Febuxostat protects rats against lipopolysaccharide-induced lung inflammation in a dose-dependent manner

Abstract

The aim of the present work was to investigate possible protective effects of febuxostat, a highly potent xanthine oxidase inhibitor, against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats. Male Sprague Dawley rats were randomly divided into six groups, as follows: (i) vehicle control group; (ii) and (iii) febuxostat 10 and febuxostat 15 groups, drug-treated controls; (iv) LPS group, receiving an intraperitoneal injection of LPS (7.5 mg/kg); (v) and (vi) febuxostat 10-LPS and febuxostat 15-LPS groups, receiving oral treatment of febuxostat (10 and 15 mg/kg/day, respectively) for 7 days before LPS. After 18 h administration of LPS, blood was collected for C-reactive protein (CRP) measurement. Bronchoalveolar lavage fluid (BALF) was examined for leukocyte infiltration, lactate dehydrogenase (LDH) activity, protein content, and total nitrate/nitrite. Lung weight gain was determined, and lung tissue homogenate was prepared and evaluated for oxidative stress. Tumor necrosis factor-α (TNF-α) was assessed in BALF and lung homogenate. Moreover, histological changes of lung tissues were evaluated. LPS elicited lung injury characterized by increased lung water content (by 1.2 fold), leukocyte infiltration (by 13 fold), inflammation and oxidative stress (indicated by increased malondialdehyde (MDA), by 3.4 fold), and reduced superoxide dismutase (SOD) activity (by 34 %). Febuxostat dose-dependently decreased LPS-induced lung edema and elevations in BALF protein content, infiltration of leukocytes, and LDH activity. Moreover, the elevated levels of TNF-α in BALF and lung tissue of LPS-treated rats were attenuated by febuxostat pretreatment. Febuxostat also displayed a potent antioxidant activity by decreasing lung tissue levels of MDA and enhancing SOD activity. Histological analysis of lung tissue further demonstrated that febuxostat dose-dependently reversed LPS-induced histopathological changes. These findings demonstrate a significant dose-dependent protection by febuxostat against LPS-induced lung inflammation in rats.

Metabolomic biomarkers predictive of early structural lung disease in cystic fibrosis

“…For example, inhibitors of purine nucleoside phosphorylase that block hypoxanthine formation [28] are in clinical trials for gout. Also, the xanthine oxidase inhibitor febuxostat was recently approved for gout [29] but has also been shown to reduce airway inflammation in an animal model of acute lung injury [30]. Although we did not detect xanthine oxidase activity in BALF supernatant, the high concentrations of xanthine and uric acid (metabolic products of xanthine oxidase) in the airway samples indicate that this enzyme is active in vivo , likely restricted to the airway epithelial cell surface.…”

Histological and immunohistochemical study of the effect of omega-3 fatty acids on ifosfamide-induced liver injury in adult male albino rat

“…The inflammatory cell infiltration seen in the portal triads and the mid zonal area could be explained on the basis of that chemotherapy increased ROS generation and increased cell death which in turn initiate an inflammatory response [21] .…”

Febuxostat Reduces Muscle Wasting in Tumor-bearing Mice via Inhibition of Reacrive Oxygen Species Generation

“…In fact, we found a signi cant correlation between reduction of wet weight of the gastrocnemius muscles and expression of TNF-α and IL-6. Besides, several studies showed anti-in ammatory effects by the administration of febuxostat in various organs, including liver, lung, and kidneys (36,37). In these studies, suppressive effects on in ammation was likely to be a result of the inhibition of ROS production, which is known to induce the expression of in ammation-related cytokines.…”