title: Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats.
abstract: The role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in the pathogenesis of acute lung injury in rats after intrapulmonary deposition of IgG immune complexes or intratracheal administration of LPS has been assessed. Critical to these studies was the cloning and functional expression of rat MIP-1 alpha. The resulting product shared 92% and 90% homology with the known murine sequence at the cDNA level and protein level, respectively. Recombinant rat MIP-1 alpha exhibited dose-dependent chemotactic activity for both rat and human monocytes and neutrophils, which could be blocked by anti-murine MIP-1 alpha Ab. Rat MIP-1 alpha mRNA and protein expression were determined as a function of time in both injury models. A time-dependent increase in MIP-1 alpha mRNA in lung extracts was observed in both models. In the LPS model, MIP-1 alpha protein could also be detected in bronchoalveolar lavage (BAL) fluids by Western blot analysis. Anti-MIP-1 alpha administered at commencement of IgG immune complex- or LPS-induced injury resulted in significant reductions in BAL neutrophils as well as in injury as measured by pulmonary vascular permeability. Under such conditions, in both models TNF-alpha content in BAL fluids was substantially reduced as compared with BAL fluids from positive control animals. These findings suggest that rat MIP-1 alpha plays an important role in the development of lung injury in these neutrophil-dependent models. The role of MIP-1 alpha seems to be related to production of TNF-alpha, which in turn up-regulates vascular adhesion molecules required for neutrophil influx.
authors.affiliation: Department of Pathology, University of Michigan Medical School, 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: H P
authors.initials: HP
authors.lastname: Friedl
authors.forename: M L
authors.initials: ML
authors.lastname: Jones
authors.forename: P A
authors.initials: PA
authors.lastname: Ward
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002199:Capillary Permeability / Q000276:immunology; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology*; D007105:Immune Complex Diseases / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins; D008297:Male; D008969:Molecular Sequence Data; D015846:Monokines / Q000494:pharmacology / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology
chemical_list: D054407:Chemokine CCL4; D016207:Cytokines; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha