A new small molecule C5a receptor antagonist inhibits the reverse-passive arthus reaction and endotoxic shock in rats

C5a is implicated as a pathogenic factor in a wide range of immunoinflammat ory diseases, including sepsis and immune complex disease, Agents that anta gonize the effects of C5a could be useful in these diseases. We have develo ped some novel C5a antagonists and have determined the acute anti-inflammat ory properties of a new small molecule C5a receptor antagonist against C5a- and LPS-induced neutrophil adhesion and cytokine expression, as well as ag ainst some hallmarks of the reverse Arthus reaction in rats. We found that a single i.v. dose (1 mg/kg) of this antagonist inhibited both C5a- and LPS -induced neutropenia and elevated levels of circulating TNF-alpha, as well as polymorphonuclear leukocyte migration, increased TNF-alpha levels and va scular leakage at the site of immune complex deposition. These results indi cate potent anti-inflammatory activities of a new C5a receptor antagonist a nd provide more evidence for a key early role for C5a in sepsis and the rev erse Arthus reaction. The results support a role for antagonists of C5a rec eptors in the therapeutic intervention of immunoinflammatory disease states such as sepsis and immune complex disease.