Microvascular Endothelial Barrier Failure in Acute Lung Inflammatory Diseases: From Epigenetic Regulation to Clinical Implications

ABSTRACT: Pulmonary microvasculature, which is intimately associated with the alveoli, carries the entire cardiac output through an extensive capillary network and plays a pivotal role in gas exchange by maintaining the structural and functional integrity of the alveolar-capillary barrier. Preservation of cell-cell junctions is essential for preventing paracellular leakage and leukocyte infiltration, which are characteristic features of acute lung inflammatory disorders, including acute respiratory distress syndrome (ARDS) and acute exacerbations of chronic lung diseases. Epigenetic regulation serves as a fundamental mechanism linking chromatin dynamics to endothelial barrier function. By modulating gene expression and downstream processes, including protein stability, subcellular localization, and enzymatic activity, epigenetic pathways regulate cell-cell junctions, ultimately determining microvascular endothelial barrier integrity. This review provides an in-depth overview of the molecular regulation of cell-cell junction dynamics in pulmonary endothelial cells under acute inflammatory stress, with a focus on the roles of epigenetic modifications. In addition, it evaluates current therapeutic strategies targeting microvascular endothelial barrier dysfunction and discusses their translational and clinical limitations. By integrating recent advances in cellular and preclinical research with translational efforts, this review identifies key knowledge gaps and outlines future directions for developing precision therapeutics to preserve microvascular endothelial barrier integrity in acute inflammatory diseases.