HC067047 as a potent TRPV4 inhibitor repairs endotoxemia colonic injury

Colonic injury causes severe inflammation during systemic infections in patients with endotoxemia. The prevention of colonic injury could effectively reduce the progression of endotoxemia. We investigated the protective effects and detailed mechanisms of the TRPV4 inhibitor HC067047 in the treatment of colonic injury caused by endotoxemia. An LPS-induced endotoxemia colonic injury model was used to assess the in vivo effects of HC067047. Colon slices were detected by hematoxylin and eosin (HE) staining and immunofluorescence assays. Spectrophotometry was used to determine the levels of MDA, calcium, GSH, and GSSG. Alterations in oxidative stress/mitophagy/inflammatory pyroptosis-related markers were evaluated by Q-PCR and western blot assays. HC067047 reduced the body weight loss and spleen weight index of endotoxemic mice and partly recovered the normal morphology of the colonic mucous layer. As an inhibitor of the calcium permeant cation channel, HC067047 suppressed the phosphorylation of the CAMKIIɑ protein and levels of MDA and calcium, upregulated the ratio of GSH/GSSG, shortened the expression of oxidative stress-related proteins, and enhanced the expression of the anti-oxidative protein CAT in damaged colon tissues. Additionally, HC067047 maintained normal mitochondrial functions in endotoxemia colons by promoting mitochondrial fusion and biosynthesis and suppressing mitochondrial fission and the PINK/Parkin/mitophagy pathway. HC067047 potently blocked inflammatory pyroptosis and protected the colonic tight junction barrier. HC067047 restores endotoxemia colons against oxidative stress, mitophagy, inflammatory pyroptosis, and colonic barrier dysfunction. Hence, HC067047 therapy may be potentially useful in the treatment of colonic injury in endotoxemia.