Acute respiratory distress syndrome (ARDS) is a devastating condition characterized by severe hypoxemia, the accumulation of noncardiogenic pulmonary edema, and lung inflammation. ARDS affects. 10% of all patients admitted to ICUs worldwide, and 35–45% of these patients die (1), predominantly of multiorgan failure. Survivors of ARDS are often left with significant long-term morbidities, and the healthcare costs associated with ARDS even 3–5 years after diagnosis match those of chronic conditions such as cardiac failure and chronic obstructive pulmonary disease (COPD)(2). Despite decades of research and many clinical trials, there remains no effective pharmacotherapy for ARDS. Patients with neutropenia illustrate only too well the critical role of neutrophils in the defense of the host against invading microbes. However, although neutrophils are the “first responders” of the innate immune system, dysregulated neutrophilic inflammation occurs in a variety of acute and chronic lung conditions, including ARDS, COPD, bronchiectasis, and some subtypes of asthma (3). Neutrophils have long been recognized as key cells in the pathogenesis of ARDS, with clinical studies showing that neutrophil accumulation within the pulmonary vasculature occurs early in the evolution of the condition (4), and neutrophilic alveolitis is a histological hallmark (5). Neutrophilia is common in the BAL fluid of patients with ARDS (6), and the extent correlates with clinical outcome (7). Experiments using ex vivo neutrophils have shown marked alterations in the phenotype and function of cells obtained from the blood and alveolar compartments of patients with ARDS, including reduced rates of constitutive apoptosis (8, 9).

Neutrophils rely almost exclusively on anaerobic glycolysis for the generation of ATP and are therefore exquisitely adapted to undertake their functions in hypoxic environments (10). However, hypoxia has been shown to have marked effects on neutrophil function, including prolonging the lifespan (reducing apoptosis), enhancing degranulation, and impairing reactive oxygen species generation and oxidase-dependent killing of organisms such as Staphylococcus aureus (11). The effect of hypoxia on neutrophil survival has been shown to be mediated via stabilization of the transcription factor HIF-1a (hypoxia-inducible factor-1a), which