Chrysin ameliorates ANTU‐induced pulmonary edema and pulmonary arterial hypertension via modulation of VEGF and eNOs

Abstract

Alpha‐naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti‐inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU‐induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague‐Dawley rats were used to induce PE (ANTU, 10\u2009mg/kg, ip) and PAH (ANTU, 5\u2009mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40\u2009mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P\u2009<\u20090.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5‐hydroxytryptamine (5‐HT), lactate dehydrogenase (LDH), and γ‐glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40\u2009mg/kg, ip) significantly (P\u2009<\u20090.05) attenuated these ANTU‐induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P\u2009<\u20090.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40\u2009mg/kg, p.o.) treatment significantly (P\u2009<\u20090.05) attenuated these alterations. ANTU‐induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P\u2009<\u20090.05) inhibited by chrysin. It also significantly (P\u2009<\u20090.05) decreased elevated levels of oxido‐nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P\u2009<\u20090.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU‐induced PE and PAH via modulation of inflammatory responses (5‐HT, LDH, and GGT), oxido‐nitrosative stress, and VEGF and eNOs levels.