title: Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury.
abstract: Lung ischemia-reperfusion (I/R) injury is a biphasic inflammatory process. Previous studies indicate that the later phase is neutrophil-dependent and that alveolar macrophages (AMs) likely contribute to the acute phase of lung I/R injury. However, the mechanism is unclear. AMs become activated and produce various cytokines and chemokines in many inflammatory responses, including transplantation. We hypothesize that AMs respond to I/R by producing key cytokines and chemokines and that depletion of AMs would reduce cytokine/chemokine expression and lung injury after I/R. To test this, using a buffer-perfused, isolated mouse lung model, we studied the impact of AM depletion by liposome-clodronate on I/R-induced lung dysfunction/injury and expression of cytokines/chemokines. I/R caused a significant increase in pulmonary artery pressure, wet-to-dry weight ratio, vascular permeability, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-2 expression, as well as decreased pulmonary compliance, when compared with sham lungs. After AM depletion, the changes in each of these parameters between I/R and sham groups were significantly attenuated. Thus AM depletion protects the lungs from I/R-induced dysfunction and injury and significantly reduces cytokine/chemokine production. Protein expression of TNF-alpha and MCP-1 are positively correlated to I/R-induced lung injury, and AMs are a major producer/initiator of TNF-alpha, MCP-1, and MIP-2. We conclude that AMs are an essential player in the initiation of acute lung I/R injury.
authors.affiliation: Department of Surgery, University of Virginia Health System, P.O. Box 801359, Charlottesville, 22908, USA. mz2v@virginia.edu
authors.forename: Minqing
authors.initials: M
authors.lastname: Zhao
authors.forename: Lucas G
authors.initials: LG
authors.lastname: Fernandez
authors.forename: Allan
authors.initials: A
authors.lastname: Doctor
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Curtis G
authors.initials: CG
authors.lastname: Tribble
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
mesh_terms: D000208:Acute Disease; D000818:Animals; D002199:Capillary Permeability / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054426:Chemokine CXCL2; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004002:Clodronic Acid / Q000494:pharmacology; D008081:Liposomes / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008170:Lung Compliance / Q000276:immunology; D016040:Lung Transplantation; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D009929:Organ Size; D011651:Pulmonary Artery / Q000276:immunology; D011669:Pulmonary Wedge Pressure / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D008081:Liposomes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid