Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase

Various pathologic conditions, such as hemorrhage, hemolysis and cell injur y, are characterized by the release of large amounts of heme. Recently, it was demonstrated that heme oxygenase (HO), the heme-degrading enzyme, and h eme are able to modulate adhesion molecule expression in vitro. In the pres ent study, the effects of heme and HO on inflammation in mice were analyzed by monitoring the biodistribution of radiolabeled liposomes and leukocytes in conjunction with immunohistochemistry. Small liposomes accumulate in in flamed tissues by diffusion because of locally enhanced vascular permeabili ty, whereas leukocytes actively mi-grate into inflammatory areas through sp ecific adhesive interactions with the endothelium and chemotaxis. Exposure to heme resulted in a dramatic increase in liposome accumulation in the pan creas, but also intestines, liver, and spleen exhibited significantly incre ased vascular permeability. Similarly, intravenously administered heme caus ed an enhanced influx of radiolabeled leukocytes into these organs. Immunoh istochemical analysis showed differential up-regulation of the adhesion mol ecules ICAM-1, P-selectin, and fibronectin in liver and pancreas in heme-tr eated animals. Heme-induced adhesive properties were accompanied by a massi ve influx of granulocytes into these inflamed tissues, suggesting an import ant contribution to the pathogenesis of inflammatory processes. Moreover, i nhibition of HO activity exacerbated heme-induced granulocyte infiltration. Here it is demonstrated for the first time that heme induces increased vas cular permeability, adhesion molecule expression, and leukocyte recruitment in vivo, whereas HO antagonizes heme-induced inflammation possibly through the down-modulation of adhesion molecules. (C) 2001 by The American Societ y of Hematology.