High-intensity training induces EIB in rats through neuron transdifferentiation of adrenal medulla chromaffin cells

Abstract

He R, Feng J, Xun Q, Qin Q, Hu C. High-intensity training induces EIB in rats through neuron transdifferentiation of adrenal medulla chromaffin cells. Am J Physiol Lung Cell Mol Physiol 304: L602-L612, 2013. First published February 15, 2013 doi:10.1152/ajplung.00406.2012.-A high prevalence of exercise-induced bronchoconstriction (EIB) can be found in elite athletes, but the underlying mechanisms remain elusive. Airway responsiveness, NGF and epinephrine (EPI) levels, and chromaffin cell structure in high-(HiTr) and moderate-intensity training (MoTr) rats with or without ovalbumin (OVA) sensitization were measured in a total of 120 male Sprague-Dawley rats. The expression of NGF-associated genes in rat adrenal medulla was tested. Both HiTr and OVA intervention significantly increased airway resistance to aerosolized methacholine measured by whole body plethysmography. HiTr significantly increased inflammatory reaction in the lung with a major increase in peribronchial lymphocyte infiltration, whereas OVA significantly increased the infiltration of various inflammatory cells with an over 10-fold increase in eosinophil level in bronchoalveolar lavage. Both HiTr and OVA intervention upregulated circulating NGF level and peripherin level in adrenal medulla, but downregulated phenylethanolamine N-methyl transferase level in adrenal medulla and circulating EPI level. HiTr ϩ OVA and HiTr ϩ ExhEx (exhaustive exercise) interventions significantly enhanced most of the HiTr effects. The elevated NGF level was significantly associated with neuronal conversion of adrenal medulla chromaffin cells (AMCC). The levels of p-Erk1/2, JMJD3, and Mash1 were significantly increased, but the levels of p-p38 and p-JNK were significantly decreased in adrenal medulla in HiTr and OVA rats. Injection of NGF antiserum and moderate-intensity training reversed these changes observed in HiTr and/or OVA rats. Our study suggests that NGF may play a vital role in the pathogenesis of EIB by inducing neuron transdifferentiation of AMCC via MAPK pathways and subsequently decreasing circulating EPI. exercise; asthma; lung; inflammation; NGF; neuron conversion; adrenal medulla EXERCISE-INDUCED BRONCHOCONSTRICTION (EIB) is the increase in airway obstruction with symptoms of coughing, wheezing, or dyspnea as a result of exercise (23). EIB occurs in ϳ11% of the general population without asthma (13). Inhalation of cold air and sudden changes in humidity or temperature have been associated with EIB (20). High prevalence of EIB is usually observed among endurance athletes (7), implicating that intensity of exercise may be associated with EIB.Although thermal and osmotic consequences of water loss play prominent roles in the emergence of EIB (2), more studies are needed to elucidate the underlying mechanism. Circulating epinephrine (EPI), produced by adrenal medulla chromaffin cells (AMCC), is believed to bind the adrenergic receptors of airway smooth muscles to achieve adrenergic bronchodilation, and a loss of this function could directly influence the sev...

Low-Intensity Aerobic Exercise Mitigates Exercise-Induced Bronchoconstriction by Improving the Function of Adrenal Medullary Chromaffin Cells in Asthmatic Rats

“…As the PNMT is predominantly expressed by the adrenergic chromaffin cells in the adrenal medullary tissues (Evinger et al 2007), the enhanced PNMT expression in the adrenal medullary tissues was at least partially attributed to the inhibition of neuronal transdifferentiation of chromaffin cells in the exercisetrained asthmatic rats. These data were partially consistent with our previous observations that moderate-intensity of exercise decreased peripherin expression in the adrenal medullary tissues and increased circulating epinephrine levels in asthmatic rats (He et al 2013). However, our previous study and those of others showed that aerobic exercise training (50-75% of maximum velocity) only increased slightly the PNMT expression in the adrenal medullary tissues of healthy animal, but the increased expression was not significantly different from that in the control animals, as detected by immunohistochemistry (Bartalucci et al 2012;He et al 2013).…”

“…These data were partially consistent with our previous observations that moderate-intensity of exercise decreased peripherin expression in the adrenal medullary tissues and increased circulating epinephrine levels in asthmatic rats (He et al 2013). However, our previous study and those of others showed that aerobic exercise training (50-75% of maximum velocity) only increased slightly the PNMT expression in the adrenal medullary tissues of healthy animal, but the increased expression was not significantly different from that in the control animals, as detected by immunohistochemistry (Bartalucci et al 2012;He et al 2013). Moreover, our previous study did not observe that moderate-intensity aerobic exercise has any effect on PNMT expression in the adrenal medullary tissues of asthmatic rats, as detected by immunohistochemistry (He et al 2013).…”

“…In addition, we found that high-intensity exercise not only promoted inflammatory responses and increased the airway resistance, but also induced neuronal transdifferentiation of AMCCs and subsequently decreased the levels of circulating epinephrine while moderate-intensity of exercise reversed these changes (He et al 2013). It is well known that nerve growth factor (NGF) is a potent inducer of neuronal differentiation of AMCCs while corticosterone stimulates the cells toward a neuroendocrine phenotype, playing an opposite role in regulating the transdifferentiation of AMCCs (Unsicker et al 1978(Unsicker et al , 1980Tischler et al 1993).…”

“…Our previous studies have shown that high-intensity aerobic exercise enhances pathological changes and endocrine dysfunction of AMCCs and reduces the levels of circulating epinephrine in asthmatic rats (He et al 2013). To understand the protective effect of low-and moderateintensity aerobic exercise, the structure of AMCCs, and the relative levels of peripherin, neurofilament, and chromogranin A in the adrenal medulla in the different groups of rats were characterized by light microscopy, transmission electron microscopy and Western blot, respectively.…”

“…Maximal running test and exercise protocol were performed on day 11, as described previously (Vieira et al 2007;Olivo et al 2012;He et al 2013). All rats were initially adapted to the treadmill running (ZH-PT, Zhenghua, Huaibei, China) at 10 m/min with 25% incline for 15 min for three consecutive days.…”