(A) Disrupted alveolar barrier function, resulting in increased permeability to water, proteins, and other solutes, is a hallmark of clinical and experimental ALI. Intra-alveolar accumulation of neutrophils, other leukocytes, and erythrocytes is also associated with altered endothelial and epithelial barrier function. TNF-α, IL-1, thrombin, and microbes and their toxins — including LPS, noxious agents, and factors generated by neutrophils and platelet-leukocyte interactions — can destabilize and disrupt alveolar barrier function, leading to increased permeability. (B) Disruption of VE-cadherin bonds is a central mechanism of altered endothelial barrier function in experimental ALI and in models of sepsis and systemic vascular destabilization. VE-cadherin is an endothelial-specific adherens junction protein that mediates Ca²⁺-dependent homophilic interactions at the lateral cell membranes of adjacent endothelial cells. VE-cadherin is regulated by cytoplasmic associations with catenins and actin and by cytoskeletal organization, in addition to intracellular signaling by Rho and Rac. Disruption of VE-cadherin bonds also facilitates transendothelial migration of leukocytes and, in some studies, is associated with accumulation of leukocytes and platelets in microvessels. (C) Stabilizing agonists (i) or small-molecule mimetics bind to stabilizing receptors (ii) on endothelial cells in alveolar and systemic vessels, restoring barrier integrity. Stabilizing agonists include S1P, Slit2N, Ang1, atrial natriuretic peptide, APC, and ATP; multiple intracellular pathways and mechanisms are implicated (iii) (reviewed in refs. 58, 61, 64). These intracellular mechanisms favorably influence cytoskeletal architecture, preserve catenin–VE-cadherin cytoplasmic interactions, prevent VE-cadherin internalization, and/or promote adherens junction formation (iv and v).