Journal of biomedical science · 2026
Endothelial ADAM17 facilitates neutrophil migration and pulmonary microvascular permeability in acute lung inflammation.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Biedritzky Anna, Kleinmaier Carolin, Fuhr Anika, Herrmann Lisa Maria, Ngamsri Kristian-Christos, Konrad Franziska, Koeppen Michael
Аннотация
BACKGROUND: Acute 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.
METHODS: Endothelial ADAM17 was deleted in ADAM17fl/fl Tie2-Cre+ mice using the Cre/loxP system. Acute lung inflammation was induced by lipopolysaccharide (LPS) inhalation. Systemic ADAM17 blockade was achieved by intraperitoneal TAPI‑1 or ADAM17/ADAM10 inhibition by GW280264X, administered 1 h before LPS. Pulmonary microvascular permeability was quantified by Evans Blue extravasation. Neutrophil trafficking across lung compartments (intravascular, endothelial adherent, interstitial, intra‑alveolar) was assessed by flow cytometry.
RESULTS: Endothelial 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.
CONCLUSION: These 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.
METHODS: Endothelial ADAM17 was deleted in ADAM17fl/fl Tie2-Cre+ mice using the Cre/loxP system. Acute lung inflammation was induced by lipopolysaccharide (LPS) inhalation. Systemic ADAM17 blockade was achieved by intraperitoneal TAPI‑1 or ADAM17/ADAM10 inhibition by GW280264X, administered 1 h before LPS. Pulmonary microvascular permeability was quantified by Evans Blue extravasation. Neutrophil trafficking across lung compartments (intravascular, endothelial adherent, interstitial, intra‑alveolar) was assessed by flow cytometry.
RESULTS: Endothelial 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.
CONCLUSION: These 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.