Transient receptor potential canonical 6 is critical for chronic lipopolysaccharide exposure-induced pulmonary injury and fibrosis

LPS-induced chronic lung injury is a precursor to pulmonary fibrosis; however, the precise molecular mechanisms underlying this pathological progression remain incompletely elucidated. TRPC6 channel has been implicated in various forms of lung disease, yet its specific contribution to LPS-driven fibrogenic processes remains poorly defined. We investigated TRPC6 function in alveolar epithelial cell injury and fibrosis following LPS exposure. We found that LPS upregulated TRPC6 expression, causing calcium influx and ROS overproduction. These perturbations culminated in mitochondrial dysfunction and enhanced apoptotics. Concurrently, LPS triggered activation of the NLRP3 and AIM2 inflammasomes, thereby facilitating the maturation of IL-1β, and activated the TGF-β1/Smad signaling pathway, leading to pulmonary fibrosis. Notably, pharmacological inhibition of TRPC6 with BI-749327 ameliorated these pathological processes, whereas TRPC6 activation via OAG exacerbated them. Consistent with the in vitro observations, Trpc6-deficient (Trpc6^-/-) mice exhibited substantially attenuated pulmonary inflammation, epithelial injury, and fibrotic sequelae following LPS challenge. These protective effects were associated with diminished activation of both TGF-β1/Smad signaling and the NLRP3 and AIM2 inflammasomes, as well as reduced circulating levels of pro-inflammatory cytokines, including IL-1β and IL-6. Collectively, our findings identify TRPC6 as a pivotal mediator in LPS-induced pulmonary fibrosis by disrupting calcium homeostasis and activating NLRP3 and AIM2 inflammasomes, eventually resulting in TGF-β1/Smad-driven fibrotic remodeling. Thus, targeting TRPC6 may represent a promising therapeutic approach for mitigating chronic inflammation-associated pulmonary fibrosis.

Inflammasome; Lipopolysaccharide; Oxidative stress; Pulmonary fibrosis; TRPC6.