Kinin System Activation in Vasculitis
Sammanfattning: The kinin system is activated when high-molecular-weight kininogen (HK) is cleaved by plasma kallikrein thus generating bradykinin. Bradykinin is a potent proinflammatory peptide that induces plasma leakage, blood pressure drop, liberation of inflammatory cytokines and pain. Vasculitis is an autoimmune systemic inflammatory disease, characterized by leukocyte inflammation in and around vessel walls leading to perturbed vessel patency and tissue damage. Many different organs may be afflicted but most commonly the kidney, respiratory tract and skin are involved. Some patients with severe vasculitis have circulating antibodies against neutrophil enzymes called anti-neutrophil-cytoplasmic antibodies (ANCAs). Theoretically kinin system activation may explain some of the inflammation seen during vasculitis. In this thesis we demonstrate, for the first time, activation of the kinin system in patients with vasculitis. Elevated kinin levels were demonstrated in the circulation and kinins were detected at sites of inflammation. We also found that neutrophil-derived proteinase 3 (PR3) cleaves HK liberating a novel vasoactive kinin, termed PR3-kinin. PR3-kinin binds to and activates kinin B1-receptors both in vitro and in vivo. In addition, PR3-ANCAs from patients with vasculitides inhibit PR3-induced HK proteolysis and subsequent PR3-kinin release. In the MRLlpr/lpr mouse, that develops systemic inflammation and vasculitis, we demonstrate B1-receptor upregulation both systemically, on circulating leukocyte-derived microparticles (MPs), and locally, in the renal vasculitic lesions. In conclusion, we demonstrate kinin system activation in vasculitis and suggest that it may partake in the pathogenesis of this inflammatory condition. We therefore propose that inhibiting kinin system activation by blockage of B1-receptors may prove to be effective by reducing the inflammatory response during vasculitis.
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