Alveolar-capillary endocytosis and trafficking in acute lung injury and acute respiratory distress syndrome

Abstract

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality but lacks specific therapeutic options. Diverse endocytic processes play a key role in all phases of acute lung injury (ALI), including the initial insult, development of respiratory failure due to alveolar flooding, as a consequence of altered alveolar-capillary barrier function, as well as in the resolution or deleterious remodeling after injury. In particular, clathrin-, caveolae-, endophilin- and glycosylphosphatidyl inositol-anchored protein-mediated endocytosis, as well as, macropinocytosis and phagocytosis have been implicated in the setting of acute lung damage. This manuscript reviews our current understanding of these endocytic pathways and subsequent intracellular trafficking in various phases of ALI, and also aims to identify potential therapeutic targets for patients with ARDS.

Keywords: acute respiratory distress syndrome; caveolae; clathrin-mediated endocytosis; endophilin; glycosylphosphatidyl inositol-anchored protein enriched early endosomal compartment pathway; macropinocytosis; phagocytosis; trafficking.

Figure 1

Schematic depiction of main endocytosis pathways and their potential roles in acute lung injury and acute respiratory distress syndrome. CME, clathrin-mediated endocytosis; CavME, caveolae-mediated endocytosis; FEME, fast endophilin-mediated endocytosis; CLIC/GEEC, clathrin-independent carriers/GPI-AP enriched early endosomal compartment; LRP2, low density lipoprotein receptor-related protein 2 (also known as megalin); ENaC, epithelial sodium channel; IV, influenza virus; RSV, respiratory syncytial virus; SARS-CoV-2, severe acute respiratory syndrome-related coronavirus. Potentially-related mechanisms are listed in gray color. Created with BioRender.com.