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Title: Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

The present study aimed to investigate the effect of the new tyrosine kinase inhibitor, nilotinib on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in rats and explore its possible mechanisms. Male Sprague-Dawley rats were given nilotinib (10 mg/kg) by oral gavage twice daily for 1 week prior to exposure to aerosolized LPS. At 24 h after LPS exposure, bronchoalveolar lavage fluid (BALF) samples and lung tissue were collected. The lung wet/dry weight (W/D) ratio, protein level and the number of inflammatory cells in the BALF were determined. Optical microscopy was performed to examine the pathological changes in lungs. Malondialdehyde (MDA) content, superoxidase dismutase (SOD) and reduced glutathione (GSH) activities as well as nitrite/nitrate (NO{sub 2}{sup -}/NO{sub 3}{sup -}) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-{alpha} (TNF-{alpha}), transforming growth factor-{beta}{sub 1} (TGF-{beta}{sub 1}) and inducible nitric oxide synthase (iNOS) were determined in lung tissues. Treatment with nilotinib prior to LPS exposure significantly attenuated the LPS-induced pulmonary edema, as it significantly decreased lung W/D ratio, protein concentration and the accumulation of the inflammatory cells in the BALF. This was supported by the histopathological examination which revealed marked attenuation of LPS-induced ALI in nilotinib treated rats. Inmore » addition, nilotinib significantly increased SOD and GSH activities with significant decrease in MDA content in the lung. Nilotinib also reduced LPS mediated overproduction of pulmonary NO{sub 2}{sup -}/NO{sub 3}{sup -} levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-{alpha}, TGF-{beta}{sub 1} and iNOS levels in the lung. Taken together, these results demonstrate the protective effects of nilotinib against the LPS-induced ALI. This effect can be attributed to nilotinib ability to counteract the inflammatory cells infiltration and hence ROS generation and regulate cytokine effects. - Research highlights: > The protective effects of nilotinib against LPS-induced ALI in rats were studied. > Nilotinib showed potent anti-inflammatory activity as it attenuated PMN infiltration and hence ROS generation. > In addition, nilotinib caused down-regulation of proinflammatory cytokine production.« less
Authors:
Publication Date:
OSTI Identifier:
21535309
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 253; Journal Issue: 2; Other Information: DOI: 10.1016/j.taap.2011.03.023; PII: S0041-008X(11)00117-7; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BUILDUP; EDEMA; GLUTATHIONE; INFLAMMATION; INJURIES; LAVAGE; LEUKOCYTES; LUNGS; LYMPHOKINES; MALES; NITRATES; NITRIC OXIDE; NITRITES; RATS; SUPEROXIDE DISMUTASE; TYROSINE AMINO ACIDS; ANIMALS; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY; BODY FLUIDS; CARBOXYLIC ACIDS; CHALCOGENIDES; DISEASES; DRUGS; ENZYMES; GROWTH FACTORS; HYDROXY ACIDS; MAMMALS; MATERIALS; MITOGENS; NITROGEN COMPOUNDS; NITROGEN OXIDES; ORGANIC ACIDS; ORGANIC COMPOUNDS; ORGANS; OXIDES; OXIDOREDUCTASES; OXYGEN COMPOUNDS; PATHOLOGICAL CHANGES; PEPTIDES; POLYPEPTIDES; PROTEINS; RADIOPROTECTIVE SUBSTANCES; RESPIRATORY SYSTEM; RESPONSE MODIFYING FACTORS; RODENTS; SYMPTOMS; VERTEBRATES