Respiratory diseasesAcute lung injury and acute respiratory distress syndrome: mechanisms and potential new therapies
Section Editor:
David Rodman—University of Colorado Health Sciences Center, Denver, CO, USA
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are serious and relatively common lung disorders. Lorraine Ware's research interests include the role of the alveolar epithelium in the pathogenesis and resolution of ALI. Here, she and her colleague Julie B. Prudhomme review what is known about the mechanisms underlying ALI and ARDS, and how understanding these mechanisms is revealing potential targets for novel therapeutics.
Introduction
Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are common and devastating clinical problems affecting 25–50 people per 100,000 per year, with a mortality rate of 30–50%. ALI and/or ARDS can occur following various insults including those that injure the lung either directly or indirectly (Box 1). To date, no pharmacologic treatments specifically target ALI, despite an extensive search for such therapies (Box 2). Enthusiasm for possible treatments has been renewed recently with the publication of the NIH ARDS Network study of a lung protective ventilation strategy, the first time a therapy has been shown to reduce mortality in patients with ALI or ARDS [1]. Likewise, activated protein C (drotecogin alfa activated) has been shown to reduce mortality in patients with severe sepsis, many of whom also had ALI or ARDS [2]. Hopefully, as our knowledge of the mechanisms responsible for these disorders grow, so will our potential for beneficial pharmacologic therapies.
Section snippets
Clinical, radiographic, and pathologic findings
The syndromes of ALI and ARDS are characterized by the acute onset of hypoxemia and bilateral infiltrates on chest radiograph; there is rapid progression to acute respiratory failure usually requiring intubation and mechanical ventilation. Pathologic findings include diffuse alveolar damage with protein-rich edema fluid filling the alveolar spaces, neutrophilic inflammation and deposition of intra-alveolar fibrin [3]. Patients who recover from their illness have slow resolution of hypoxemia and
Tissue factor
Tissue factor is a membrane bound receptor that is a potent activator of the coagulation cascade. It complexes with factor VIIa, which in turn activates X to Xa eventually resulting in thrombin generation and ultimately the formation of a fibrin clot [4]. Recently, there has been significant interest in the role of altered coagulation and fibrinolysis in the pathogenesis of ALI and ARDS. This has been fueled, in part, by the landmark study, which demonstrated a reduction in mortality in
β-adrenoceptors
In recent years, β-adrenoceptors have been implicated in modulation of neutrophil adhesion and chemotaxis, modulation of inflammatory mediators, preservation of endothelial barrier function, and augmentation of alveolar fluid clearance [12]. Both in vitro and in vivo studies suggest that β-agonists might be beneficial in acute lung injury via these mechanisms. ALI/ARDS is characterized by flooding of the alveolar space with protein-rich edema fluid that inactivates surfactant and interferes
Summary of stages
The early phase of ALI and ARDS is characterized by loss of lung endothelial and epithelial barrier integrity followed by flooding of the alveolar space with protein-rich edema fluid. Clinically the alveolar edema causes impaired gas exchange and progressive respiratory failure. Through mechanisms that are not well understood, alveolar coagulation is initiated early in ALI and ARDS by tissue factor and soluble coagulation proteins that lead to the deposition of a fibrin clot that lines the
Conclusion
ALI and ARDS are serious clinical disorders for which there is currently no effective pharmacologic therapy. Understanding of the complex mechanisms involved in the pathogenesis of this disorder has grown significantly over the past two years. There is considerable optimism in the field regarding the potential for new therapies, stemming directly from recent work (Table 1). Although there are several realistic therapeutic targets that have been discussed in this review, some outstanding issues (
Acknowledgement
Special thanks to Steve VanHook, MD for his artful rendering of the alveolus in health and disease.
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