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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 (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

Citation Formats

El-Agamy, Dina S., E-mail: dinaagamy1@yahoo.com. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats. United States: N. p., 2011. Web. doi:10.1016/j.taap.2011.03.023.
El-Agamy, Dina S., E-mail: dinaagamy1@yahoo.com. Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats. United States. doi:10.1016/j.taap.2011.03.023.
El-Agamy, Dina S., E-mail: dinaagamy1@yahoo.com. Wed . "Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats". United States. doi:10.1016/j.taap.2011.03.023.
@article{osti_21535309,
title = {Nilotinib ameliorates lipopolysaccharide-induced acute lung injury in rats},
author = {El-Agamy, Dina S., E-mail: dinaagamy1@yahoo.com},
abstractNote = {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.},
doi = {10.1016/j.taap.2011.03.023},
journal = {Toxicology and Applied Pharmacology},
number = 2,
volume = 253,
place = {United States},
year = {Wed Jun 01 00:00:00 EDT 2011},
month = {Wed Jun 01 00:00:00 EDT 2011}
}
  • Highlights: •Activation of PPARα attenuated LPS-mediated acute lung injury. •Pretreatment with Wy-14643 decreased the levels of IFN-γ and IL-6 in ALI. •Nitrosative stress and lipid peroxidation were downregulated by PPARα activation. •PPARα agonists may be potential therapeutic targets for acute lung injury. -- Abstract: Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-α (PPARα) by its ligands, which include Wy-14643, has been implicated as a potential anti-inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARα activation was investigatedmore » in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age-matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARα by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARα might have a therapeutic effect on LPS-induced ALI.« less
  • The purpose of the present study was to investigate the protective role of acteoside (AC) on lipopolysaccharide (LPS)-induced acute lung injury (ALI). BalB/c mice intraperitoneally received AC (30, and 60 mg/kg) or dexamethasone (2 mg/kg) 2 h prior to or after intratracheal instillation of LPS. Treatment with AC significantly decreased lung wet-to-dry weight (W/D) ratio and lung myeloperoxidase (MPO) activity and ameliorated LPS-induced lung histopathological changes. In addition, AC increased super oxide dismutase (SOD) level and inhibited malondialdehyde (MDA) content, total cell and neutrophil infiltrations, and levels of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6)more » in bronchoalveolar lavage fluid (BALF) in LPS-stimulated mice. Furthermore, we demonstrated that AC inhibited the phosphorylation of IκBα, nuclear factor-κB (NF-κB) p65, inhibitor of nuclear factor kappa-B kinase-α (IKK-α) and inhibitor of nuclear factor kappa-B kinase-β (IKKβ) in LPS-induced inflammation in A549 cells. Our data suggested that LPS evoked the inflammatory response in lung epithelial cells A549. The experimental results indicated that the protective mechanism of AC might be attributed partly to the inhibition of proinflammatory cytokine production and NF-κB activation. - Highlights: • Acteoside inhibited inflammation in LPS-induced lung injury in mice. • Acteoside inhibited inflammation in lung epithelial cells A549. • Acteoside inhibited NF-kB activation in LPS-induced mice and lung epithelial cells A549.« less
  • Hypoxic acute kidney injury (AKI) is often incompletely repaired and leads to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. The Slit2 family of secreted glycoproteins is expressed in the kidney, it has been shown to exert an anti-inflammatory activity and prevent ischemic renal injury in vivo. However, whether Slit2 reduces renal fibrosis and inflammation after hypoxic and inflammatory epithelial cells injury in vitro remains unknown. In this study, we aimed to evaluate whether Slit2 ameliorated fibrosis and inflammation in two renal epithelial cells line challenged with hypoxia and lipopolysaccharide (LPS). Renal epithelial cells were treatedmore » with hypoxia and LPS to induce cell injury. Hoechst staining and Western blot analysis was conducted to examine epithelial cells injury. Immunofluorescence staining and Western blot analysis was performed to evaluate tubulointerstitial fibrosis. Real-time polymerase chain reaction (PCR) tested the inflammatory factor interleukin (IL)−1β and tumor necrosis factor (TNF)-α, and Western blot analysis determined the hypoxia-inducible factor (HIF)−1α, Toll-like receptor 4 (TLR4) and nuclear factor (NF)-κB. Results revealed that hypoxia induced epithelial cells apoptosis, inflammatory factor IL-1β and TNF-α release and tubulointerstitial fibrosis. LPS could exacerbate hypoxia -induced epithelial cells apoptosis, IL-1β and TNF-α release and fibrosis. Slit2 reduced the expression of fibronectin, the rate of epithelial cell apoptosis, and the expression of inflammatory factor. Slit2 could also inhibit the expression of TLR4 and NF-κB, but not the expression of HIF-1α. Therefore, Slit2 attenuated inflammation and fibrosis after LPS- and hypoxia-induced epithelial cells injury via the TLR4/NF-κB signaling pathway, but not depending on the HIF-1α signaling pathway. - Highlights: • Slit2 ameliorates inflammation after hypoxia-and LPS-induced epithelial cells injury. • Slit2 ameliorates fibrosis after hypoxia-and LPS-induced epithelial cells injury. • Slit2 ameliorates inflammation and fibrosis after hypoxia-and LPS-induced renal epithelial cells injury via TLR4/NF-κB.« less
  • As part of a study on the effects of acute ozone stress on the lung surfactant system, we correlated morphometric, biochemical, and functional indices of lung injury using male rats exposed to 3 ppm ozone for 1, 2, 4, and 8 hr. Evaluation of lung mechanics, using the Pulmonary Evaluation and Diagnostic Laboratory System, revealed a significant decrease in dynamic lung compliance (ml/cmH[sub 2]O/kg) from a control value of 0.84 [plus minus] 0.02 (SEM) to 0.72 [plus minus] 0.04 and 0.57 [plus minus] 0.06 at 4 and 8 hr, respectively. At 2 hr there was a transient increase in PaO[submore » 2] to 116 torr (control = 92 torr) followed by a decrease at 4 hr (65 torr) and 8 hr (55 torr). Morphometry of lung tissue, fixed by perfusion of fixative via the pulmonary artery at 12 cm H[sub 2]O airway distending pressure, demonstrated an increase in the area of the intravascular compartment at 8 hr, in association with a 65 and 39% replacement of the alveolar area by fluid in ventral and dorsal lung regions, respectively. There was a positive correlation (r = 0.966) between alveolar edema and transudated proteins in lavage fluid. A stepwise multiple regression model, with edema as the dependent variable, suggested that pulmonary vasodilatation, hypoxemia, and depletion of surfactant tubular myelin in lavage fluid were indices for predicting alveolar edema. In a second model, with lavage protein concentration as the dependent variable, decreasing dynamic compliance and hypoxemia were predictors of progressive, intraalveolar transudation of plasma proteins. The above structural-functional relationships support the concept that ozone-induced high-protein alveolar edema is pathogenetically linked to pulmonary hyperemia, deficiency of surfactant tubular myelin, and associated lung dysfunctions.« less
  • To test the hypothesis that neutrophils contribute to acute, ozone-induced epithelial damage in the lung, rats were depleted of their circulating neutrophils by intraperitoneal injection of a rabbit anti-rat neutrophil serum (ANS) 12 hr prior to an 8-hr exposure to 1.0 ppm ozone. Additional rats were given an injection of normal rabbit serum (NRS) prior to ozone exposure. Exposures were followed by postexposure periods in filtered air for 0, 4, or 16 hr. Control rats were given either ANS or NRS and then exposed only to filtered air. Analysis of bronchoalveolar lavage fluid (BALF) from NRS-treated rats revealed a significantmore » increase in total neutrophils above that of controls at the 4- and 16-hr postexposure times, with a peak increase at 4 hr postexposure. In contrast, there was almost total ablation of the BALF neutrophil response in the ANS-treated rats at all times. Ozone caused an increase in BALF protein, fibronectin, and interleukin-6 above those in controls in both the NRS- and ANS-treated rats, but the only significant difference between the two groups was a level of fibronectin in the neutrophil-depleted animals higher than that in the neutrophil-sufficient animals at the 0-hr postexposure time. Electron microscopic morphometry on lungs fixed by intravascular perfusion demonstrated no significant differences in the volume per surface area epithelial basal lamina (Vs) of necrotic and degenerating epithelial cells in central acini between the neutrophil-depleted and neutrophil-sufficient animals. From these results, we concluded that neutrophils do not play a detectable role in contributing to the early epithelial damage in the lung caused by an acute exposure to ozone.« less