Resiniferatoxin (RTX) ameliorates acute respiratory distress syndrome (ARDS) in a rodent model of lung injury

Hahka, Taija M.; Xia, Zhiqiu; Hong, Juan; Kitzerow, Oliver; Nahama, Alexis; Zucker, Irving H.; Wang, Hanjun

Acute lung injury (ALI) is associated with cytokine release, pulmonary edema and in the longer term, fibrosis. A severe cytokine storm and pulmonary pathology can cause respiratory failure due to acute respiratory distress syndrome (ARDS), which is one of the major causes of mortality associated with ALI. In this study, we aimed to determine a novel neural component through cardiopulmonary spinal afferents that mediates lung pathology during ALI/ARDS. We ablated cardiopulmonary spinal afferents through either epidural T1-T4 dorsal root ganglia (DRG) application or intra-stellate ganglia delivery of a selective afferent neurotoxin, resiniferatoxin (RTX) in rats 3 days post bleomycin-induced lung injury. Our data showed that both epidural and intra-stellate ganglia injection of RTX significantly reduced plasma extravasation and reduced the level of lung pro-inflammatory cytokines providing proof of principle that cardiopulmonary spinal afferents are involved in lung pathology post ALI. Considering the translational potential of stellate ganglia delivery of RTX, we further examined the effects of stellate RTX on blood gas exchange and lung edema in the ALI rat model. Our data suggest that intra-stellate ganglia injection of RTX improved pO2 and blood acidosis 7 days post ALI. It also reduced wet lung weight in bleomycin treated rats, indicating a reduction in lung edema. Taken together, this study suggests that cardiopulmonary spinal afferents play a critical role in lung inflammation and edema post ALI. This study shows the translational potential for ganglionic administration of RTX in ARDS.