Ketaki Poorey¹, Manish Lamoria^2*, Elvy Oommen³, Sushil Sharma⁴

¹Assistant Professor,²Associate Professor, ⁴Tutor, Department of Physiology, Jaipur National University Institute for Medical Sciences and Research Centre, Jaipur, Rajasthan, INDIA.

³Professor & HOD, Department of Physiology, Parul Institute of Medical Sciences and Research, Vadodara, Gujarat., INDIA.

Email: mhlamoria@gmail.com

DISCUSSION

Exercise is a remarkable example of the integrative and adaptive capacities of the body. Smoking may impose limitations on the capacity of the body to acquire, transport, and utilize oxygen in various ways. This limitation in aerobic capacity can be tested by calibrated exercise, either graded or global. In this study, we have compared changes in lung function before and after sub maximal exercise in healthy male volunteers and healthy male asymptomatic smokers in the age group of 18 to 25 years. Normal subjects show considerable airway dilatation during exercise and this appears to result from inhibition of resting vagal tone ⁶. Exercise mediated bronchodilation in normal individuals is most likely to occur in peripheral airways because they are more compliant. Through the assessment of the pulmonary function test following exercise challenge, the present study demonstrated that the asymptomatic smoker group with absolutely normal spirometry result at rest, had significant decrease in FEV1 and all other flow rates after exercise challenge. It seems to uncover the early underlying disease. Evaluating in term of a sensitive Forced Expiratory Spirogram (FES) parameter FEV1, 13 asymptomatic smokers out of 24, who were found responsive, had drop in FEV1 more than 15% within 20 minutes of post exercise recovery period (table 3). It shows that bronchodilatation response to exercise is weak in these smokers which may be because of the associated heightened pathophysiology of inflammation of airways. Similar results were seen in a study done in Nepal by Pokhrel et al.. where they found 22 responsive smokers out of 42 asymptomatic smokers ⁽⁴⁾. However, they have not compared healthy non-smokers with the smokers for hyper-responsiveness to the modality of challenge used. Another study in the asymptomatic smokers by Quaedvlieg et al.. also has demonstrated the Broncho-constrictive response to cold air challenge which is extending largely into the small peripheral airways by impedance measurement method which was not seen in normal subjects⁷. In few early studies bronchial reactivity was not demonstrably greater in younger smokers than in non-smokers less than 36 years old (which used higher concentrations of histamine). Several other investigations of young symptomless smokers with normal lung function have also failed to detect any consistent difference in bronchial reactivity though one report found slightly diminished reactivity.⁽⁸⁾ On the contrary, our study which focused on young asymptomatic smokers (18 to 25 years) found significant number of young early smokers (13 out of 24) to having bronchial reactivity and the rest non-responsive also showed some decline in the peripheral airway function after challenge at p<0.001 level of significance when compared with the normal healthy volunteers (Table 3). As shown in fig.1, most of the asymptomatic smokers had a decrease in FEV1 from the baseline after exercise challenge (shown as red spots in the scatter diagram) while most of the healthy non- smokers had a increase in FEV1 after exercise challenge (shown as blue spots). The difference of results in studies may have been due to the difference in type of bronco-provocation used. Indirect challenges act by causing the release of endogenous mediators that cause the airway smooth muscle to contract, with or without effect in inducing microvascular leakage. Because the responses to these challenges are modified or even completely inhibited by inhaled steroids, the airway response to these challenges may be a closer reflection of active airway inflammation. ⁹ In the current study, a clear trend of decline in FEV1 in smokers with comparable history and nicotine dependence ascertained by Fagerstrom Test for Nicotine Dependence questionnaire, may emphasize that exercise challenge testing might be useful tool for screening mechanical abnormalities induced by smoke inhalation even before there is any change in pulmonary function at rest. Different processes might be responsible for the changes in airway function during and after in both modes of the challenges, but the post exercise decline in FEV1 was the pertinent fact in both of the cases. There are ample evidences available which have shown a broncho-constrictive response to various nonspecific stimuli including exercise challenge and airway hyper responsiveness to provocative agents in asymptomatic smokers having an alteration of ventilatory functions due to hyper reactive peripheral airways.⁽¹⁰⁾ The pathological changes found in smoker’s lung which could be responsible for active muscle constriction and airway narrowing following the challenges may include: a) airway epithelial damage, resulting in increased permeability and impairment of other epithelial functions; b) chronic airway inflammation; c) structural changes in the airway wall; and d) loss of alveolar attachments. However, one or more than one processes might be at work in smokers or might be not all smokers develop the above mentioned airway abnormalities ⁽¹¹⁾. The effects of smoking on small or peripheral airways have been addressed by many studies in asymptomatic smokers ^(12)(13). However, the effect of exercise challenge on peripheral airway mechanics in asymptomatic smokers is the novel part of our research. The airway dilatation and thus decrease in airway resistance is a common physiological response to exercise for normal people, but it appears that partial airway obstruction and weak elastic recoil of lungs is evident in smokers which is leading to a subclinical alteration of ventilatory patterns of small or peripheral airways due to active cigarette smoking.  Hyperventilation during the exercise causes drying of the airways, which increases the osmolarity of fluid lining the airways. This provides an osmotic stimulus for water to maneuver from any cell nearby, leading to cell volume loss ⁽¹⁴⁾. The change in regulatory volume after cell shrinkage is believed to be the factor causing release of inflammatory mediators, which then cause the contraction of airway smooth muscles resulting in narrowing of airways. In-vitro studies of human lung mast cells show that increased osmolarity of the solution bathing the cells is a potent stimulus for release of histamine. J A Dosman et al., who evaluated peripheral airways in middle age heavy smokers by helium flow-volume curves and single breath nitrogen test, also indicate that the individuals who responded to inhaled histamine had increase in airways reactivity and peripheral airways dysfunction both. Finnerty J and Holgate S in their study have supported role for histamine release by the finding that some histamine H1 receptor antagonists have an inhibitory effect on exercise induced bronchoconstriction (EIB) ¹⁵. Leukotrienes are involved in the genesis of EIB and in sustaining the bronchoconstriction following exercise. Reiss T F et al.. have reported increases in urinary leukotriene E4 following EIB. Extensive mast cell infiltration in asymptomatic smokers at all levels bronchial mucosa predominantly in the airway smooth muscle compartment has been reported by A Ekberg-Jansson et al..¹⁶. Smoke exposure has been shown to induce activation/ degranulation in airway resident mast cells and elevated levels of histamine and tryptase have been measured in the bronchoalveolar lavage fluid of active smokers. Mast cell-secreted proteinases (MCPTs), including tryptases, have been considered to be the contributors of pathological airway remodelling. Andrea Small-Howard and Helen Turner in their study concluded that chronic exposure to cigarette smoke up-regulates MCPT levels in mast cells at both the protein and the mRNA level. They suggested that the pathological airway remodelling that has been described in clinical studies of smoke inhalation may be attributable to MCPT overproduction in vivo ¹⁷. Thus, we can say that by using exercise as a bronchoprovocation test we are actually getting the warning of the ignition factor of pathological changes for COPD in future. Exercise being a non-pharmacological and non-invasive tool can be easily used for screening the otherwise healthy smokers with normal spirometry. All these changes which are a deviation from normal airway function may go un-noticed if pulmonary function test parameters at rest are only considered ⁽¹⁸⁾. Although, cigarette smoke causes the airway hyper responsiveness which is a primary risk factor for development of COPD (chronic obstructive pulmonary disease) or chronic bronchitis, most of the smokers do not develop symptomatic COPD, probably because of the large physiological reserve of the lung. Interestingly, around 15- 20% do experience accelerated loss of lung function, and the basis for heightened susceptibility in the smokers is yet to be known ¹⁹. In our study flow rates at rest were a little higher in smokers as compared to the non-smokers but after exercise challenge there was a decline in smokers while an increment in non-smokers. This also makes it clear that the negative reaction in smokers was not merely due to morphometric difference in the airways at rest as suggested by Taylor R et al. and Brusasco V et al.. ^8,20. A more specific effect of smoking, which is apparent within a few days of the starting of smoking, is increase in airway permeability, as shown by the rapid removal from the lungs of radiolabelled diethylenetriamine penta-acetic acid (DTPA) aerosol by Taylor R et al. Increased permeability of the airways, however, cannot account entirely for the abnormal bronchial reactivity of smokers. Probability of increase in bronchial reactivity during the smoking years by an immunological mechanism is more likely⁸. Observation of our study supports the point and suggests that the so called healthy smokers who have not been smoking cigarettes for long and seem to have good lung function at rest, are actually in the early phase of cigarette smoke induced mechanical deformity of airways.

CONCLUSION

Increment was seen in all parameters of Forced expiratory spirogram (FES) after the exercise challenge in healthy volunteers which was distinct in the most peripheral airways while in smokers there was a significant decrease in all parameters of FES. In our study 54% of asymptomatic smokers were found to have hyper-responsiveness, when they were subjected to exercise challenge as an indirect bronchoprovocation test. It shows that bronchodilation response to exercise is weak in these smokers which may be because of associated inflammation of airways. Using the indirect bronchoprovocation test like exercise we can uncover abnormal functioning of airways before any permanent damage to the airways is done by smoke in the so called ‘healthy smokers’ and reports deviating from normality may also motivate smokers to quit smoking early. On the contrary, spirometry at rest may not detect the early smoking induced changes in the airways and will give a false assurance that airway functions are normal. Exercise being a non-pharmacological and non-invasive tool can become an integral part in identifying early obstructive airway disease in future. Early detection of smoking induced changes in airway function and timely intervention may prevent the development of lifelong disability due to COPD. A combination of pharmacological and non-pharmacological test can give more elaborated results though but exercise induced are good tool for screening purposes. Further in-depth study by correlating it with molecular level histamine release and histological changes in bronchial wall at small airways can be planned.

Acknowledgements

The authors are thankful for the active participation of all the study participants. We are also thankful to our teachers who guided us throughout the study.

REFERENCES