Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

Abstract

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article.

The Future of Exogenous Surfactant Therapy

“…In addition, several synthetic exogenous surfactants are under clinical study and laboratory research. [16][17][18][19][20][21][22][23][24] …”

“…(Adapted from Reference 14, with permission.) pharmaceutical surfactants to native surfactant is highly variable, and clinical preparations can be divided conceptually into 3 groups 5,16,18,25 :…”

“…The complex pathophysiology of ALI/ARDS is reviewed elsewhere. 18,[114][115][116][117][118][119][120][121] It is important for therapeutic applications to recognize that lung injury in ALI/ARDS is a dynamic process. Initial acute inflammation and surfactant dysfunction can evolve to a state where pulmonary pathology is heterogeneous and includes important aspects of chronic or sub-chronic inflammation, fibroproliferative repair, vascular remodeling, and so on.…”

“…A large number of studies have identified significant differences in activity between surfactant drugs at the laboratory level. 5,16,18,72 Differences in exogenous surfactant activity are likely to be more crucial in treating ALI/ARDS, compared to RDS. Successful treatment of ALI/ARDS requires the most robust surfactants because of the need to resist inhibition by substances that leak into the alveolar space as a result of permeability injury.…”

“…Detailed discussion of combination therapy approaches for ALI/ARDS are reviewed elsewhere. 18,212 In summary, it is likely that surfactant will find a place in our armamentarium for the treatment of ALI/ARDS when some of the above issues are clarified. As the famous philosopher Yogi Berra so eloquently stated, "Predictions are difficult, particularly about the future."…”