Herold S, Gabrielli NM, Vadász I. Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction. Am J Physiol Lung Cell Mol Physiol 305: L665-L681, 2013. First published September 13, 2013 doi:10.1152/ajplung.00232.2013In this review we summarize recent major advances in our understanding on the molecular mechanisms, mediators, and biomarkers of acute lung injury (ALI) and alveolar-capillary barrier dysfunction, highlighting the role of immune cells, inflammatory and noninflammatory signaling events, mechanical noxae, and the affected cellular and molecular entities and functions. Furthermore, we address novel aspects of resolution and repair of ALI, as well as putative candidates for treatment of ALI, including pharmacological and cellular therapeutic means. alveolar-capillary barrier dysfunction; molecular mechanism; pharmacological and cell-based therapy; pulmonary edema; zaacute lung injury/acute respiratory distress syndrome Immune Cells and Inflammatory Signaling Pathways in ALIOne of the central concepts in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is that an unbalanced quantity or quality of the inflammatory response aggravates epithelial or endothelial injury. This includes a dysregulated recruitment of leukocytes and/or an exaggerated activation of these cells; inappropriate expression of cytokines, lipid mediators, or reactive oxygen species; enhanced activation of death receptor signaling (97,98,140,207,240); or an uncontrolled activity of platelets or the coagulation cascade (154). In general, these responses are initiated and maintained by recognition of danger-or pathogen-associated molecular patterns

FXYD5 (also known as dysadherin), a regulatory subunit of the Na,K-ATPase, impairs intercellular adhesion by a poorly understood mechanism. Here, we determined whether FXYD5 disrupts the transdimerization of Na,K-ATPase molecules located in neighboring cells. Mutagenesis of the Na,K-ATPase β 1 subunit identified four conserved residues, including Y199, that are crucial for the intercellular Na,K-ATPase trans-dimerization and adhesion. Modulation of expression of FXYD5 or of the β 1 subunit with intact or mutated β 1 -β 1 binding sites demonstrated that the anti-adhesive effect of FXYD5 depends on the presence of Y199 in the β 1 subunit. Immunodetection of the plasma membrane FXYD5 was prevented by the presence of O-glycans. Partial FXYD5 deglycosylation enabled antibody binding and showed that the protein level and the degree of O-glycosylation were greater in cancer than in normal cells. FXYD5-induced impairment of adhesion was abolished by both genetic and pharmacological inhibition of FXYD5 O-glycosylation. Therefore, the extracellular O-glycosylated domain of FXYD5 impairs adhesion by interfering with intercellular β 1 -β 1 interactions, suggesting that the ratio between FXYD5 and α 1 -β 1 heterodimer determines whether the Na,K-ATPase acts as a positive or negative regulator of intercellular adhesion.