Melatonin Alleviates Pulmonary Fibrosis Induced by Atrazine Targeting the Pulmonary Capillary Microenvironment

Atrazine (ATZ), a common herbicide, accumulates in water sources, raising concerns about lung hazards from excessive tap water residues. Pulmonary capillary endothelial cells (PCECs) are primary targets of bloodborne toxins. Melatonin (MLT), an endogenous neuroendocrine hormone, shows promise in mitigating lung disease. This study developed a mouse model for studying the pulmonary effects of ATZ through drinking water and the protective effect of MLT. The results indicate that ATZ-induced pulmonary injury primarily alters PCECs, upregulating the Notch ligand Jag1 via a β-catenin-dependent manner, recruiting Notch1-expressing perivascular M2 macrophages, and promoting fibrosis. MLT attenuated lung injury and collagen deposition by restoring autophagy and inhibiting the Wnt1/β-catenin pathway, thereby reducing Jag1 expression and M2 macrophage activation. MLT also mitigated ATZ-induced lung necrosis and apoptosis. In conclusion, this study highlights MLT's potential in treating ATZ-induced lung injury by blocking Jag1-mediated macrophage phenotypic switching.