Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation.

backgroundAcute respiratory distress syndrome (ARDS) is characterized by endothelial barrier disruption, excessive neutrophil recruitment, and sustained pulmonary inflammation. The A Disintegrin and Metalloproteinase 17 (ADAM17) regulates inflammatory signaling through ectodomain shedding of adhesion molecules and cytokine receptors, yet its endothelial-specific contribution to acute lung injury remains poorly defined.

methodsEndothelial ADAM17 was deleted in ADAM17

resultsEndothelial ADAM17 emerged as a central regulator of vascular permeability, neutrophil trafficking, and inflammatory amplification in LPS-induced acute pulmonary inflammation. LPS markedly increased pulmonary ADAM17 expression, whereas endothelial-specific deletion reduced total lung ADAM17 mRNA by 77.5%, highlighting the dominant endothelial contribution. Endothelial ADAM17 deficiency preserved endothelial junction integrity through maintenance of JAM-A surface expression and was associated with preserved expression of VE-cadherin and the tight junction proteins ZO-1, occludin, and claudin-5, thereby reducing protein-rich pulmonary edema. These changes were accompanied by enhanced neutrophil transmigration into interstitial and alveolar compartments through altered PSGL-1 and CD49d expression. Mechanistically, endothelial ADAM17 enhanced TNF receptor 1 and IL-6 receptor signaling, elevating TNF-α, myeloperoxidase, and neutrophil elastase levels. Pharmacological ADAM17 inhibition recapitulated the protective phenotype of endothelial ADAM17 deficiency, attenuating neutrophil recruitment, preserving endothelial barrier integrity, and limiting vascular leakage.

conclusionThese findings strengthen the evidence that endothelial ADAM17 is a key driver of inflammatory vascular dysfunction in ARDS and support ADAM17 as a rational therapeutic target.