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Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction
Ikuo Nakamichi, … , Eugene C. Butcher, M. Bishr Omary
Ikuo Nakamichi, … , Eugene C. Butcher, M. Bishr Omary
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3007-3014. https://doi.org/10.1172/JCI24912.
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Research Article Cell biology

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

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Abstract

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-1α 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.

Authors

Ikuo Nakamichi, Aida Habtezion, Bihui Zhong, Christopher H. Contag, Eugene C. Butcher, M. Bishr Omary

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Figure 1

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Effect of hemin or pancreatic injury on HO-1 induction and inhibition of...
Effect of hemin or pancreatic injury on HO-1 induction and inhibition of pancreatic injury by hemin. (A and B) Total tissue homogenates were obtained from pancreata of caerulein-injected (cae-injected) or CDD-fed mice. Two age- and sex-matched mice were used for each time point. Homogenates were tested by blotting, using antibodies to HO-1 or HO-2. (C) Mice (3 mice/condition) were given hemin (H) by i.p. injection (4 times during 1 week or 8 times during 2 weeks). Two control (Co) mice were injected with vehicle alone. Pancreatic homogenates were then obtained and blotted with anti–HO-1 and anti–HO-2. (D–G) Mice were injected with saline (S), hemin, or vehicle (V) (8 mice/group) 3 times (arrows) followed by feeding with CDD for 3 days, then harvesting of the pancreata. HO-1 and HO-2 were analyzed by blotting of pancreatic homogenates (3 mice/group). The number of mice that died in each cohort of 8 mice is shown, and the survival difference was significant (P < 0.03) when comparing controls (saline and vehicle) with hemin-injected mice. Representative H&E stainings of pancreata from mice that survived CDD feeding are shown. Scale bar: 50 μm. Note the marked pancreas edema (ED) and necrosis (N) in the saline- (not shown) and vehicle-injected mice as compared with the hemin group.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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