allopurinol and Acute-Lung-Injury

The herbicide paraquat causes fatal lung toxicity by induction of xanthine oxidase, production of free radicals and inflammation. Febuxostat, a xanthine oxidase inhibitor and anti-gout has recently shown anti-inflammatory activity. Accordingly, this study was carried out to investigate whether febuxostat may attenuate paraquat-induced lung toxicity and to explore the possible underlying mechanisms.. Rats were administered either vehicle, a single dose of paraquat (30 mg/kg, i.p.), febuxostat (15 mg/kg, oral), or both for 14 successive days. Serum LDH and sRAGE were estimated. Lung tissue xanthine oxidase activity, SOD, TAC, MDA, and RAGE, HMGB1 gene expression, PI3K/Akt and β-catenin protein expression, MMP-9, IL-8, VEGF and COX-2 gene expression were estimated.. Results showed that paraquat induced lung injury characterized by enhanced oxidative stress and inflammation, upregulated RAGE, HMGB1 gene expression, PI3K/Akt and β-catenin protein expression. Administration of febuxostat inhibited the deleterious effects of paraquat on lung through inhibition of xanthine oxidase activity and related oxidative stress, downregulation of RAGE/PI3K/Akt pathway, and suppression of β-catenin protein expression and its downstream inflammatory mediators.. The present study showed that febuxostat may abrogate paraquat-induced lung toxicity and demonstrated a novel mechanism for its ameliorative effects.

Topics: Acute Lung Injury; Animals; beta Catenin; Febuxostat; Inflammation; Lung; Lung Injury; Male; Oxidative Stress; Paraquat; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pulmonary Edema; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Xanthine Oxidase

Naringenin is a naturally occurring flavanones and has been found to exhibit free radical scavenging, enzyme inhibition, antioxidants, anti-inflammatory, and anticancer activities. Present study was designed to evaluate the protective role of naringenin against benzo[a]pyrene (B[a]P)-induced oxidative stress and pulmonary toxicity. Rats were treated with naringenin at a dose of 100 mg/kg body weight (b. wt.), by oral gavage. B[a]P in a single dose of 50 mg/kg b. wt. was given intraperitoneally. Total protein, total cell counts, lactate dehydrogenase, lipid peroxidation, reduced glutathione, antioxidant enzymes activities, lung histology and expression of nuclear factor kappa B (NF-κB), and cyclo-oxygenase-2 (COX-2) was assessed to evaluate protective effects of naringenin. Histopathological and immunohistochemical studies were also carried out to observe lung toxicity and inflammation. B[a]P administration enhanced the levels of lung injury markers and reduced antioxidant enzymes activities. Naringenin treatment attenuated the levels of oxidative stress by restoring antioxidant enzymes, further improved lung histological damage and significant decrease in inflammatory responses. Naringenin also effectively decreased the expression of NF-κB, and COX-2 induced by B[a]P. These findings suggest that naringenin supplementation is beneficial in maintaining the integrity of alveoli and the epithelium that may be used as a protective agent in B[a]P-induced oxidative stress and lung damage. However, further studies are warranted to elucidate the potential mechanism of action of naringenin.

Topics: Acute Lung Injury; Animals; Antioxidants; Benzo(a)pyrene; Bronchoalveolar Lavage Fluid; Carcinogens; Catalase; Cyclooxygenase 2; Flavanones; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; L-Lactate Dehydrogenase; Lung; Male; NF-kappa B; Oxidative Stress; Rats, Wistar; Superoxide Dismutase; Xanthine Oxidase

Experimental studies indicate that sepsis causes remote organ injury although the molecular mechanism has not been clearly defined. In this report, the role of oxidative damage, and inflammation on lung injury, following sepsis model by cecal ligation and puncture, and the effects of quercetin, antioxidant, and anti-inflammatory flavonoid, in the lung tissue were investigated. In the present study, we found that administration of single-dose quercetin before cecal ligation and puncture procedure, while markedly diminishing the levels of YKL-40 and oxidant molecules (xanthine oxidase (XO), nitric oxide (NO), and malondialdehyde (MDA)), increases the antioxidant enzymes levels. Quercetin is beneficial to acute lung injury by decreasing the levels of oxidative stress markers and increasing the antioxidant enzyme activities. Quercetin also causes a decrease in the serum levels of YKL-40 and periostin in the oxidative lung injury induced by the experimental sepsis model.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Antioxidants; Cecum; Cell Adhesion Molecules; Chitinase-3-Like Protein 1; Disease Models, Animal; Inflammation; Malondialdehyde; Nitric Oxide; Oxidative Stress; Quercetin; Rats; Rats, Wistar; Sepsis; Xanthine Oxidase

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.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Bronchoalveolar Lavage Fluid; C-Reactive Protein; Dose-Response Relationship, Drug; Febuxostat; Glutathione; L-Lactate Dehydrogenase; Leukocyte Count; Lipopolysaccharides; Lung; Male; Malondialdehyde; Nitric Oxide; Pulmonary Edema; Rats, Sprague-Dawley; Superoxide Dismutase; Tumor Necrosis Factor-alpha; Xanthine Oxidase

To investigate the relationship between donor liver cold preservation, lung surfactant (LS) changes and acute lung injury (ALI) after liver transplantation.. Liver transplantation models were established using male Wistar rats. Donor livers were preserved in University of Wisconsin solution at 4  °C for different lengths of time. The effect of ammonium pyrrolidinedithiocarbamate (PDTC) on ALI was also detected. All samples were harvested after 3 h reperfusion. The severity of ALI was evaluated by lung weight/body weight ratio, lung histopathological score, serum nitric oxide (NO) and endothelin (ET)-1 levels, lung tumor necrosis factor (TNF)-α and interleukin (IL)-1β levels. Lung surfactants (LSs) were determined by micellar electrokinetic capillary chromatography.. With extended donor liver cold preservation time (CPT), lung histopathological scores, serum ET-1 levels, lung weight/body weight ratio and the level of TNF-α and IL-1β in lung were increased significantly in the 180-min group compared with the sham group (3.16 ± 0.28 vs 1.12 ± 0.21, P < 0.001; 343.59 ± 53.97 vs 141.53 ± 48.48, P < 0.001; 0.00687 ± 0.00037 vs 0.00557 ± 0.00056, P < 0.001; 17.5 ± 3.0 vs 1.3 ± 0.3, P < 0.001; 10.8 ± 2.3 vs 1.8 ± 0.4, P < 0.001), but serum NO levels decreased remarkably (74.67 ± 10.01 vs 24.97 ± 3.18, P < 0.001). The expression of lung phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI) and phosphatidylserine (PS) increased when CPT was < 120 min, and decreased when CPT was > 180 min (PC: 1318.89 ± 54.79 vs 1011.18 ± 59.99, P < 0.001; PE: 1504.45 ± 119.96 vs 1340.80 ± 76.39, P = 0.0019; PI: 201.23 ± 34.82 vs 185.88 ± 17.04, P = 0.2265; PS: 300.43 ± 32.95 vs 286.55 ± 55.55, P = 0.5054). All these ALI-associated indexes could be partially reversed by PDTC treatment.. Prolonged CPT could induce or inhibit the expression of LSs at the compensation or decompensation stage, and some antioxidants (e.g., PDTC) may reverse the pathological process partially.

Topics: Acute Lung Injury; Adenosine; Allopurinol; Animals; Cryopreservation; Glutathione; Insulin; Interleukin-1beta; Liver; Liver Transplantation; Lung; Male; Organ Preservation Solutions; Phospholipids; Pulmonary Surfactants; Raffinose; Random Allocation; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Uric acid released from injured tissue is considered a major endogenous danger signal and local instillation of uric acid crystals induces acute lung inflammation via activation of the NLRP3 inflammasome. Ventilator-induced lung injury (VILI) is mediated by the NLRP3 inflammasome and increased uric acid levels in lung lavage fluid are reported. We studied levels in human lung injury and the contribution of uric acid in experimental VILI.. Uric acid levels in lung lavage fluid of patients with acute lung injury (ALI) were determined. In a different cohort of cardiac surgery patients, uric acid levels were correlated with pulmonary leakage index. In a mouse model of VILI the effect of allopurinol (inhibits uric acid synthesis) and uricase (degrades uric acid) pre-treatment on neutrophil influx, up-regulation of adhesion molecules, pulmonary and systemic cytokine levels, lung pathology, and regulation of receptors involved in the recognition of uric acid was studied. In addition, total protein and immunoglobulin M in lung lavage fluid and pulmonary wet/dry ratios were measured as markers of alveolar barrier dysfunction.. Uric acid levels increased in ALI patients. In cardiac surgery patients, elevated levels correlated significantly with the pulmonary leakage index. Allopurinol or uricase treatment did not reduce ventilator-induced inflammation, IκB-α degradation, or up-regulation of NLRP3, Toll-like receptor 2, and Toll-like receptor 4 gene expression in mice. Alveolar barrier dysfunction was attenuated which was most pronounced in mice pre-treated with allopurinol: both treatment strategies reduced wet/dry ratio, allopurinol also lowered total protein and immunoglobulin M levels.. Local uric acid levels increase in patients with ALI. In mice, allopurinol and uricase attenuate ventilator-induced alveolar barrier dysfunction.

Topics: Acute Lung Injury; Adult; Allopurinol; Animals; Bronchoalveolar Lavage Fluid; Capillary Permeability; Carrier Proteins; Gene Expression Regulation; Humans; I-kappa B Proteins; Male; Mice; Mice, Inbred C57BL; Microvessels; NF-KappaB Inhibitor alpha; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Alveoli; Toll-Like Receptor 2; Toll-Like Receptor 4; Urate Oxidase; Uric Acid; Ventilator-Induced Lung Injury

Oxidants and their generator, xanthine oxidase (XO), play a major role in the damaging of the structural and functional integrity of the lung. Such damage has been recently demonstrated in the presence of pancreas ischemia-reperfusion (IR). We investigated whether mannitol, a clinically used agent and antioxidant, prevented lung damage after pancreas IR. Rats (n = 48) were anesthetized, after which each pancreas was isolated and perfused (controls), or made ischemic (IR) for 40 min, or made ischemic and treated upon reperfusion with four different doses of mannitol administered in the perfusate (8 replicates/group). Ischemia was followed by in-series 15-min pancreas plus normal isolated lung reperfusion. Isolated lungs were subsequently perfused for 45 min with the 15-min accumulated effluents. Pancreas injury occurred in all IR organs as demonstrated by abnormal reperfusion pressure, the wet-to-dry ratio, amylase and lipase leakage into the circulation, and XO activity and reduced glutathione (GSH) pool in the tissues. Pulmonary plateau pressure increased by 80%, and final PO(2)/FiO(2) decreased by 28% in the IR-untreated paired lungs. Bronchoalveolar lavage volume increased by 50% and 2- to 8-fold increase in their contained XO and GSH were recorded as well. The above indices of injury in lungs perfused with 0.77 mM mannitol were the least detected, compared with negligible efficacy of other (0.55 < 0.22 < 1.1 mM) dosages. Amylase and lipase did not contribute to lung injury. Ex vivo acute pancreatitis induces acute lung injury via oxidants/antioxidants imbalance, which is preventable by mannitol.

Topics: Acute Lung Injury; Amylases; Animals; Antioxidants; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutathione; Lipase; Lung; Male; Mannitol; Oxidative Stress; Pancreas; Pancreatic Diseases; Rats; Rats, Wistar; Reperfusion Injury; Time Factors; Xanthine Oxidase

Oxidants (and their generator, xanthine oxidase [XO]) play a role in inducing acute lung injury (ALI) expressed both structurally and functionally. Such damage has recently been demonstrated in the presence of pancreas ischemia-reperfusion (IR). We now investigated whether methylene blue (MB), a clinically used coloring agent and antioxidant in itself, protected the lung exposed to pancreas IR.. Isolated pancreata (eight replicates/group) were (1) continuously perfused (controls), (2) made ischemic (IR-0) for 40 min and reperfused without treatment, (3) organs procured from allopurinol-treated rats made ischemic and reperfused with allopurinol, and (4) made ischemic and treated upon reperfusion with three different doses of MB contained in the perfusate. All perfusate solutions were directed into the isolated lungs' circulation whereby they were perfused for 60 min.. Pancreas injury was documented in all IR organs by abnormally high reperfusion pressure, wet-to-dry ratio, amylase and lipase concentrations, and abnormal XO activity and reduced glutathione in the circulation. Lungs paired with IR-0 pancreata developed approximately 60% increase in ventilatory plateau pressure and final PO(2)/FiO(2) decrease by 35%. Their weight during reperfusion and bronchoalveolar lavage (BAL) volume and contents increased 1.5-2.5 times the normal values; XO and reduced glutathione values were abnormal both in the BAL and in the lung tissues. Lungs exposed to IR effluents containing allopurinol or 68 microM MB were minimally damaged, whereas perfusion solutions containing 42 or 128 microM MB were ineffective in preventing lung injury.. Ex vivo pancreas IR-induced ALI is preventable by MB, although at a narrow dose range.

Topics: Acute Lung Injury; Allopurinol; Amylases; Analysis of Variance; Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Glutathione; Lipase; Male; Methylene Blue; Pancreas; Probability; Pulmonary Circulation; Random Allocation; Rats; Rats, Wistar; Reperfusion Injury; Xanthine Oxidase