title: Pancreatic ascites hemoglobin contributes to the systemic response in acute pancreatitis.
abstract: Upon hemolysis extracellular hemoglobin causes oxidative stress and cytotoxicity due to its peroxidase activity. Extracellular hemoglobin may release free hemin, which increases vascular permeability, leukocyte recruitment, and adhesion molecule expression. Pancreatitis-associated ascitic fluid is reddish and may contain extracellular hemoglobin. Our aim has been to determine the role of extracellular hemoglobin in the local and systemic inflammatory response during severe acute pancreatitis in rats. To this end we studied taurocholate-induced necrotizing pancreatitis in rats. First, extracellular hemoglobin in ascites and plasma was quantified and the hemolytic action of ascitic fluid was tested. Second, we assessed whether peritoneal lavage prevented the increase in extracellular hemoglobin in plasma during pancreatitis. Third, hemoglobin was purified from rat erythrocytes and administered intraperitoneally to assess the local and systemic effects of ascitic-associated extracellular hemoglobin during acute pancreatitis. Extracellular hemoglobin and hemin levels markedly increased in ascitic fluid and plasma during necrotizing pancreatitis. Peroxidase activity was very high in ascites. The peritoneal lavage abrogated the increase in extracellular hemoglobin in plasma. The administration of extracellular hemoglobin enhanced ascites; dramatically increased abdominal fat necrosis; upregulated tumor necrosis factor-α, interleukin-1β, and interleukin-6 gene expression; and decreased expression of interleukin-10 in abdominal adipose tissue during pancreatitis. Extracellular hemoglobin enhanced the gene expression and protein levels of vascular endothelial growth factor (VEGF) and other hypoxia-inducible factor-related genes in the lung. Extracellular hemoglobin also increased myeloperoxidase activity in the lung. In conclusion, extracellular hemoglobin contributes to the inflammatory response in severe acute pancreatitis through abdominal fat necrosis and inflammation and by increasing VEGF and leukocyte infiltration into the lung.
authors.affiliation: Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot, Valencia, Spain.
authors.forename: Salvador
authors.initials: S
authors.lastname: Pérez
authors.affiliation: Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Pereda
authors.affiliation: Department of Surgery, University of Valencia, University Clinic Hospital, 46010 Valencia, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Sabater
authors.affiliation: Department of Physiology, School of Pharmacy, University of Valencia, 46100 Burjasot, Valencia, Spain. Electronic address: juan.sastre@uv.es.
authors.forename: Juan
authors.initials: J
authors.lastname: Sastre
mesh_terms: D050153:Abdominal Fat / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001201:Ascites / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001202:Ascitic Fluid / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006454:Hemoglobins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008297:Male; D009336:Necrosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010533:Peritoneal Lavage; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013656:Taurocholic Acid; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D006454:Hemoglobins; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D016753:Interleukin-10; D013656:Taurocholic Acid; D009195:Peroxidase
keywords: Acute pancreatitis; Cytokines; Extracellular hemoglobin; Free radicals; Inflammation; Oxidative stress