Parkin regulates lipopolysaccharide-induced proinflammatory responses in acute lung injury.
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.
Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois, Chicago, Ill. Electronic address: eletsiou@gmail.com.
Eleftheria
E
Letsiou
Arizona Health Sciences Center, University of Arizona, Ariz.
Saad
S
Sammani
Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois, Chicago, Ill.
Huashan
H
Wang
Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois, Chicago, Ill.
Patrick
P
Belvitch
Division of Pulmonary, Critical Care, Sleep, and Allergy, University of Illinois, Chicago, Ill.
Steven M
SM
Dudek
D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004727:Endothelium / Q000378:metabolism; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D063306:Mitophagy; D011014:Pneumonia / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism*
D015415:Biomarkers; D008070:Lipopolysaccharides; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein