Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction.
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.
Nakamichi
Ikuo
I
Department of Medicine, VA Palo Alto Health Care System, Palo Alto, California, USA.
Habtezion
Aida
A
Zhong
Bihui
B
Contag
Christopher H
CH
Butcher
Eugene C
EC
Omary
M Bishr
MB
D000208:Acute Disease; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D004790:Enzyme Induction; D005260:Female; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000502:physiology; D006427:Hemin / Q000502:physiology*; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010179:Pancreas / Q000201:enzymology* / Q000473:pathology*; D010195:Pancreatitis / Q000201:enzymology* / Q000473:pathology*
D006427:Hemin; D051547:Heme Oxygenase-1