Melatonin counteracts necroptosis and pulmonary edema in cadmium-induced chronic lung injury through the inhibition of angiotensin II

The renin-angiotensin system (RAS) is an important regulator in pulmonary physiology. In our study, we identified the efficacy of melatonin to control the RAS in cadmium (Cd) induced chronic lung injury in a mouse model. Swiss albino mice exposed to CdCl2 intraperitoneally (I.P.) (1 mg/kg b.w.; 12 weeks) showed increased release of lactate dehydrogenase in bronchoalveolar lavage fluid, generating reactive oxygen species, impaired antioxidant enzymes function, and disrupted alveolar structure along with increased expression of Angiotensin-II (Ang-II) in lung tissue. Cd-induced angiotensin-converting enzyme-2-Ang-II axis imbalance triggered the onset of Ang-II induced tumour necrosis factor alpha (TNF-alpha) mediated necroptosis by upregulating the signalling molecules RIP-1, RIP-3, and p-mixed lineage kinase domain-like. In an in vitro study, colocalization of Ang-II-RIP-3 molecule in Cd intoxicated L-132 cells (human alveolar epithelial cell line), as well as pretreatment of Cd exposed cells with the inhibitor's captopril (10 mu M), necrostatin-1 (50 mu M), and etanercept (5 mu g/ml) indicated TNF-alpha induced necroptotic cell death via activation of the key molecule, Ang-II. Moreover, Ang-II disrupted the alveolar-capillary barrier by decreasing tight junctional proteins (zonula occludens-1 and occludin) and endothelial VE-cadherin expression. The use of human umbilical vein endothelial cells as a model of junctional protein-expressing cells showed that captopril pretreatment (25 mu M) restored VE-cadherin expression in Cd-treated human umbilical vein endothelial cells. In CdCl2 intoxicated mice, melatonin pretreatment (10 mg/kg b.w.; 12 weeks, I.P.) inhibited inflammatory mediators (TNF-alpha, interleukin [IL]-1 beta, and IL-6) release and effectively suppressed (Cd-induced) Ang-II mediated necroptotic cell death and alveolar-capillary breaching due to Cd toxicity.

Automated summary

The study demonstrates the efficacy of melatonin in controlling the renin-angiotensin system (RAS) in the context of chronic lung injury induced by cadmium (Cd) exposure. Melatonin treatment effectively inhibits inflammatory responses and necroptotic cell death mediated by Angiotensin-II (Ang-II), thereby protecting the alveolar-capillary barrier from Cd toxicity.