HEME OXYGENASE - A NOVEL TARGET FOR THE MODULATION OF THE INFLAMMATORY RESPONSE

Chronic inflammatory diseases place a heavy social and economic burden on the resources of many nations, but the number of safe and effectiv e treatments is limited. To date, the major research effort has concen trated on those mediators responsible for the initiation and maintenan ce of the pathological process. In contrast, little attention has been focused on endogenous factors responsible for the resolution of the i nflammation. Heme oxygenase ((HO); EC 1.14.99.3) is the rate-limiting enzyme in the catabolism of heme to biliverdin (which is converted to bilirubin by biliverdin reductase), free iron and carbon monoxide (CO) , Two isoforms of HO have been characterized, the constitutive isoform , HO-2, which is the major isoform present under physiological conditi ons, and the stress-induced isoform, HO-1, which has also been classif ied as heat-shock protein 32K (ref. 1). Increases in HO activity have been implicated in tissue protection against oxidative stress(2). In t his communication, we describe the effects of modulating HO during an acute complement-dependent inflammatory response. Elevation of this en zyme resulted in a striking suppression, whereas inhibition of the enz yme led to a potentiation of the inflammatory response. Such novel enz yme modulation has application on the one hand to the treatment of inf lammatory diseases and on the other hand to immunosuppressed states in which the impaired ability to mount an adequate inflammatory response may result in death from opportunistic infections.