explained that this adaptive mechanism improves the cell response to oxidative stress over time, and that the effect is likely systemic.

These results have potential implications for exercise in people with CF. While the initial increase in ROS that occurs with acute exercise would be unfavorable for this population due to the already elevated ROS levels, an improved long-term antioxidant effect with regular exercise would be beneficial. Although the antioxidant effect of long-term exercise may be different in people with CF due to differences within the cell, it may be possible that some of the mechanisms are similar. People with CF have decreased levels of the antioxidant glucothione (GSH) due to CFTR dyfunction, which is likely the cause of oxidative stress within the cell.[120] If the antioxidant enzymes MnSOD and iNOS are able to function despite CFTR dysfunction, they may provide a way to compensate for decreased GSH. Increasing the levels of these enzymes through long-term exercise in people with CF could potentially decrease the level of ROS. Therefore, regular moderate-intensity exercise could lead to decreased oxidative stress within the epithelial cells of people with CF. However, it should be noted that this idea is purely theoretical and has not been studied in research.

Another theory regarding the effect of exercise on oxidative stress in the cells of people with CF was proposed by Cholewa et al.[10] This theory suggests that the activation of AMPK by exercise may lead to decreased oxidative stress within the airway epithelial cells of people with CF.[10] This theory demonstrates potential because AMPK activation has been found to decrease ROS levels within the epithelial cells of other organs in people without CF.[10][72],[73],[74],[131] One mechanism by which AMPK may reduce ROS levels is through inhibition of protein kinase C, which then reduces NAD(P)H oxidase activity.[131] The reduced NAD(P)H oxidase activity then results in decreased production of ROS.[131] However, this response was found following glucose-induced oxidative stress in human umbilical endothelial cells[131] and appears to differ from other studies showing AMPK activation of protein kinase C.[69] Future research will need to test the effects of exercise-induced AMPK activation in the airway epithelial cells of people with CF to determine if the same effect occurs in the airway in this population. If indeed exercise-induced AMPK activation is found to reduce ROS levels in the airway epithelial cells of people with CF, this cellular mechanism could provide evidence to support exercise interventions for this population in the future.

Implications

While there is no research on the effects of exercise on oxidative stress in people with CF, theoretically, regular exercise may decrease oxidative stress in this population. However, exercise also has the potential to increase oxidative stress. Therefore, no reliable exercise recommendations can be made based on the effect of exercise on oxidative stress, but the clinician should be aware that exercise may impact oxidative stress in people with CF and look for future research on this topic.

VIII. Sex related differences and Exercise

Sex related differences between males and females in CF have only been recently studied and prior to, there was only speculation that there were gender differences between males and females with CF. While CF is not sex linked, studies have shown that women may have faster lung function decline, contract pneuomonia earlier on than males,[132] have more exacerbations and flare ups,[133] and have a decreased lifespan and have increased lung disease[134],[135]. In a study by Zeitlin et al, it was reported that in women, elevated levels of 17β estradiol can reduce Ca²⁺- activated chloride channels (CaCC).[136] As discovered previously, CaCCs are important as they provide a means for Cl^- secretion when CFTR is defective.[137] Therefore, a reduction in function of the CaCC can decrease mucus clearance, dehydrate the lungs, and cause an increased risk for infection.[136] The study by Coakley hypothesized that 17β estradiol (receptor mediated) can actually inhibit Ca²⁺ activation, which is important for homeostasis and maintaining adequate ASL in the airways in patients with CF.[138]

In females, the main form of estrogen present is 17β estradiol and it achieves its highest levels a few days prior to ovulation.[138] Interestingly, both Ca²⁺ and IP3 signaling pathways influence 17β estradiol action.[139],[140],[141] To determine what effect estrogen levels had on Ca²⁺ signaling, nasal TPD was calculated based on the same methods as previously discussed.[11] Readings were taken throughout a woman’s monthly reproductive cycle and the authors concluded that when estrogen was increased 4 times the normal level (in days prior to ovulation), UTP-stimulated Cl^- secretion was inhibited by 50%.[138] When looking at polarized airway cultures, they concluded that 17α estradiol receptor inhibited the influx of Ca²⁺ which would decrease Cl^- secretion and decrease ASL volume as shown in the figure below.[138] They found that there was no difference in the amiloride-sensitive TPD magnitude of change regardless of estrogen level in both patients with CF and patients without CF, indicating that estrogen levels did not have a direct effect on Na⁺ absorption.[138] UTP-stimulation via addition of a low Cl^- solution showed a decrease in TPD of about 50% in patients with CF and 40% in patients without CF during times of maximal estrogen presence.[138] The authors also concluded that the effects of increased estrogen (17β estradiol) were only seen in the P2 signaling pathway and that the c-AMP and the CFTR pathways were not affected.[138] In fact, it was concluded in a variety of studies that an increase in 17β estradiol actually increased CFTR expression.[142],[143] While there is conflicting evidence, this may be important to understanding the upregulation of CFTR. Conversely, at higher levels of 17β estradiol in the study by Coakley et al., there was no increase in Cl^- secretion with isoprotenerol to facilitate Cl^- secretion through c-AMP mediated pathways that utilize CFTR.[138] The authors explained that while in some studies it was determined that 17β estradiol could upregulate CFTR, it may not be enough to effect the TPD or counteract the inhibitory effect 17β estradiol had on Ca²⁺-mediated pathways.[136] Coakley also found that anti-estrogen therapy such as Tamoxifen may increase Cl^- secreted by limiting the inhibitory effects of Ca²⁺ pathways from increased estrogen.[138] However, it is important to consider the side effects of tamoxifen such as possible stroke, deep vein thrombosis (DVT), cancer of the uterus, cataracts, or pulmonary embolisms to name a few.[136]

Figure 3: Estrogen and its Effect on ASL Volume[136]
http://www.jci.org/articles/view/37778/figure/1

Implications

While the effect of exercise is unknown on the modulation of 17β estradiol and the effects it has on Cl^- secretion, it is possible that exercise can increase Ca²⁺ signaling and thus increase Cl^- secretion with the CaCC via an increase in ATP. As stated previously, exercise is accompanied with an increased ventilation rate which can cause phasic stress in the airways.[27] The phasic stress can trigger the realease of ATP which can stimulate P₂Y₂ to increase Cl^- secretions.[27] However, it is important to consider another concept concluded by Coakley et al. as they found that after 48 hours of phasic stress in in vitro HBEC (Human bronchial epithelial cells), when estrogen levels increase even for an hour, there was a 50% reduction in ASL volume.[138] These values were taken in vitro so continuous ATP activation during exercise may still have a different effect. Additionally, while Tamoxifen was effective in increasing and maintaining Cl^- secretions in the presence of increased estrogen levels, the side effects of tamofixen may outweigh its benefits.[136] If the negative effects of estrogen can be reduced even in the presence of increased estrogen, this may be very beneficial for women.

Recommendations

In conclusion, while there is no direct evidence to prove that exercise can actually decrease the inhibitory effects increased estrogen levels have on Cl^- secretion, it is theorized that by way of ATP activation and subsequent activation of CaCC, exercise may potentially be able to increase or maintain adequate ASL volume during periods of high estrogen levels and decrease a female’s suseceptibility to infection during this time.

IX. Conclusion and Recommendations for Exercise in People with CF

Research indicates that exercise may benefit people with CF by improving ion regulation in the airways,[9],[10] thereby increasing ASL height and improving airway clearance, and by increasing growth hormone levels,[96] which may help to prevent decreased bone mineral density. Additionally, based on studies with children and adolescents with CF, high-intensity intermittent exercise appears to be the optimal exercise intensity because it has been shown to increase growth hormone levels while minimizing the inflammatory response.[96] Inflammation leads to muscle wasting and decreased bone mineral density for people with CF,[96],[97],[100],[101],[102],[103],[104],[105] and so the risk of an exercise-induced inflammatory response must be considered when initiating exercise interventions for this population. The effect of exercise on oxidative stress in people with CF has not yet been researched. Theoretically, regular exercise may help to decrease oxidative stress over time,[10],[125] but the potential risk of increasing oxidative stress with exercise must also be considered. During periods of high estrogen levels, exercise may help to offset the negative effects of estrogen and improve Cl^- secretion for females with CF.[138]

It should be noted that research on the cellular effects of exercise for people with CF is limited. Many of the exercise interventions used in the existing research on this topic consist only of single bouts of exercise instead of long-term exercise programs. Also, most of the studies looking at the inflammatory response to exercise included children and adolescents with CF, but not adults. Clearly, more research is needed to determine the effects of regular exercise on cellular mechanisms in people of all ages with CF, as well as the impact of these cellular effects on functional outcomes and disease progression. Future research should explore the effects of regular exercise over time on ion regulation in the airway epithelial cells, inflammatory and growth hormone responses, and oxidative stress in people with CF. Additionally, the optimal exercise frequency, intensity, and duration based on cellular effects should be further examined. While the effects of exercise on the animal models of CF have yet to be researched, these models present an excellent opportunity for future research. Exercise research with the animal models could address a gap in the literature by providing detailed information on the effects of long-term, regular exercise at the cellular and systemic levels, as well as the impact of exercise on CF disease progression.

In conclusion, research has shown that exercise positively impacts functional and systemic outcomes in people with CF,[6],[7],[8] but research regarding cellular level outcomes is lacking. While the research on functional outcomes provides evidence to support exercise interventions in this population, it is important to understand the cellular effects of exercise to ensure the interventions do not cause damage or progression of the disease. Research on cellular mechanisms is especially useful to determine the optimal type and intensity of exercise with respect to its risks and benefits for this population. Although more research is needed, the available evidence indicates that high-intensity intermittent exercise may maximize the benefits while minimizing the risks of exercise at the cellular level for people with CF.[96] As always, the clinician should consider the individual needs of each patient and his or her response to the intervention when implementing these recommendations.

Click here to see a video demonstrating the impact of exercise on the life of one person with CF.

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Susan Wilson 12 Jan 2012 12:47

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Last edited on 11 Mar 2012 15:22 by Susan Wilson Show more

PTXXIV 04 Mar 2012 14:48

I'm offended! lol

Emily Offenberger 29 Feb 2012 22:52

Great pictures for the TEP section! Great work Megan!

JennyKohr 07 Mar 2012 03:28

This exercise page is coming along really well! You all are doing a great job of synthesizing the exercise effects and applying it to CF. I really enjoyed reading the sex related differences and exercise section and learning about the inhibitory role that estrogen plays on calcium activation! The pictures also really help to clarify information!

Scott Sheaffer 07 Mar 2012 21:12

I like the layout when you list "Study 1" and then its important info and then "Study 2" and its important info. I would suggest keeping a consistent format though. When reading the page I wondered why I only found this layout at 2 points on the page. Overall, I think your page is informative and demonstrates hard work.

Sarah Hendershot 07 Mar 2012 22:53

Thanks for the suggestion Scott! We really appreciate you reading our page and providing us with constructive feedback. The varied format in the presentation of the literature is likely due to the varied amount and type of information available on each topic. We will look into this suggestion as we begin editing the page and try to make the format as consistent as possible.

Lynn Krimmer 07 Mar 2012 22:03

Like others have said, this page is coming along really well! I think the use of pictures in the beginning of the page are helpful to walk through the process of determining the nasal potential difference. I also like the use of tables in the inflammatory section to help break up the large amount of information.

DR Ebner 09 Mar 2012 19:41

I know this page is mostly based on cellular responses to exericse, but I was wondering if there was any increases in VO2 in people with CF who exercise and if that alters their symptoms. If there is an increase in VO2 would you know if it is due to improved lung function, decrease inflammation, or improvement in oxygen utilization in the mitochondira similar to healthy subjects when exercising. I think the page looks very good.

Sarah Hendershot 09 Mar 2012 20:38

DR, thanks for bringing up this point! Yes, there is evidence to show that exercise improves more functional and body systems outcomes, including VO2 max and pulmonary function—which is huge for this population! There is even one study that followed a group of people with CF for 8 years and found that higher aerobic capacity at the beginning of the study was associated with a lower risk of dying throughout the study period. We will briefly address these outcomes in the introduction. For the purposes of this page, our main goal is to show how exercise affects people with CF at the cellular level to determine the optimal exercise intensity, as well as the risk vs benefits of exercise in terms of disease progression. (However, we found a big gap in the literature. As you can see from the page, there is very limited research on the effects of regular exercise on cellular mechanisms in people with CF.)

Cara Whalen 09 Mar 2012 22:52

Yes, and to piggyback off of Sarah, in the studies that I looked at where inflammation either increased or did not change in response to exercise VO2 increased with exercise training. So from that limited research, it would appear that improved VO2max is somewhat independent of inflammatory responses. As I think it should be, because in healthy individuals, it is normal to have increased inflammation with exercise and yet people are still capable of improving their VO2 max. But perhaps, VO2max would improve more with less of an inflammatory response (as in with trained athletes). But I am not aware of any studies that specifically look at this, and I certainly did not run across this in my research for CF.

nsmith5232 10 Mar 2012 05:22

nice job handeling the conflicting research, it is hard to recommend exercise when either two studies totally disagree, or there is no clear evidence of studies on humans with a particular disease looking at the cell factor you are describing. Sometimes it is nice to look at the bigger picture when recommending exercise and make justifications based on those studies. sweet page though, someone is definately a syntax master.

Last edited on 10 Mar 2012 05:23 by nsmith5232 Show more

Emily L Smith 10 Mar 2012 17:12

Like Scott said, I like how you present your studies 1 and 2 in the beginning. The format is really easy to read and understand. It would be helpful to have more studies in similar format. I also like that you have an implications and recommendations section after most types of exercise. Good work!

Megan Vandrak 10 Mar 2012 18:32

Thank you both Emily and Scott for the suggestions! By default I had to put my study 1 and study 2 into sort of a list format because I was unable to make a list/bullet items in a table hence the difference in format amongst all the difference studies. If anyone knows how to put bullets or lists in a table, please let me know! :-)

Megan B 10 Mar 2012 17:35

Overall, I think this page looks really good. You might want to consider using consistent subheadings (implications and recommendations) for each section throughout the page. Nice job with Figures 1 and 2!

Kara Armstrong 11 Mar 2012 13:04

I think your group did a good job analyzing the studies critically (talking about studies validity and the negative aspects of the study). Also I love the addition of the video at the end. It puts a face with your page and shows us it is possible to train at high levels regardless!

Alyssa Meyer 11 Mar 2012 16:06

I'm glad you watched the video Kara! It really is inspirational!

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