title: Amelioration of bleomycin-induced lung fibrosis in rats by valproic acid and butyrate: Role of nuclear factor kappa-B, proinflammatory cytokines and oxidative stress.
abstract: Bleomycin is one of the anticancer agents used frequently in management of various types of tumors. Pulmonary fibrosis is the major limiting factor for the use of bleomycin. Mechanisms of fibrosis may include disordered wound healing, infiltration with inflammatory cells and fibroblasts and release of reactive oxygen species and growth factors. The aim of this study was to investigate the effect of valproic acid and butyrate on lung fibrosis induced by bleomycin, and to clarify their mechanisms of action. Fifty male Wistar rats were divided into 5 equal groups as follows: control group; bleomycin group; bleomycin+valproic acid group; bleomycin+butyrate group and bleomycin+valproic acid+butyrate group. Weight of rats, lung tissue hydroxyproline, malondialdehyde, superoxide dismutase and catalase were measured. Also, bronchoalveolar lavage (BAL) was analyzed for total and differential leukocytic count, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and transforming growth factor-beta 1 (TGF-β1). Lung tissue was examined histopathologically and immunostained for nuclear factor kappa B (NF-κB). Valproic acid and/or butyrate resulted in significant improvement of the body weight gain, oxidative stress, TGF-β1, IL-6, TNF-α, hydroxyproline and BAL cellularity together with significant improvement of the histopathological and immunohistochemical picture. The use of valproic acid/butyrate combination was better than the use of each of these drugs alone in bleomycin-induced pulmonary fibrosis. In conclusion, valproic acid/butyrate combination may be used prophylactically for amelioration of bleomycin-induced pulmonary fibrosis.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt; Department of Clinical Pharmacy, College of Pharmacy, Taif University, Taif, Saudi Arabia. Electronic address: drakabel@gmail.com.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Kabel
authors.affiliation: Chemistry Department, Faculty of Science, Benha University, Benha, Egypt; Division of Biochemistry, Pharmacology and Toxicology Department, College of Pharmacy, Taif University, Taif, Saudi Arabia.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Omar
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt.
authors.forename: Maaly A Abd
authors.initials: MAA
authors.lastname: Elmaaboud
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000009:adverse effects / Q000627:therapeutic use; D002087:Butyrates / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004358:Drug Therapy; D004359:Drug Therapy, Combination; D064420:Drug-Related Side Effects and Adverse Reactions / Q000517:prevention & control*; D006909:Hydroxyproline / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013482:Superoxide Dismutase / Q000378:metabolism; D014635:Valproic Acid / Q000627:therapeutic use*
chemical_list: D002087:Butyrates; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D001761:Bleomycin; D014635:Valproic Acid; D013482:Superoxide Dismutase; D006909:Hydroxyproline
keywords: Bleomycin; Butyrate; Inflammation; Lung fibrosis; Valproic acid