title: Blunt Chest Trauma in Mice after Cigarette Smoke-Exposure: Effects of Mechanical Ventilation with 100% O2.
abstract: Cigarette smoking (CS) aggravates post-traumatic acute lung injury and increases ventilator-induced lung injury due to more severe tissue inflammation and apoptosis. Hyper-inflammation after chest trauma is due to the physical damage, the drop in alveolar PO2, and the consecutive hypoxemia and tissue hypoxia. Therefore, we tested the hypotheses that 1) CS exposure prior to blunt chest trauma causes more severe post-traumatic inflammation and thereby aggravates lung injury, and that 2) hyperoxia may attenuate this effect. Immediately after blast wave-induced blunt chest trauma, mice (n=32) with or without 3-4 weeks of CS exposure underwent 4 hours of pressure-controlled, thoraco-pulmonary compliance-titrated, lung-protective mechanical ventilation with air or 100% O2. Hemodynamics, lung mechanics, gas exchange, and acid-base status were measured together with blood and tissue cytokine and chemokine concentrations, heme oxygenase-1 (HO-1), activated caspase-3, and hypoxia-inducible factor 1-α (HIF-1α) expression, nuclear factor-κB (NF-κB) activation, nitrotyrosine formation, purinergic receptor 2X4 (P2XR4) and 2X7 (P2XR7) expression, and histological scoring. CS exposure prior to chest trauma lead to higher pulmonary compliance and lower PaO2 and Horovitz-index, associated with increased tissue IL-18 and blood MCP-1 concentrations, a 2-4-fold higher inflammatory cell infiltration, and more pronounced alveolar membrane thickening. This effect coincided with increased activated caspase-3, nitrotyrosine, P2XR4, and P2XR7 expression, NF-κB activation, and reduced HIF-1α expression. Hyperoxia did not further affect lung mechanics, gas exchange, pulmonary and systemic cytokine and chemokine concentrations, or histological scoring, except for some patchy alveolar edema in CS exposed mice. However, hyperoxia attenuated tissue HIF-1α, nitrotyrosine, P2XR7, and P2XR4 expression, while it increased HO-1 formation in CS exposed mice. Overall, CS exposure aggravated post-traumatic inflammation, nitrosative stress and thereby organ dysfunction and injury; short-term, lung-protective, hyperoxic mechanical ventilation have no major beneficial effect despite attenuation of nitrosative stress, possibly due to compensation of by regional alveolar hypoxia and/or consecutive hypoxemia, resulting in down-regulation of HIF-1α expression.
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany; Klinik für Anästhesiologie, Universitätsklinikum, Ulm, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gröger
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany.
authors.forename: Oscar
authors.initials: O
authors.lastname: McCook
authors.affiliation: Institut für Pathologie, Universitätsklinikum, Ulm, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Scheuerle
authors.affiliation: Laboratoire HIFIH, UPRES EA 3859, PRES l'UNAM, IFR 132, CNRS UMR 6214, INSERM U1083, Université Angers, Département de Réanimation Médicale et de Médecine Hyperbare, Centre Hospitalier Universitaire, Angers, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Asfar
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Stahl
authors.affiliation: Klinik für Unfall-, Hand-, Plastische und Wiederherstellungschirurgie, Universitätsklinikum, Ulm, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Huber-Lang
authors.affiliation: Institut für Unfallchirurgische Forschung und Biomechanik, Universitätsklinikum, Ulm, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
authors.affiliation: Abteilung Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Jung
authors.affiliation: Abteilung Respiratory Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach/Riss, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Duechs
authors.affiliation: Institut für Pathologie, Universitätsklinikum, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Möller
authors.affiliation: Klinik für Anästhesiologie, Universitätsklinikum, Ulm, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Georgieff
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Calzia
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Radermacher
authors.affiliation: Institut für Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Ulm, Germany; Klinik für Anästhesiologie, Universitätsklinikum, Ulm, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Wagner
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018496:Hyperoxia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D026361:Reactive Nitrogen Species / Q000378:metabolism; D058469:Receptors, Purinergic P2X / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D013898:Thoracic Injuries / Q000150:complications* / Q000503:physiopathology / Q000628:therapy*; D014949:Wounds, Nonpenetrating / Q000150:complications* / Q000503:physiopathology / Q000628:therapy*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026361:Reactive Nitrogen Species; D058469:Receptors, Purinergic P2X