Therapeutic targeting of acute lung injury and acute respiratory distress syndrome

Abstract

There is no Food and Drug Administration-approved treatment for acute respiratory distress syndrome (ARDS), in spite of the relatively large number of patients with the diagnosis. In this report, we provide an overview of preclinical studies and a description of completed and future clinical trials in humans with ARDS. Preclinical studies dealing with acute lung injury have suggested roles for complement and complement receptors, as well as the evolving role of histones, but details of these pathways are inadequately understood. Anti-inflammatory interventions have not been convincingly effective. Various cell growth factors are being considered for clinical study. Interventions to block complement activation or its products are under consideration. Stem cell therapies have shown efficacy in preclinical studies, which have motivated phase I/II trials in humans with ARDS.

Figure 1

Histological and radiographic features of ARDS. A. Lung from a patient with ARDS, stained with hematoxylin and eosin. There are prominent “hyaline membranes” consisting of fibrin deposits along alveolar walls, widespread interstitial edema accompanied by neutrophils. Alveolar spaces also contain RBCs and fibrin strands. Panels B and C are radiographic appearance of exudative and fibroproliferative phases of ARDS. The exudative phase is characterized by diffuse ground glass and alveolar opacities, whereas the fibroproliferative phase is characterized by residual linear opacities, traction bronchiectasis and honeycombing.

Figure 2

Pathophysiological pathways in experimental ALI. These involve component activation, engagement of the two C5a receptors, and engagement of TLRs and NLRs. PAMPs are pathogen-associated molecular patterns, such as LPS released from gram negative bacteria and LTA released from gram positive bacteria. DAMPs are danger-associated molecular patterns released from damaged tissues (HMGB1, heat shock proteins, DNA, RNA, etc.). Downstream events include release of cytokines and chemokines, formation of neutrophil extracellular traps (NETs), and release of histones which are highly cell and tissue damaging.