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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 5

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Protective effect of hemin-primed peritoneal cells on CDD-induced pancre...
Protective effect of hemin-primed peritoneal cells on CDD-induced pancreatitis. (A) Peritoneal cells are isolated from hemin- or vehicle-pretreated mice (3 injections indicated by arrows), then transferred i.p. into naive recipient littermates followed by immediate initiation of CDD feeding. (B–E) After 2.5 days of CDD, sera were collected to measure amylase and BUN (mean ± SD, 6 mice/group). Pancreata were also collected for gross tissue assessment and for histological staining and scoring. Scale bar: 50 μm. Vac, vacuoles; ED, edema; Hem, hemorrhage; m1 and m2, pancreatic tissues from 2 separate mice per hemin- or vehicle-pretreated group.

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