Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction

• Published in: The Journal of clinical investigation 2005-11, Vol.115 (11), p.3007-3014
• Main Authors: Nakamichi, Ikuo, Habtezion, Aida, Zhong, Bihui, Contag, Christopher H, Butcher, Eugene C, Omary, M Bishr
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Biomedical research; Cell Movement - physiology; Disease Models, Animal; Enzyme Induction; Enzymes; Female; Heme Oxygenase-1 - biosynthesis; Heme Oxygenase-1 - physiology; Hemin - physiology; Injuries; Macrophages - enzymology; Macrophages - pathology; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - pathology; Mice; Mice, Inbred BALB C; Mice, Transgenic; Pancreas; Pancreas - enzymology; Pancreas - pathology; Pancreatitis; Pancreatitis - enzymology; Pancreatitis - pathology; Proteins; Signal transduction
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci24912

Hemin upregulates heme oxygenase-1 (HO-1), a stress-induced enzyme implicated in protection from a variety of injuries while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. We show that HO-1 is induced in pancreatitis caused by caerulein and more prominently in severe pancreatitis caused by feeding a choline-deficient diet (CDD). Intraperitoneal hemin administration dramatically increases peritoneal and pancreas macrophages that overexpress HO-1 in association with pancreatic induction of the chemoattractants monocyte chemotactic protein-1 and macrophage inflammatory protein-1alpha but not RANTES or macrophage inflammatory protein-2. Hemin administration before CDD feeding protected 8 of 8 mice from lethality while 7 of 16 controls died. Protection is mediated by HO-1-overexpressing macrophages since hemin-primed macrophages home to the pancreas after transfer to naive mice and protect from CDD-induced pancreatitis. Suppression of hemin-primed peritoneal cell HO-1 using HO-1-specific small interfering RNA prior to cell transfer abolishes protection from CDD-induced pancreatitis. Similarly, hemin pretreatment in caerulein-induced pancreatitis reduces serum amylase and lipase, decreases pancreatic trypsin generation, and protects from lung injury. Therefore, hemin-like compounds or hemin-activated macrophages may offer novel therapeutic approaches for preventing acute pancreatitis and its pulmonary complication via upregulation of HO-1.