T1 Aspirin reduces pulmonary inflammation in an inhaled lipopolysaccharide model of acute respiratory distress syndrome (ARDS) in healthy volunteers and in a human ex vivo lung perfusion model of ARDS

Introduction Platelet activation may play a role in the pathogenesis of ARDS. 1 Animal studies have shown that aspirin therapy reduces pulmonary oedema and development of lung injury. 2 Our recent observational study has shown patients with ARDS on aspirin had a reduced risk of death. 3 Objective To test the hypothesis that aspirin reduces pulmonary inflammation in clinically relevant models of ARDS induced by inhaled lipopolysaccharide (LPS). Methods Healthy subjects were enrolled in a double-blind, placebo-controlled, allocation concealed study and were randomised to receive aspirin 75 mg or aspirin 1200 mg or placebo (1:1:1) for seven days prior to LPS inhalation. Measurements were performed in bronchoalveolar lavage (BAL) fluid obtained at 6 h after inhaling 50 micrograms of LPS. Parallel experiments were run in an ex vivo lung perfusion model (EVLP) using human lungs to determine the effects of aspirin on inflammatory cytokine production and BAL neutrophils in response to intra-bronchial administration of LPS (6 mg). Results 33 healthy volunteers were enrolled. There was no significant difference between aspirin 75 mg and aspirin 1200 mg. Data for both aspirin groups were combined as per the a priori analysis plan. Aspirin pre-treatment reduced LPS-induced BAL neutrophilia (Figure 1a), MMP-9 (33 ng/ml vs 48 ng/ml, p = 0.03), the neutrophil-specific protease MMP-8 (3 ng/ml vs 6 ng/ml, p = 0.03) and the pro-inflammatory cytokine TNF-α (80 pg/ml vs 106 pg/ml, p = 0.02). There was also a non-significant trend towards reduction in a range of inflammatory cytokines (IL-1 β, IL-8 and IL-6). Pre-treatment with aspirin in the EVLP model also showed a similar reduction in BAL neutrophilia (Figure 1b), along with a trend towards reduction in pro-inflammatory cytokines (IL-8, IL-6, TNF-α, MCP-1). Conclusion This is the first data to find that aspirin can reduce neutrophilic inflammation in both these models of ARDS. Further clinical studies are planned to assess the role of aspirin in ARDS. References Kuebler WM. J Clin Invest . 2006 Dec;116(12):3106–8 Looney MR et al . J Clin Invest . 2009;119(11): 3450–61 Boyle A et al . Thorax 2013;68:Suppl 3 A142–A143