Acute lung injury-induced collagen deposition is associated with elevated asymmetric dimethylarginine and arginase activity

Evidence suggests that lung structure and function are partly maintained by a balance between the competing arginine-metabolizing enzymes arginase and nitric oxide (NO) synthase. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthase. It is metabolized by dimethylarginine dimethylaminohydrolase 2 (DDAH-2), which is oxidant-sensitive. The mechanism that induces excess lung collagen deposition in burned patients has not yet been explored. Our objective was to investigate the role of ADMA and the arginase pathway in acute lung injury. An ovine model for burn and smoke inhalation injury was used to assess excess lung collagen deposition. Sheep were deeply anesthetized during the injury, mechanically ventilated, resuscitated with fluid, and killed after either 2 or 3 weeks. Lungs were assessed histologically and biochemically for collagen content, arginase activity, lipid peroxidation product and antioxidant concentration, and protein concentrations. Plasma was assessed for amino acid and nitrate/nitrite concentrations. Burn and inhalation injury resulted in significantly reduced pulmonary function and increased lung collagen deposition. These physiological changes were associated with significantly increased lung arginase activity, collagen synthesis precursor ornithine aminotransferase, and ornithine decarboxylase, which is associated with cell proliferation. Significant decreases in plasma nitrate/nitrite after injury were associated with increased lung ADMA concentrations and decreased DDAH-2 expression. The decreased DDAH-2 expression was associated with significantly increased lipid peroxidation product and decreased antioxidant content in the lung. These data support that excess lung collagen deposition and reduced pulmonary function in acute lung injury after burn and inhalation injury are mediated through the arginase pathway.     

Differential metabolic impact of gastric bypass surgery versus dietary intervention in obese diabetic subjects despite identical weight loss

Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention.     

Determination of an oral aflatoxin dose that acutely impairs hepatic function in domestic pigeons (Columba livia)

Aflatoxin B1 is a common hepatotoxin in birds. The goal of this study was to establish an acute model for hepatotoxicosis and decreased hepatic function in the white Carneaux pigeon (Columba livia) via oral administration of this mycotoxin. Aflatoxin B1 was orally administered at a dose of 3 mg/kg dissolved in dimethyl sulfoxide to 3 groups of pigeons every 24 hours for 2, 4, and 6 consecutive days, respectively. Diagnostic modalities used to evaluate hepatic damage and impaired hepatic function pre- and postaflatoxin administration included liver enzyme activity, bile acid levels, scintigraphy, and histopathologic evaluation of liver biopsy specimens. Deaths occurred in all groups, increasing with the number of consecutive days the aflatoxin B1 was dosed. Significant histopathologic lesions were seen on evaluation of hepatic tissue from each group after accumulated aflatoxin exposure (P < .05); therefore, an oral aflatoxin B1 dose of 3 mg/kg given for 2 consecutive days was selected for the purpose of inducing acute hepatic damage while minimizing mortality. However, although increased liver enzyme activity indicated hepatocellular damage at this dosage, bile acids testing and hepatobiliary scintigraphy did not show significantly decreased hepatic function.