Dietary Chlorogenic Acid and Omega-3 Relieve Methotrexate-Induced Lung Injury Through Modulation of SIRT1/ PGC-1α/ NF-κB Signaling Axis.

Methotrexate (MTX) is a pivotal chemotherapeutic drug which is also used to treat serious chronic inflammatory disorders. However, it causes perilous pulmonary injury. This study aimed to explore the protective effects of CGA and ω-3 on MTX-induced pulmonary toxicity in rats via modulation of SIRT1/PGC-1α/ NF-κB signaling axis. Twenty-four male Sprague-Dawley rats were randomly divided into four groups; normal, MTX, MTX + CGA, and MTX + ω-3, rats were injected with MTX single dose intraperitoneally (20 mg/kg) followed by an oral administration of CGA (100 mg/kg) or ω-3 (400 mg/kg) for seven days. Both CGA and ω-3 relieved MTX-induced-pulmonary histopathological changes by decreasing alveolar epithelial loss and inflammatory cell infiltration. Also, CGA and ω-3 markedly ameliorated the oxidative stress by lowering pulmonary MDA content along with significant increment in pulmonary GSH content. Moreover, both CGA and ω-3 suppressed pulmonary inflammation as proved by marked lowering of serum CRP level via downregulation of pulmonary NF-κB, TNF-α and MPO levels along with upregulation of pulmonary SIRT1/PGC-1α expression and IL-10 level. Additionally, the antioxidant and anti-inflammatory activities of CGA and ω-3 promote pulmonary Bcl-2 expression and inhibit pulmonary caspase 3 expression which in turn suppress apoptotic cell death in the lungs of MTX-intoxicated rats. These protective effects of CGA and ω-3 suggest the potentiality of using them in conjunction with MTX treatment protocols to diminish their undesirable lung toxicity.