title: Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats.
abstract: 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 (10mg/kg) by oral gavage twice daily for 1week prior to exposure to aerosolized LPS. At 24h 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(2)(-)/NO(3)(-)) levels were measured in lung tissues. The expression of inflammatory cytokines, tumor necrosis factor-α (TNF-α), transforming growth factor-β(1) (TGF-β(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. In 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(2)(-)/NO(3)(-) levels. Importantly, nilotinib caused down-regulation of the inflammatory cytokines TNF-α, TGF-β(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.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt. dinaagamy1@yahoo.com
authors.forename: Dina S
authors.initials: DS
authors.lastname: El-Agamy
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D009566:Nitrates / Q000032:analysis; D009573:Nitrites / Q000032:analysis; D018384:Oxidative Stress / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D009566:Nitrates; D009573:Nitrites; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C498826:nilotinib