NGF, an important neurotrophic factor, was shown to increase in asthma and was related to the degree of bronchial hyperreactivity [11, 17]. Hyperinnervation of the airway was observed in transgenic mice overexpressing NGF, and these mice were more sensitive to capsaicin-induced increases in airway resistance . It has also been demonstrated that NGF increased sensory innervations, which led to changes in airway function . Some studies have indicated that anti-NGF decreased airway hyperresponsiveness caused by allergen challenge, and this could be a therapeutic strategy for the treatment of allergic asthma [13, 19–21]. We found recently that hyperinnervation of the adrenal medulla in asthmatic rats may contribute to the greater expression of NGF; the change of the adrenal medulla led to functional changes, which was associated with the transformation of AMCCs in asthma .
Because of a common origin from sympathoadrenal precursor cells, AMCCs can be transformed into sympathetic neurons under the stimulation of NGF, which is involved in neuronal growth, survival, and differentiation. An animal study indicated that prenatal injections of NGF, initiated in gestation and continued after birth with subcutaneous administration, produced massive transformation of chromaffin in sympathetic nerve cells of the adrenal medulla . We recently found that asthma during pregnancy induced a tendency toward transformation from AMCCs to sympathetic neurons in offspring rats, which was also related to elevated NGF in the asthmatic dams . These results suggested that the effect of NGF in asthma was strongly associated with the transformation of AMCCs.
In this study, all of pup groups (OCP, OAP, ONP, and OANP) were sensitized and challenged with OVA. In other words, all of pups were suffered from asthma, and the OCP pups were not the negative control pups but the asthmatic control pups. For this reason, the differences of NGF levels between OCP and OAP were existed (P < 0.05), but the changes may not be significant compared to that between the negative control and the asthmatic rats. It should be well noted that the differences in the function and ultrastructure of AMCCs were found among the four offspring groups from birth to adolescence prior to sensitization and challenge with OVA . Compared with the pups form control pregnant rats, the pups from asthmatic pregnant rats showed a trend toward transformation of AMCCs . When sensitized and challenged with OVA, the pathophysiology and phenotype changes of OAP rats were significant compared to that of OCP rats in this study. These results suggested that the susceptibility to OVA in asthmatic rats is also related to the phenotype state of AMCCs.
PNMT, the rate-limiting enzyme of EPI, is mainly expressed in adrenergic chromaffin cells but not in neurons. In this study, the expression of PNMT in OAP rats was lower than that of OCP rats, further reduction was found in ONP rats, and PNMT expression was enhanced in the OANP group. Interestingly, the level of PNMT in each group coincided with the expression of EPI. This indicated that the degree of injury in endocrine function of AMCCs was different among the four offspring groups, and related to the sensitivity to OVA.
Glucocorticoids are mainly secreted from the adrenal cortex. Similar to EPI, supplementing exogenous glucocorticoids is an effective treatment in asthma patients. Studies have shown that glucocorticoids could promote the expression of PNMT in the adrenal medulla, and that PNMT catalyzed the conversion of norepinephrine to EPI [23–25], which may be a mechanism underlying the value of glucocorticoids in the treatment of asthma. High concentration of glucocorticoids prevented fiber outgrowth from medullary chromaffin cells and inhibited the transformation of adrenal cells into neurons [26–28]. To a certain extent, the fate of AMCCs was determined by the balance of NGF and glucocorticoids in the milieu at any given time [28, 29].
In the present study, although the glucocorticoid levels were increased in the OAP and ONP groups compared to the OCP, yet there was also a tendency toward transformation of AMCCs to sympathetic neurons in these groups. These results may suggest that NGF predominately played a role in this process. In other words, the volume of glucocorticoids was insufficient to counter that of the NGF, and the effect of glucocorticoids in alleviating bronchospasm may be obviated by elevated NGF.
During the development and regeneration of nerve cells, peripherin (a type III intermediate filament) plays an important role in establishing cellular architecture by regulating axon formation . In fact, neurons with peripherin-siRNA demonstrated significantly impaired initiation, extension, and maintenance of neurites . AMCCs were implicated in the active downregulation of the intermediate filament protein that occurs during embryonic development . One study found that cells reactive to peripherin constituted a specific sub-population of AMCCs; this notion was supported by the fact that AMCCs, which highly expressed peripherin, had a distinct shape that was more like that of nerve cells .
In the present study, we showed that peripherin expression was higher in the OAP rats than in the OCP, and was higher still in the ONP, while reduced in the OANP. Accordingly, notable alterations in AMCCs such as neurite-like processes were found in the ONP rats. On the other hand, signs of reparation of AMCCs, such as collagen deposition, were found in the OANP rats. These results further indicate that the degree of alteration in AMCCs were significantly different among these offspring groups and suggests that peripherin plays a role in the transformation process.