Dataset Information

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

ABSTRACT: RATIONALE: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. OBJECTIVE:To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS. METHODS: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. RESULTS: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 ? 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. CONCLUSIONS: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. TRIAL REGISTRATION NUMBER:NCT01659307 Results.

SUBMITTER: Hamid U

PROVIDER: S-EPMC5858553 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

Hamid U U Krasnodembskaya A A Fitzgerald M M Shyamsundar M M Kissenpfennig A A Scott C C Lefrancais E E Looney M R MR Verghis R R Scott J J Simpson A J AJ McNamee J J McAuley D F DF O'Kane C M CM

Thorax 20170112 11

<h4>Rationale</h4>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.<h4>Objective</h4>To test the hypothesis that aspirin reduces inflammation in clinically relevant human models that recapitulate pathophysiological mechanisms implicated in the development of ARDS.<h4>Methods</h4>Healthy volunteers were randomised to receive plac ...[more]

PMID: 28082531

Similar Datasets

Project description:Acute respiratory distress syndrome (ARDS) is a common destructive syndrome with high morbidity and mortality rates. Currently, few effective therapeutic interventions for ARDS are available. Clinical trials have shown that the effectiveness of aspirin is inconsistent. The contribution of platelets to the inflammatory response leading to the development of ARDS is increasingly recognized. The antiplatelet agent aspirin reportedly exerts a protective effect on acid- and hyperoxia-induced lung injury in murine models. Our previous study showed that pretreatment with aspirin exerts protective effects on hyperoxia-induced lung injury in mice. However, the mechanisms and therapeutic efficacy of aspirin in the posttreatment of hyperoxia-induced acute lung injury (ALI) remain unclear. In this study, we used a homozygous NF-κB-luciferase+/+ transgenic mouse model and treated mice with low-dose (25 μg/g) or high-dose (50 μg/g) aspirin at 0, 24, and 48 h after exposure to hyperoxia (inspired oxygen fraction (FiO2) > 95%). Hyperoxia-induced lung injury significantly increased the activation of NF-κB in the lung and increased the levels of macrophages infiltrating the lung and reactive oxygen species (ROS), increased the HO-1, NF-κB, TNF-α, IL-1β, and IL-4 protein levels, and reduced the CC10, SPC, eNOS, Nrp-1, and IκBα protein levels in the lung tissue. Pulmonary edema and alveolar infiltration of neutrophils were also observed in the lung tissue of mice exposed to hyperoxia. However, in vivo imaging revealed that posttreatment with aspirin reduced luciferase expression, suggesting that aspirin might reduce NF-κB activation. Posttreatment with aspirin also reduced hyperoxia-induced increases in the numbers of lung macrophages, intracellular ROS levels, and the expression of TNF-α, IL-1β, and IL-4; it also increased CC10, SPC and Nrp-1 levels compared with hyperoxia exposure alone. Lung histopathology also indicated that the aspirin posttreatment significantly reduced neutrophil infiltration and lung edema compared with hyperoxia exposure alone. Aspirin effectively induces an anti-inflammatory response in a model of hyperoxia-induced lung injury. Thus, aspirin may have potential as a novel treatment for hyperoxia-induced ALI.

Project description:ObjectivesSevoflurane is identified as an effective candidate drug for acute lung injury (ALI) treatment, but its curing effects and detailed mechanisms have not been fully disclosed. The present study was designed to resolve this academic issue.MethodsThe ALI mice models were established, and Hematoxylin-eosin staining assay was performed to examine tissue morphologies. Cell viability was determined by CCK-8 assay, and Annexin V-FITC/PI double staining assay was used to examine cell apoptosis. The expression levels of proteins were determined by performing Western Blot analysis and immunofluorescence staining assay. ROS levels were examined by using DCFH-DA staining assay.ResultsIn this study, we investigated this issue and the ALI models were respectively established by treating the BALB/c mice and the murine macrophage cell line RAW264.7 with different concentrations of lipopolysaccharide (LPS) in vivo and in vitro, which were subsequently subjected to sevoflurane co-treatment. The results showed that sevoflurane reduced LPS-induced ALI in mice and suppressed LPS-triggered oxidative stress and apoptotic cell death in the RAW264.7 cells. Interestingly, we evidenced that the elimination of reactive oxygen species (ROS) by N-acetyl-L-cysteine (NAC) reversed LPS-induced cell apoptosis in RAW264.7 cells. Then, we verified that sevoflurane suppressed oxidative damages to restrain LPS-induced apoptotic cell death in the RAW264.7 cells through activating the anti-oxidant Keap1/Nrf2 pathway. Mechanistically, sevoflurane down-regulated Keap1 and upregulated Nrf2 in nucleus to activate the downstream anti-oxidant signaling cascades, which further ameliorated LPS-induced cell apoptosis and lung injury by eliminating oxidative damages.DiscussionTaken together, our study illustrated that the sevoflurane attenuates LPS-induced ALI by inhibiting oxidative stress-mediated apoptotic cell death and inflammation, and the Keap1/Nrf2 pathway played an important role in this process.

Project description:The acute respiratory distress syndrome (ARDS) is a life-threating disorder that contributes significantly to critical illness. No specific pharmacological interventions directed at lung injury itself have proven effective in improving outcome of patients with ARDS. Platelet activation was identified as a key component in ARDS pathophysiology and may provide an opportunity for preventive and therapeutic strategies. We hypothesize that use of acetyl salicylic acid (ASA) may prevent and/or attenuate lung injury.We conducted a systematic review of preclinical studies and meta-analysis of clinical studies investigating the efficacy of ASA in the setting of lung injury. Medline, embase, and cochrane databases were searched.The literature search yielded 1,314 unique articles. Fifteen preclinical studies and eight clinical studies fulfilled the in- and exclusion criteria. In the animal studies, the overall effect of ASA was positive, e.g., ASA improved survival and attenuated inflammation and pulmonary edema. Mechanisms of actions involved, among others, are interference with the neutrophil-platelets interaction, reduction of leukotrienes, neutrophil extracellular traps, and prostaglandins. High-dose ASA may be the drug of choice. A meta-analysis of three clinical studies showed an association between ASA use and a reduced incidence of ARDS (OR 0.59, 95% CI 0.36-0.98), albeit with substantial between-study heterogeneity. All studies had their own shortcomings in methodological quality.This systematic review of preclinical studies and meta-analysis of clinical studies suggests a beneficial role for ASA in ARDS prevention and treatment. However, the currently available data is insufficient to justify an indication for ASA in ARDS. The body of literature does support further studies in humans. We suggest clinical trials in which the mechanisms of action of ASA in lung injury models are being evaluated to guide optimal timing and dose, before prospective randomized trials.

Dataset Information

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

Publications

Aspirin reduces lipopolysaccharide-induced pulmonary inflammation in human models of ARDS.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets