Neuro‐immune Mechanisms and Pulmonary Fibrosis

Pulmonary neuroendocrine cells are widely distributed throughout the airway mucosa of mammals. They may exist as solitary cells or aggregate to form neuro‐epithelial bodies (NEBs), which are implicated in lung development and response to tissue injury. Pulmonary fibrosis (PF) is a devastating disease thought to be caused by various pulmonary injuries. Repair after injury is a complex process that involves interactions amongst a network of players including soluble mediators such as cytokines and growth factors produced by inflammatory, endothelial, and epithelial cells. Interestingly, NEBs are connected with the vagus nerve, which in turn is related to each component of this network. We have shown that disrupting the NEB‐Vagal System (NVS) by vagotomy decreases TGF‐β and IL‐4 production, reduces the number of myofibroblasts and M2 macrophages, and ameliorates collagen deposition in lung tissue after bleomycin‐induced lung injury. More recently, we hypothesized that lung injury may activate the NVS and polarize T help (Th) cells and macrophages (M) toward fibrogenic phenotypes (altered balance of Th2/Th1 cells and M2/M1 macrophages), thereby promoting PF. Using the bleomycin‐induced lung injury model (i.v.), we assessed the role of neuro‐immune mechanisms in PF by comparing innervated and denervated lungs in mice subjected to unilateral vagotomy. Using immune‐histochemical staining of whole mount tissues, we found that NEBs in the trachea‐bronchial tree increased significantly after bleomycin, but this was ameliorated in denervated lungs. FACS analysis revealed an increase in CD11b + and CD4 + three weeks after bleomycin, while the numbers of CD11b + cells were the same in innervated and denervated lungs. CD4 + cells, on the other hand, were increased in innervated lungs. T regulatory (Treg) cells were increased in the vagotomized lung when compared to the intact lung. Of note, bleomycin increased production of bombesin, which is contained in NEB and is known to promote fibroblast transdifferentiation into myofibroblasts. Further studies performed in vitro suggest that bombesin and 5‐HT increase the M2/M1 ratio. Together, our data suggest that lung injury activates NVS, which stimulates a Th2 response and decreases suppressor Treg cells, thereby promoting PF. Support or Funding Information Pulmonary Fibrosis Foundation and VA Merit Review Award PULM‐024‐17S This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .