title: Analysis of monocyte chemoattractant protein 1-mediated lung injury using rat lung organ cultures.
abstract: Using a rat lung organ culture system, we analyzed the role of monocyte chemoattractant protein 1 (MCP 1) in leukocyte to lung adhesive interactions and monocyte-mediated lung injury. Quantitative leukocyte to lung adhesive interactions were examined using an adaptation of the Woodruff-Stamper frozen section binding assay. Pretreatment of organ cultures with recombinant human tumor necrosis factor (rhTNF alpha) resulted in a protein synthesis-dependent increase in the adhesiveness of lung tissue for peripheral blood monocytes. Adhesion of monocytes to lung tissue was not increased above baseline after 7 hours but increased more than twofold by 24 hours and persisted through 48 hours. Binding of monocyte to lung tissue was further increased when recombinant rat MCP 1 was added to monocyte suspensions immediately before being layered onto lung sections derived from either TNF alpha-treated or untreated organ cultures. Addition of antibody directed against rat CD11b/c resulted in a moderate reduction in monocyte binding. TNF or lipopolysaccharide-induced activation of mononuclear cells in the presence of [3H]leucine-labeled organ cultures resulted in lung injury as assessed by radioisotope release. Mononuclear cell-mediated organ culture injury could be partially inhibited with anti-rat MCP 1 antibody, anti-rat CD11b/c antibody, or antioxidants including catalase and deferoxamine. Anti-MCP 1 and anti-CD11b/c increased the absolute numbers of monocytes that could be retrieved from monocyte-lung co-cultures while catalase and deferoxamine did not. In vitro studies revealed that isolated rat peripheral blood monocytes produce O2- in response to MCP 1. These data provide a functional correlate for recent in vitro studies which suggest that MCP 1 may mediate leukocyte adhesive processes by up-regulating beta 2 integrin expression on monocytes. This study provides evidence that monocytes activated by MCP 1 can damage lung tissue through an oxidant-mediated mechanism. Monocyte chemoattractant protein 1 may participate in the pathogenesis of monocyte-mediated lung injury by modulating inflammatory cell adhesion as well as through monocyte activation.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602.
authors.forename: J S
authors.initials: JS
authors.lastname: Warren
authors.forename: M L
authors.initials: ML
authors.lastname: Jones
authors.forename: C M
authors.initials: CM
authors.lastname: Flory
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018845:CD11 Antigens; D002374:Catalase / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D018932:Chemokine CCL2; D002630:Chemotactic Factors / Q000032:analysis* / Q000502:physiology; D003676:Deferoxamine / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009000:Monocytes / Q000502:physiology; D009924:Organ Culture Techniques; D016877:Oxidants / Q000378:metabolism; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D018845:CD11 Antigens; D018932:Chemokine CCL2; D002630:Chemotactic Factors; D016877:Oxidants; D014409:Tumor Necrosis Factor-alpha; D002374:Catalase; D003676:Deferoxamine