Vagus nerve stimulation enhances the cholinergic anti-inflammatory pathway to reduce lung injury in acute respiratory distress syndrome via STAT3

The cholinergic anti-inflammatory pathway (CAIP) is important for antagonizing inflammation and treating several diseases, including acute respiratory distress syndrome (ARDS), and is related to vagus nerve integrity. However, its underlying pathophysiological mechanism is still unclear. We hypothesized that CAIP regulates lung injury repair after ARDS through the STAT3 signaling pathway, which is an important downstream effector of alpha 7nAchR. We enhanced CAIP activity by subjecting rats to vagus nerve stimulation (VNS), and administered the alpha-7 acetylcholine receptor (alpha 7nAchR) agonist and antagonist to determine whether VNS can reduce lung injury by regulating the pulmonary inflammatory response through CAIP. After being subjected to VNS, the secretion of TNF-alpha and IL-1 beta was decreased, while the level of IL-10 was increased in the rat model of ARDS. Moreover, VNS treatment reduced lung mRNA levels of M1 macrophage markers, while increased those of M2 macrophage markers. The expression of Caspase-1 decreased, while that of STAT3 increased in lung tissue after VNS treatment. The aforementioned effects of VNS were reversed by cutting the cervical vagus efferent branch and blocking alpha 7nAchR. These findings suggest that VNS inhibits the ARDS inflammatory response by promoting CAIP activity. Next, we used lentivirus knockdown of STAT3 expression to explore the mechanism of VNS through CAIP on lung inflammation in ARDS model rats. VNS activates alpha 7nAchR, increases STAT3 expression, reduces Caspase-1 expression, suppresses inflammation by inhibiting inflammatory pyroptosis and M1 to M2 macrophage transformation, which may constitute the main mechanism of VNS action in ARDS.