The acute respiratory distress syndrome (ARDS) is a serious condition resulting from direct or indirect lung injury that is associated with high mortality and morbidity. A key biological event in the pathogenesis of the acute lung injury (ALI) that causes acute respiratory distress syndrome is activation of the lung endothelium cells (ECs)， which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive accumulation of neutrophils. Recently， we demonstrated that imatinib protects against lipopolysaccharide (LPS)-induced EC activation by inhibiting c-Abl kinase. In the present study， we explored the role of parkin， a novel c-Abl substrate， in ALI. Parkin is an E3 ubi... More
The acute respiratory distress syndrome (ARDS) is a serious condition resulting from direct or indirect lung injury that is associated with high mortality and morbidity. A key biological event in the pathogenesis of the acute lung injury (ALI) that causes acute respiratory distress syndrome is activation of the lung endothelium cells (ECs)， which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive accumulation of neutrophils. Recently， we demonstrated that imatinib protects against lipopolysaccharide (LPS)-induced EC activation by inhibiting c-Abl kinase. In the present study， we explored the role of parkin， a novel c-Abl substrate， in ALI. Parkin is an E3 ubiquitin ligase originally characterized in the pathogenesis of Parkinson disease; however， its potential role in acute inflammatory processes and lung EC function remains largely unknown. Using parkin deficient (PARK2-/-) mice， we now demonstrate that parkin mediates LPS-induced ALI. After LPS， PARK2-/- mice have reduced total protein and cell levels in bronchoalveolar lavage (BAL) compared to wild type. Moreover， in LPS-treated PARK2-/- lungs， the sequestration and activation of neutrophils and release of inflammatory cytokines (interleukin 6 [IL-6]， tumor necrosis factor alpha [TNF-α]) are significantly reduced. The BAL levels of soluble VCAM-1 and ICAM-1 are also decreased in LPS-treated PARK2-/- mice compared to wild type. In cultured human lung endothelial cells， downregulation of parkin by small interfering RNA decreases LPS-induced VCAM-1 expression， IL-8 and IL-6 secretion， and NF-kB phosphorylation. These results suggest a previously unidentified role of parkin in mediating endotoxin-induced endothelial proinflammatory signaling and indicate that it may play a critical role in acute inflammation.
