title: Antifibrotic effect of meloxicam in rat liver: role of nuclear factor kappa B, proinflammatory cytokines, and oxidative stress.
abstract: This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (α-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-β), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), total nitric oxide (NO), interleukin-l beta (IL 1β), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-κB level and subsequent proinflammatory cytokine production (TNF-α, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-β. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, Taibah University, P.O. Box 30050, El-Madinah, El-Munaworah, Saudi Arabia. memymahmoud@yahoo.com.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azahr University, Cairo, Egypt. memymahmoud@yahoo.com.
authors.forename: Memy H
authors.initials: MH
authors.lastname: Hassan
authors.affiliation: Department of Medical Laboratories Technology, Faculty of Applied Medical Sciences, Taibah University, El-Madinah, El-Munaworah, Saudi Arabia.|Department of Histology, Faculty of Medicine, Tanta University, Tanta, Egypt.
authors.forename: Mohamed M
authors.initials: MM
authors.lastname: Ghobara
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism*; D019610:Cytoprotection; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D000077239:Meloxicam; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D013843:Thiazines; D013844:Thiazoles; D002251:Carbon Tetrachloride; D000077239:Meloxicam
keywords: CCl4; Inflammation; Liver fibrosis; Meloxicam; NF-κB; Oxidative stress