title: Synergy between acid and endotoxin in an experimental model of aspiration-related lung injury progression.
abstract: Aspiration is a common cause of lung injury, but it is unclear why some cases are self-limited while others progress to acute respiratory distress syndrome (ARDS). Sporadic exposure to more than one insult could account for this variable progression. We investigated whether synergy between airway acid and endotoxin (LPS) amplifies injury severity in mice and whether LPS levels in human patients could corroborate our experimental findings. C57BL/6 mice aspirated acid (pH 1.3) or normal saline (NS), followed by LPS aerosol or nothing. Bronchoalveolar lavage fluid (BALF) was obtained 2 to 49 h later. Mice were injected with FITC-dextran 25 h after aspiration and connected to a ventilator, and lung elastance (H) measured periodically following deep inflation (DI). Endotracheal and gastric aspirates were also collected from patients in the intensive care unit and assayed for pH and LPS. Lung instability (ΔH following DI) and pressure-volume hysteresis in acid- or LPS-exposed mice was greater than in controls but markedly greater in the combined acid/LPS group. BALF neutrophils, cytokines, protein, and FITC-dextran in the acid/LPS mice were geometrically higher than all other groups. BALF from acid-only mice markedly amplified LPS-induced TNF-α production in cultured macrophages. Human subjects had variable endotracheal LPS levels with the highest burden in those at higher risk of aspiration. Acid aspiration amplifies LPS signaling in mice to disrupt barrier function and lung mechanics in synergy. High variation in airway LPS and greater airway LPS burden in patients at higher risk of aspiration could help explain the sporadic progression of aspiration to ARDS.
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont; Siberian State Medical University, Tomsk, Russia; and.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Tetenev
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont;
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cloutier
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont;
authors.forename: Jessica A
authors.initials: JA
authors.lastname: von Reyn
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ather
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont;
authors.forename: James
authors.initials: J
authors.lastname: Candon
authors.affiliation: Vermont Lung Center, Department of Medicine, University of Vermont, Burlington, Vermont; Department of Medicine, University of Vermont Medical Center, Burlington, Vermont Gil.Allen@uvm.edu.
authors.forename: Gilman B
authors.initials: GB
authors.lastname: Allen
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D011015:Pneumonia, Aspiration / Q000276:immunology* / Q000378:metabolism; D013270:Stomach / Q000276:immunology; D014132:Trachea / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides
keywords: ARDS; acid aspiration; acute lung injury; endotoxin; forced oscillations; lung mechanics; respiratory impedance