Endothelial ADAM17 Promotes Neutrophil Migration and Pulmonary Microvascular Permeability in ARDS

Abstract

Acute respiratory distress syndrome (ARDS) is characterized by profound endothelial barrier disruption, excessive neutrophil recruitment, and sustained pulmonary inflammation. A Disintegrin and Metalloproteinase 17 (ADAM17) regulates inflammatory signaling through ectodomain shedding of adhesion molecules and cytokine receptors, yet its endothelial-specific contribution to ARDS remains poorly defined. We identify endothelial ADAM17 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 ADAM17 deletion reduced total lung ADAM17 mRNA by 77.5%. Endothelial ADAM17 promoted disruption of endothelial junctions and protein-rich pulmonary edema by modulating JAM-A and VE-cadherin. Concomitantly, endothelial ADAM17 facilitated neutrophil transmigration into interstitial and alveolar compartments through altered expression of PSGL-1 and CD49d. Mechanistically, endothelial ADAM17 enhanced TNF receptor 1 and IL-6 receptor signaling, increasing proinflammatory mediator release. Pharmacological ADAM17 inhibition recapitulated the protective phenotype of endothelial ADAM17 deficiency, attenuating neutrophil recruitment and preserving endothelial barrier integrity. These findings establish endothelial ADAM17 as a key driver of inflammatory vascular dysfunction in ARDS and support ADAM17 as a rational therapeutic target.