The acute respiratory distress syndrome: from mechanism to translation

Abstract

The acute respiratory distress syndrome (ARDS) is a form of severe hypoxemic respiratory failure that is characterized by inflammatory injury to the alveolar capillary barrier, with extravasation of protein-rich edema fluid into the airspace. Although many modalities to treat ARDS have been investigated over the past several decades, supportive therapies remain the mainstay of treatment. In this article, we briefly review the definition, epidemiology, and pathophysiology of ARDS and present emerging aspects of ARDS pathophysiology that encompass modulators of the innate immune response, damage signals, and aberrant proteolysis that may serve as a foundation for future therapeutic targets.

Figure 1

The acute exudative phase of ARDS. Shown is a low-magnification hematoxylin and eosin stain micrograph showing alveolar inflammatory infiltration and filling of air sacs with protein-rich fluid (16).

Figure 2. Pathophysiology of the acute respiratory distress syndrome

Initial inflammatory insults including mitochondrial DAMPs activate alveolar macrophages via TLRs and NLRs signaling pathways. Activated alveolar macrophages release proinflammatory cytokines and recruit circulating macrophages and neutrophils to injured sites. Excessive neutrophils and persistently activated macrophages cause extensive damage to lung epithelia and endothelia resulting in an impaired alveolar-capillary barrier. Disruption of this barrier allows protein-rich fluid to enter the alveoli causing fluid accumulation in alveolar spaces (pulmonary edema) interfering with gas exchange. Ubiquitination (Ⓤ) plays an important role in modulating the abundance of key proteins in ARDS resulting in secretion of cytokines, lower levels of surfactant proteins, and decreased function of ion channels (Na, K-ATPase and ENaC). ARDS is associated with surfactant depletion leading to increased NETosis, a process that alters lung cell viability. Mitochondrial DAMPs can directly increase microvascular permeability independent to leukocytes. Mitochondrial DAMPs, mitochondrial-derived products released by cellular damage, which serve as danger-associated molecular patterns; TLRs, Toll-like receptors; NLRP, nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain containing; Alveolar MØ, alveolar macrophage; NETs, neutrophil extracellular traps; MSC, mesenchymal stem cell; ENaC, epithelial Na+ channel; Ⓤ, ubiquitination.