Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats

Journal Article · Wed Jun 01 04:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.03.023· OSTI ID:21535309

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. 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{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.

• OSTI ID: 21535309
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 253; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
AMINO ACIDS
ANIMALS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
BUILDUP
CARBOXYLIC ACIDS
CHALCOGENIDES
DISEASES
DRUGS
EDEMA
ENZYMES
GLUTATHIONE
GROWTH FACTORS
HYDROXY ACIDS
INFLAMMATION
INJURIES
LAVAGE
LEUKOCYTES
LUNGS
LYMPHOKINES
MALES
MAMMALS
MATERIALS
MITOGENS
NITRATES
NITRIC OXIDE
NITRITES
NITROGEN COMPOUNDS
NITROGEN OXIDES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXIDES
OXIDOREDUCTASES
OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PEPTIDES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
RATS
RESPIRATORY SYSTEM
RESPONSE MODIFYING FACTORS
RODENTS
SUPEROXIDE DISMUTASE
SYMPTOMS
TYROSINE
VERTEBRATES