PEPTIDES DERIVED FROM C-REACTIVE PROTEIN INHIBIT NEUTROPHIL ALVEOLITIS

C-reactive protein (CRP) is the classic acute phase reactant in humans , with serum levels elevated up to 1000-fold after the onset of inflam mation. CRP inhibits chemotaxis of complement (C5a)-, LTB(4)-, IL-8-, and FMLP-stimulated neutrophils in vitro, and rabbits and transgenic m ice with elevated serum CRP levels exhibit diminished neutrophil infil tration and vascular permeability in models of chemotactic factor-indu ced alveolitis. To evaluate the mechanism of CRP inhibition on chemoat tractant-induced neutrophil inflammation in vivo, experiments were per formed in mice infused with peptides of human CRP shown to inhibit C5a - and FMLP-stimulated neutrophil chemotaxis in vitro. After direct tra cheal instillation of FMLP, mice previously injected via the retro-orb ital plexus with CRP peptide 77-82 or 201-206 showed significant reduc tions (up to 90%) of neutrophils in the bronchoalveolar lavage fluid c ompared with vehicle-treated mice. Both CRP peptides also significantl y (up to 55%) inhibited the increase in alveolar total protein levels, Control injections of native rabbit CRP (3 mu M) inhibited neutrophil influx by 93% and protein leak by 55% in mice intratracheally instill ed with FMLP. Despite similar levels of inhibition, approximately 10-f old more peptide by weight than native CRP was required. These data su ggest that CRP degradation products at sites of tissue injury, in part icular CRP peptides 77-82 and 201-206, are anti-inflammatory and can d iminish lung injury by a reduction in neutrophil influx and protein le akage into alveoli following FMLP-induced inflammation.