ARDS is characterized as an acute diffuse, inflammatory lung injury, leading to increased pulmonary vascular permeability, decreased lung compliance, and loss of aerated lung tissue leading to severe perturbations in gas exchange. The classic histological finding of ARDS is diffuse alveolar damage with edema, inflammation, and hyaline membrane formation [6]. During the early, exudative stage (days 1–7), the pathology is dominated by diffuse alveolar damage, epithelial injury and apoptosis, with significant inflammatory infiltration, and disruption of the capillary and epithelial barrier function with resultant interstitial and intraalveolar edema. In the later fibroproliferative stage, fibroblast proliferation, activation and migration dominate, with type II cell hyperplasia, and fibroproliferation. Interestingly, the majority of patients have resolution of fibroproliferation and pulmonary function improves over time. One of the unanswered questions in ARDS is what determines whether lung injury resolves or progresses to end-stage fibrosis? Why does fibroproliferation in ARDS resolve, but not in other chronic fibrosing diseases such as Idiopathic Pulmonary Fibrosis?

The mainstay of treatment of ARDS remains supportive, including avoidance of iatrogenic injury. The ARDS Network trials demonstrated improved outcomes with low tidal volume mechanical ventilation [7], positive end-expiratory pressure [8], and conservative fluid management [9]. However, despite the presence of acute inflammation and role of inflammatory cells such as neutrophils [10], trials targeting the inflammatory process have failed to show definitive clinical benefit [2]. Specific therapeutics tested in clinical trials include corticosteroids, prostaglandins, nitric oxide, prostacyclin, surfactant, lisofylline, ketoconazole, N-acetylcysteine, granulocyte macrophage colony-stimulating factor, procysteine, indomethacin, simvastatin, pentoxyfilline, activated protein C and fish oil, none of which have shown a statistically significant improvement in mortality, despite promising preclinical trials in animal models [2]. Thus, new treatment options for ARDS remain a major unmet need.

Despite intense research over the past 40 years, we still have an incomplete understanding of the pathophysiology of the disease. Furthermore, treatment remains largely supportive. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair. Because ARDS is a complex syndrome with a broad clinical phenotype, it has been challenging to translate the results of cell and animal studies to pharmacologic therapies that reduce mortality in humans [11, 12]. Nevertheless, laboratory-based investigations have produced valuable insights into the mechanisms responsible for the pathogenesis and resolution of lung injury, and preclinical studies paved the way for important improvements in supportive care. Currently, the use of mesenchymal stem cells for severe ARDS (NCT01775774) is being tested in a phase 2 clinical trial for ARDS, based on promising animal studies, and in vitro and ex vivo data [13]. Understanding the appropriate uses of animal models and in vitro studies, as well as defining the pathophysiologic subtypes of acute lung injury are necessary for the field to move forward from the descriptive phase of ARDS.