Reactive oxygen intermediates (ROI) have been implicated in the pathogenesis of inflammatory pulmonary diseases. Stimulation of phagocytic leukocytes results in production of large quantities of ROI. Superoxide (02-) is the first product of leukocyte oxygen metabolism and dismutates to form hydrogen peroxide (H202). Myeloperoxidase (MPO), an enzyme found in the granules of neutrophils and monocytes, catalyzes the oxidation of chloride (Cl-) by H202 to yield hypochlorous acid, which in turn reacts with amines, forming chloramines. These oxidants, while exerting a beneficial effect by killing microorganisms, may also have a deleterious effect by causing inflammatory tissue destruction. The long range goal of this study is to identify agents which may suppress inflammatory damage to host tissues without compromising host defense.
The specific aim i s to characterize the inhibition of leukocyte peroxidases by the sulfone compound, dapsone (4,4'-diaminodiphenyl sulfone). The antimicrobial properties of dapsone have been utilized in the treatment of leprosy and Pneumocystis carinii pneumonia. Dapsone has also proved useful as an anti-inflammatory agent in the treatment of some dermatologic diseases. Dapsone has been shown to inhibit MPO, and it has been suggested that this is the mechanism of its anti-inflammatory action. Preliminary studies suggest that inhibition of leukocyte peroxidases by dapsone is pH dependent and may be more effective at neutral pH than at acid pH. Dapsone also appears more effective as an inhibitor of eosinophil peroxidase (EPO) than of MPO. Finally, there is preliminary work suggesting a cooperative effect between dapsone and superoxide dismutase (SOD) in inhibiting MPO-mediated cytotoxicity. The pH dependence and mechanism of dapsone inhibition of MPO (EPO) will be characterized using both purified enzymes and stimulated leukocytes. Leukocyte antimicrobial activity in the presence of dapsone will be assessed with regard to both extracellular and intracellular killing. As a model of inflammatory tissue destruction, erythrocytes will be used as targets to evaluate the effect of dapsone on leukocyte cytotoxicity. Leukocyte antimicrobial activity and cytotoxicity assays will be examined in the presence of both dapsone and SOD. Dapsone inhibition will also be compared with that of similar aromatic amines, such as sulfanilamide and aminotriazole. These studies will increase understanding of the peroxidase/Cl-/H2O2 system, will elucidate the mechanism of dapsone's anti-inflammatory actions, and may suggest treatment modalities to block inflammatory tissue destruction.
| Thomas, E L; Bozeman, P M; Jefferson, M M et al. (1995) Oxidation of bromide by the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase. Formation of bromamines. J Biol Chem 270:2906-13 |
| Bozeman, P M; Learn, D B; Thomas, E L (1992) Inhibition of the human leukocyte enzymes myeloperoxidase and eosinophil peroxidase by dapsone. Biochem Pharmacol 44:553-63 |
