Panhematin provides a therapeutic benefit in experimental pancreatitis
| Autor: | Stephen D. Collins, Raymond Kwan, M. Bishr Omary, Eugene C. Butcher, Stephen Wanaski, David K. Stevenson, Ehsaan Akhtar, Aida Habtezion, Ronald J. Wong |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Chemokine CXCL1
medicine.medical_treatment Drug Evaluation Preclinical Mice Inbred Strains Mice Transgenic Inflammation Pharmacology Arginine Article Drug Administration Schedule Gene Expression Regulation Enzymologic Mice Downregulation and upregulation medicine Animals Pancreas Carbon Monoxide business.industry Gastroenterology medicine.disease Up-Regulation Disease Models Animal medicine.anatomical_structure Cytokine Liver Pancreatitis Acute Disease Immunology Cytokines Hemin Acute pancreatitis Female Tumor necrosis factor alpha Inflammation Mediators Pancreatic injury medicine.symptom business Heme Oxygenase-1 Spleen |
| Zdroj: | Gut. 60:671-679 |
| ISSN: | 0017-5749 |
| DOI: | 10.1136/gut.2010.217208 |
| Popis: | Background and aim Acute pancreatitis (AP) can result in pancreatic necrosis and inflammation, with subsequent multi-organ failure. AP is associated with increased neutrophil recruitment and a rise in pro-inflammatory cytokines such as TNFα. Pretreatment with haemin, results in recruitment of haem-oxygenase-1 (HO-1) + macrophages and protects against experimental pancreatitis. It is not clear whether modulation of HO-1 after onset of disease has a protective role. In this study, we tested the utility of Panhematin, a water-soluble haemin formulation, in activating and inducing pancreatic HO-1, and as a therapeutic agent in treating mouse acute pancreatitis. Methods We defined the distribution of radiolabelled haemin, then used in vivo HO-1–luciferase bioluminescence imaging and the CO-release assay to test Panhematin-induced upregulation of HO-1 transcription and activity, respectively. Using two well-defined AP murine models, we tested the therapeutic benefit of Panhematin, and quantified cytokine release using a luminex assay. Results Intravenously administered Panhematin induces rapid recruitment of HO-1 + cells to the pancreas within 2 h and de novo splenic HO-1 transcription by 12 h. Despite high baseline spleen HO-1 activity, the pancreas is particularly responsive to Panhematin-mediated HO-1 induction. Panhematin-treated mice, at various time points after AP induction had significant reduction in mortality, pancreatic injury, together with upregulation of HO-1 and downregulation of pro-inflammatory cytokines and CXCL1, a potent neutrophil chemoattractant. Conclusions Despite AP-associated mortality and morbidity, no effective treatment other than supportive care exists. We demonstrate that Panhematin leads to: (i) rapid induction and activation of pancreatic HO-1 with recruitment of HO-1 + cells to the pancreas, (ii) amelioration of AP even when given late during the course of disease, and (iii) a decrease in leucocyte infiltration and pro-inflammatory cytokines including CXCL1. The utility of Panhematin at modest doses as a therapeutic in experimental pancreatitis, coupled with its current use and safety in humans, raises the potential of its applicability to human pancreatitis. |
| Databáze: | OpenAIRE |
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