title: Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine response to systemic endotoxin.
abstract: Previous animal studies have identified a role for activation of innate immunity in the pathogenesis of ventilator-associated lung injury. These studies have used large tidal volume ventilation to study the effect of alveolar overdistension on induction of inflammatory pathways. We hypothesized an alternative mechanism for the pathogenesis of lung injury in which moderate tidal volume ventilation does not independently cause clinical inflammation but rather interacts with innate immune activation by bacterial products, resulting in an enhanced inflammatory response. We measured cytokine expression and lung injury in normal and lipopolysaccharide (LPS)-treated anesthetized rabbits randomized to either spontaneous respiration or mechanical ventilation. Outcome parameters were analyzed by two-way factorial analysis of variance to identify synergism between ventilation and systemic LPS. Mechanical ventilation alone resulted in minimal cytokine expression in the lung but did enhance LPS-induced expression of tumor necrosis factor-alpha, the CXC chemokines interleukin-8 and growth-related protein-alpha, and the CC chemokine monocyte chemoattractant protein-1. Increased mRNA expression and activation of the transcription factors nuclear factor-kappaB and activator protein-1 accompanied the cytokine responses. We conclude that moderate volume ventilation strategies augment the innate immune response to bacterial products in the lung and may play a role in the development of acute lung injury in patients with sepsis.
authors.affiliation: Division of Pulmonary & Critical Care Medicine, University of Washington, Seattle 98195-6522, USA. billa@u.washington.edu
authors.forename: William A
authors.initials: WA
authors.lastname: Altemeier
authors.forename: Gustavo
authors.initials: G
authors.lastname: Matute-Bello
authors.forename: Charles W
authors.initials: CW
authors.lastname: Frevert
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Kawata
authors.forename: Osamu
authors.initials: O
authors.lastname: Kajikawa
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Martin
authors.forename: Robb W
authors.initials: RW
authors.lastname: Glenny
mesh_terms: D000418:Albumins / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D011014:Pneumonia / Q000276:immunology / Q000503:physiopathology*; D011650:Pulmonary Alveoli / Q000276:immunology / Q000503:physiopathology; D011817:Rabbits; D012121:Respiration, Artificial; D013047:Specific Pathogen-Free Organisms; D013990:Tidal Volume; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000418:Albumins; D018932:Chemokine CCL2; D019743:Chemokines, CXC; D016207:Cytokines; D016209:Interleukin-8; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha