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Abstract: Ivermectin is an FDA-approved antiparasitic agent with antiviral and anti-inflammatory properties. Although recent studies reported the possible anti-inflammatory activity of ivermectin in respiratory injuries, its potential therapeutic effect on pulmonary fibrosis (PF) has not been investigated. The present study aimed to explore the ability of ivermectin (0.6 mg/kg) to alleviate bleomycin-induced biochemical derangements and histological changes in an experimental PF rat model. This can provide the means to validate the clinical utility of ivermectin as a treatment option for idiopathic PF. The results showed that ivermectin mitigates the bleomycin-evoked pulmonary injury, as manifested by the reduced infiltration of inflammatory cells, as well as decreased the inflammation and fibrosis scores. Intriguingly, ivermectin decreased collagen fiber deposition and suppressed transforming growth factor-beta (b2%29&ck%5b%5D=abstract&ck%5b%5D=keyword'>b>TGF-b2;b%5D=abstract&ck%5b%5D=keyword'>b>1) and fibronectin protein expressions, highlighting its anti-fibrotic activity. The current study revealed for the first time that ivermectin can suppress the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, as manifested by the reduced gene expression of NLRP3 and the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), with a subsequent decline in the interleukin b%5D=abstract&ck%5b%5D=keyword'>b>1b2; level. In addition, ivermectin inhibited the expression of intracellular nuclear transcription factor kappa b (bA%29&ck%5b%5D=abstract&ck%5b%5D=keyword'>b>NF-bA;b) and hypoxia b%5D=abstract&ck%5b%5D=keyword'>b>1b%5D=abstract&ck%5b%5D=keyword'>b>1;inducible factor b%5D=abstract&ck%5b%5D=keyword'>b>1b%5D=abstract&ck%5b%5D=keyword'>b>1;b%5D=abstract&ck%5b%5D=keyword'>b>1bb%5D=abstract&ck%5b%5D=keyword'>b>1; (HIF-b%5D=abstract&ck%5b%5D=keyword'>b>1bb%5D=abstract&ck%5b%5D=keyword'>b>1;) proteins along with lowering the oxidative stress and apoptotic markers. Altogether, the present study revealed that ivermectin could ameliorate pulmonary inflammation and fibrosis induced by bleomycin. These beneficial effects were mediated, at least partly, via the downregulation of b2%29&ck%5b%5D=abstract&ck%5b%5D=keyword'>b>TGF-b2;b%5D=abstract&ck%5b%5D=keyword'>b>1 and fibronectin, as well as the suppression of NLRP3 inflammasome through modulating HIF b%5D=abstract&ck%5b%5D=keyword'>b>1b%5D=abstract&ck%5b%5D=keyword'>b>1;b%5D=abstract&ck%5b%5D=keyword'>b>1bb%5D=abstract&ck%5b%5D=keyword'>b>1; and bA%29&ck%5b%5D=abstract&ck%5b%5D=keyword'>b>NF-bA;b expressions.