Acute lung injury: epidemiology, pathogenesis, and treatment

Abstract

Acute lung injury (ALI) remains a significant source of morbidity and mortality in the critically ill patient population. Defined by a constellation of clinical criteria (acute onset of bilateral pulmonary infiltrates with hypoxemia without evidence of hydrostatic pulmonary edema), ALI has a high incidence (200,000 per year in the US) and overall mortality remains high. Pathogenesis of ALI is explained by injury to both the vascular endothelium and alveolar epithelium. Recent advances in the understanding of pathophysiology have identified several biologic markers that are associated with worse clinical outcomes. Phase III clinical trials by the NHLBI ARDS Network have resulted in improvement in survival and a reduction in the duration of mechanical ventilation with a lung-protective ventilation strategy and fluid conservative protocol. Potential areas of future treatments include nutritional strategies, statin therapy, and mesenchymal stem cells.

FIG. 1.

The normal alveolus (left-hand side) and the injured alveolus in the acute phase of ALI and the acute respiratory distress syndrome. In the acute phase of the syndrome (right-hand side), there is sloughing of both the bronchial and alveolar epithelial cell, with the formation of protein-rich hyaline membranes on the denuded basement membrane. Neutrophils are shown adhering to the injured capillary endothelium and marginating through the interstitium into the air space, which is filled with protein-rich edema fluid. In the air space, an alveolar macrophage is secreting cytokines, interleukin (IL)-1, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α, which act locally to stimulate chemotaxis and activate neutrophils. Interleukin-1 can also stimulate the production of extracellular matrix by fibroblasts. Neutrophils can release oxidants, proteases, leukotrienes, and other proinflammatory molecules, such as platelet-activating factor (PAF). A number of anti-inflammatory mediators are also present in the alveolar milieu, including IL-1-receptor antagonists, soluble TNF receptors, autoantibodies against IL-8, and cytokines such as IL-10 and IL-11 (not shown). The influx of protein-rich edema fluid into the alveolus has led to the inactivation of a surfactant. ALI, acute lung injury; MIF, macrophage inhibitory factor. Reprinted with the permission of the publisher.⁽¹²⁾ Copyright 2000 Massachusetts Medical Society. All rights reserved.

FIG. 2.

The natural history of ALI/ARDS includes resolution and repair versus persistence and progression. Clinical and epidemiologic studies demonstrate that ALI/ARDS resolves with return of alveolar function to normal or near normal in some patients, whereas in others there is persistence and/or progression of injury. The outcomes of persistence and progression include multiple organ failure, fibrosing alveolitis, pulmonary vascular obliteration with pulmonary hypertension, and death. The genetic, cellular, molecular. and iatrogenic factors that contribute to each of these outcomes remain largely unknown. In addition, rational mechanism-based strategies that favorably influence repair of the alveolar–capillary membrane are undefined. Reprinted with the permission of the publisher.⁽²³⁾ Copyright 2005 American Thoracic Society. All rights reserved.