title: Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.
abstract: Platelets play an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). Animal and observational studies have shown aspirin's antiplatelet and immunomodulatory effects may be beneficial in ARDS.
  
  
  
  To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS.
  
  
  
  Healthy volunteers were randomised to receive placebo or aspirin 75  or 1200 mg (1:1:1) for seven days prior to lipopolysaccharide (LPS) inhalation, in a double-blind, placebo-controlled, allocation-concealed study. Bronchoalveolar lavage (BAL) was performed 6 hours after inhaling 50 µg of LPS. The primary outcome measure was BAL IL-8. Secondary outcome measures included markers of alveolar inflammation (BAL neutrophils, cytokines, neutrophil proteases), alveolar epithelial cell injury, systemic inflammation (neutrophils and plasma C-reactive protein (CRP)) and platelet activation (thromboxane B2, TXB2). Human lungs, perfused and ventilated ex vivo (EVLP) were randomised to placebo or 24 mg aspirin and injured with LPS. BAL was carried out 4 hours later. Inflammation was assessed by BAL differential cell counts and histological changes.
  
  
  
  In the healthy volunteer (n=33) model, data for the aspirin groups were combined. Aspirin did not reduce BAL IL-8. However, aspirin reduced pulmonary neutrophilia and tissue damaging neutrophil proteases (Matrix Metalloproteinase (MMP)-8/-9), reduced BAL concentrations of tumour necrosis factor α and reduced systemic and pulmonary TXB2. There was no difference between high-dose and low-dose aspirin. In the EVLP model, aspirin reduced BAL neutrophilia and alveolar injury as measured by histological damage.
  
  
  
  These are the first prospective human data indicating that aspirin inhibits pulmonary neutrophilic inflammation, at both low and high doses. Further clinical studies are indicated to assess the role of aspirin in the prevention and treatment of ARDS.
  
  
  
  NCT01659307 Results.
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: U
authors.initials: U
authors.lastname: Hamid
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: A
authors.initials: A
authors.lastname: Krasnodembskaya
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: M
authors.initials: M
authors.lastname: Fitzgerald
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: M
authors.initials: M
authors.lastname: Shyamsundar
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kissenpfennig
authors.affiliation: School of Pharmacy, Queen's University of Belfast, Belfast, Northern Ireland, UK.
authors.forename: C
authors.initials: C
authors.lastname: Scott
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lefrancais
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, California, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Looney
authors.affiliation: Northern Ireland Clinical Trials Unit, Royal Victoria Hospital, Belfast, UK.
authors.forename: R
authors.initials: R
authors.lastname: Verghis
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle-upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Scott
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle-upon Tyne, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Simpson
authors.affiliation: Regional Intensive Care Unit, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: J
authors.initials: J
authors.lastname: McNamee
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.|Regional Intensive Care Unit, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, UK.
authors.forename: D F
authors.initials: DF
authors.lastname: McAuley
authors.affiliation: Centre for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Northern Ireland, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: O'Kane
mesh_terms: D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D018893:Bronchoalveolar Lavage; D002097:C-Reactive Protein / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D001239:Inhalation; D016209:Interleukin-8 / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D008297:Male; D009504:Neutrophils / Q000276:immunology; D011446:Prospective Studies; D012128:Respiratory Distress Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D016896:Treatment Outcome; D014838:Volunteers
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D016207:Cytokines; D016209:Interleukin-8; D008070:Lipopolysaccharides; D002097:C-Reactive Protein; D001241:Aspirin
keywords: ARDS; Innate Immunity; Neutrophil Biology