Inhibition of TRPV4 attenuates ferroptosis against LPS-induced ALI via Ca(2+) pathway

Acute lung injury (ALI) is an inflammation of the lungs with high incidence rate and mortality. Ferroptosis is a new cell death, which has influence in body organs. Transient receptor potential vanillin-4 (TRPV4) channel is a key mediator of Ca(2+), its activation induces ferroptosis. The purpose of the study is to investigate the function of TRPV4 on ferroptosis in ALI mice induced by lipopolysaccharide (LPS). In vitro, the regulation of TRPV4 on Ca(2+) and ferroptosis was detected by CCK-8, fluorescent probe, and western blot in BEAS-2B cells. In vivo, the role of TRPV4 antagonists on ALI mice was analyzed by determination of pulmonary inflammation, pulmonary edema, and ferroptosis. In vitro, ferroptosis was induced in ALI. TRPV4 expression and intracellular Ca(2+) concentration were up-regulated in ALI, and TRPV4 antagonist suppressed LPS-induced ferroptosis in BEAS-2B cells, including decreased MDA and ROS levels, increased GPX4 protein level and cell viability. In vivo, ALI mice showed activated ferroptosis compared with the control group, and administration of TRPV4 inhibition had protective effects on ALI mice, including improving lung pathological characteristics, and reducing the degree of pulmonary edema, inflammation, and ferroptosis. The results manifested that ferroptosis mediated lung injury in LPS-induced ALI, and TRPV4 antagonists might moderate LPS-induced damage by suppressing ferroptosis.