Pharmacotherapy of acute lung injury and the acute respiratory distress syndrome

Abstract

Acute lung injury and the acute respiratory distress syndrome are common syndromes with a high mortality rate that affect both medical and surgical patients. Better understanding of the pathophysiology of acute lung injury and the acute respiratory distress syndrome and advances in supportive care and mechanical ventilation have led to improved clinical outcomes since the syndrome was first described in 1967. Although several promising pharmacological therapies, including surfactant, nitric oxide, glucocorticoids and lysofylline, have been studied in patients with acute lung injury and the acute respiratory distress syndrome, none of these pharmacological treatments reduced mortality. This article provides an overview of pharmacological therapies of acute lung injury and the acute respiratory distress syndrome tested in clinical trials and current recommendations for their use as well as a discussion of potential future pharmacological therapies including beta(2)-adrenergic agonist therapy, keratinocyte growth factor, and activated protein C.

Fig 1

The normal alveolus (left-hand side) and the injured alveolus in the acute phase of acute lung injury 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. IL-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 antagonist, soluble TNF receptor, 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 surfactant. MIF denotes macrophage inhibitory factor. Reprinted with the permission of the publisher [146]. Copyright © 2000 Massachusetts Medical Society. All rights reserved.

Fig 2

Mechanisms important in the resolution of acute lung injury and acute respiratory distress syndrome. On the left side of the alveolus, the alveolar epithelium is being repopulated by the proliferation and differentiation of alveolar type II cells. Resorption of alveolar edema fluid is shown at the base of the alveolus, with sodium and chloride being transported through the apical membrane of type II cells. Sodium is taken up by the epithelial sodium channel and through the apical membrane of type II cells by the sodium pump (Na⁺/K⁺-ATPase). The relevant pathways for chloride transport are unclear. Water is shown moving through water channels, the aquaporins, located primarily on type I cells. Some water may also cross by a paracellular route. Soluble protein is probably cleared primarily by paracellular diffusion and secondarily by endocytosis by alveolar epithelial cells. Macrophages remove insoluble protein and apoptotic neutrophils by phagocytosis. On the right side of the alveolus, the gradual remodeling and resolution of intra-alveolar and interstitial granulation tissue and fibrosis are shown. Reprinted with the permission of the publisher [146]. Copyright © 2000 Massachusetts Medical Society. All rights reserved.