title: Requirement for C-X-C chemokines (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) in IgG immune complex-induced lung injury.
abstract: The C-X-C chemokines of the IL-8 family possess potent chemotactic activity for neutrophils, but their in vivo role in inflammatory responses is not well understood. In the IgG immune complex-induced model of acute lung inflammatory injury in the rat we have evaluated the roles of two rat chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC). Both mRNA and protein for MIP-2 and CINC appeared in a time-dependent manner after initiation of IgG immune complex deposition in lung. There exists a 69% homology between the amino acid sequences for these proteins, and we found cross-reactivity between polyclonal Abs raised to these chemokines. By purifying the blocking Abs using double affinity methods (with Ag-immobilized beads), this cross-reactivity was removed. Individually, anti-MIP-2 and anti-CINC Ab significantly reduced lung injury (as measured by 125I-labeled albumin leakage from the pulmonary vasculature) and reduced neutrophil accumulation in the lung (as determined by myeloperoxidase (MPO content) and neutrophil counts in bronchoalveolar lavage (BAL) fluids); however, no change in TNF-alpha levels in BAL fluids was found. Chemotactic activity in BAL fluids collected 2 h after injury from animals undergoing immune complex deposition could be shown to be chiefly due to the combined contributions of MIP-2 (39%), CINC (28%), and C5a (21%). When either MIP-2 or CINC was blocked in vivo, up-regulation of Mac-1 expression on neutrophils obtained from BAL fluids was significantly reduced. These data suggest that, in the model studied, both MIP-2 and CINC contribute significantly to the influx of neutrophils and their activation.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor 48109, USA.
authors.forename: T P
authors.initials: TP
authors.lastname: Shanley
authors.forename: H
authors.initials: H
authors.lastname: Schmal
authors.forename: R L
authors.initials: RL
authors.lastname: Warner
authors.forename: E
authors.initials: E
authors.lastname: Schmid
authors.forename: H P
authors.initials: HP
authors.lastname: Friedl
authors.forename: P A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015936:Complement C5a / Q000502:physiology; D003429:Cross Reactions; D006133:Growth Substances / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007074:Immunoglobulin G / Q000633:toxicity*; D036341:Intercellular Signaling Peptides and Proteins; D007958:Leukocyte Count; D008168:Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D015846:Monokines / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000906:Antibodies; D000936:Antigen-Antibody Complex; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513296:Cxcl2 protein, rat; D006133:Growth Substances; D007074:Immunoglobulin G; D036341:Intercellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; D015936:Complement C5a; D009195:Peroxidase