title: Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation.
abstract: Mechanical ventilation, through overdistension of the lung, induces substantial inflammation that is thought to increase mortality among critically ill patients. The mechanotransduction processes involved in converting lung distension into inflammation during this ventilator-induced lung injury (VILI) remain unclear, although many cell types have been shown to be involved in its pathogenesis. This study aimed to identify the profile of in vivo lung cellular activation that occurs during the initiation of VILI. This was achieved using a flow cytometry-based method to quantify the phosphorylation of several markers (p38, ERK1/2, MAPK-activated protein kinase 2, and NF-κB) of inflammatory pathway activation within individual cell types. Anesthetized C57BL/6 mice were ventilated with low (7 ml/kg), intermediate (30 ml/kg), or high (40 ml/kg) tidal volumes for 1, 5, or 15 min followed by immediate fixing and processing of the lungs. Surprisingly, the pulmonary endothelium was the cell type most responsive to in vivo high-tidal-volume ventilation, demonstrating activation within just 1 min, followed by the alveolar epithelium. Alveolar macrophages were the slowest to respond, although they still demonstrated activation within 5 min. This order of activation was specific to VILI, since intratracheal lipopolysaccharide induced a very different pattern. These results suggest that alveolar macrophages may become activated via a secondary mechanism that occurs subsequent to activation of the parenchyma and that the lung cellular activation mechanism may be different between VILI and lipopolysaccharide. Our data also demonstrate that even very short periods of high stretch can promote inflammatory activation, and, importantly, this injury may be immediately manifested within the pulmonary vasculature.
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Woods
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Alicia A C
authors.initials: AA
authors.lastname: Waite
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Kieran P
authors.initials: KP
authors.lastname: O'Dea
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Halford
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom.
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, United Kingdom michael.wilson@imperial.ac.uk.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wilson
mesh_terms: D000818:Animals; D004727:Endothelium / Q000166:cytology / Q000473:pathology; D004789:Enzyme Activation; D004848:Epithelium / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000166:cytology / Q000276:immunology; D008297:Male; D040542:Mechanotransduction, Cellular / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000473:pathology; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000401:mortality; D020545:Respiratory Mucosa / Q000166:cytology / Q000473:pathology; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000276:immunology* / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: inflammation; lipopolysaccharide; mitogen-activated protein kinase; nuclear factor-κB; ventilator-induced lung injury