Ye Gao, Ni Wang, Zhaoyang Xiao
VNS protects against sepsis-associated lung injury through suppression of elevated pulmonary proBDNF, a process dependent on intact vagal signaling and, at least in part, mediated by α7nAChR-dependent peripheral cholinergic pathways. These findings identify proBDNF as a possible downstream effector of VNS-mediated lung protection.
BACKGROUND: Sepsis-associated acute respiratory distress syndrome (ARDS) remains a major contributor to mortality among critically ill patients. Vagus nerve stimulation (VNS) may attenuate inflammatory injury, but the downstream molecular mechanisms underlying its protective effects in septic lung injury remain incompletely understood. The role of proBDNF in VNS-mediated immunoregulation remains unclear. This study aimed to explore whether pulmonary proBDNF contributes to VNS-induced protection against sepsis-associated lung injury.
METHODS: Sepsis-associated lung injury was induced by cecal ligation and puncture (CLP) in rats. The effects of VNS on lung injury, inflammation, and pulmonary proBDNF expression were evaluated. Vagotomy was conducted to assess the dependence of VNS effects on intact vagal signaling. Peripheral cholinergic signaling was probed using methyllycaconitine, an α7 nicotinic acetylcholine receptor (α7nAChR) antagonist. Pulmonary overexpression of proBDNF was achieved via adeno-associated virus (AAV) delivery to determine its functional significance. Histological, molecular, and functional analyses assessed lung injury, inflammation, pulmonary proBDNF, pulmonary edema, and BALF total protein levels.
RESULTS: VNS significantly alleviated CLP-induced lung injury, reduced pulmonary inflammatory cytokine expression, decreased pulmonary edema and BALF total protein levels, and partially restored barrier-associated gene expression. Pulmonary proBDNF levels were markedly increased after CLP but suppressed by VNS, whereas vagotomy further elevated proBDNF. Brain proBDNF levels remained largely unchanged across groups. α7nAChR blockade attenuated the inhibitory effect of VNS on pulmonary proBDNF. Immunofluorescence identified macrophages as a major source of proBDNF in injured lungs. Notably, AAV-mediated pulmonary overexpression of proBDNF weakened the beneficial effects of VNS on inflammation, pulmonary edema, alveolar-capillary barrier leakage, and lung damage.
CONCLUSION: VNS protects against sepsis-associated lung injury through suppression of elevated pulmonary proBDNF, a process dependent on intact vagal signaling and, at least in part, mediated by α7nAChR-dependent peripheral cholinergic pathways. These findings identify proBDNF as a possible downstream effector of VNS-mediated lung protection.