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 inflammation. CRP inhibits chemotaxis of complement (C5a)-, LTB4-, IL-8-, and FMLP-stimulated neutrophils in vitro, and rabbits and transgenic mice with elevated serum CRP levels exhibit diminished neutrophil infiltration and vascular permeability in models of chemotactic factor-induced alveolitis. To evaluate the mechanism of CRP inhibition on chemoattractant-induced neutrophil inflammation in vivo, experiments were performed in mice infused with peptides of human CRP shown to inhibit C5a- and FMLP-stimulated neutrophil chemotaxis in vitro. After direct tracheal instillation of FMLP, mice previously injected via the retro-orbital plexus with CRP peptide 77-82 or 201-206 showed significant reductions (up to 90%) of neutrophils in the bronchoalveolar lavage fluid compared with vehicle-treated mice. Both CRP peptides also significantly (up to 55%) inhibited the increase in alveolar total protein levels. Control injections of native rabbit CRP (3 microM) inhibited neutrophil influx by 93% and protein leak by 55% in mice intratracheally instilled with FMLP. Despite similar levels of inhibition, approximately 10-fold more peptide by weight than native CRP was required. These data suggest that CRP degradation products at sites of tissue injury, in particular CRP peptides 77-82 and 201-206, are anti-inflammatory and can diminish lung injury by a reduction in neutrophil influx and protein leakage into alveoli following FMLP-induced inflammation.
Heuertz
R M
RM
Department of Medicine, Section of Pulmonary and Critical Care, University of Chicago, IL 60637, USA.
Ahmed
N
N
Webster
R O
RO
D000595:Amino Acid Sequence; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002097:C-Reactive Protein / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects*; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011817:Rabbits
D010446:Peptide Fragments; D011506:Proteins; D002097:C-Reactive Protein