Parkin regulates LPS-induced pro-inflammatory responses in acute lung injury

• Published in: Translational research : the journal of laboratory and clinical medicine
• Main Authors: Letsiou, E, Sammani, S, Wang, H, Belvitch, P, Dudek, S.M
• Format: Journal Article
• Language: English
• Published: 2016
• Subjects: Internal Medicine; endothelial cells; NF-kB; ICAM-1; small interfering RNA; HPAEC; acute lung injury; PARK2; LPS; lung injury; inflammation; PARK2 -; cytokines; intensive care unit; parkin deficient; vascular cell adhesion molecule 1; ARDS; EC; nuclear factor kappa-light-chain-enhancer of activated B cells; endothelium; intracellular adhesion molecule-1; siRNA; human pulmonary artery endothelial cells; VCAM-1; acute respiratory distress syndrome; ICU; lipopolysaccharide; ALI
• ISSN: 1931-5244
• DOI: 10.1016/j.trsl.2016.09.002

Abstract 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 ARDS is activation of the lung endothelium (EC), which is triggered by a variety of inflammatory insults leading to barrier disruption and excessive adhesion/activation of neutrophils. Recently, we demonstrated that imatinib protects against 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’s disease; however its potential role in acute inflammatory processes and lung EC function remain largely unknown. Using parkin deficient (PARK2-/-) mice, we now demonstrate a crucial role for parkin in mediating LPS-induced ALI. After LPS, PARK2-/- mice have reduced total protein and cell levels in bronchoalveolar lavage (BAL) compared to wild type (WT). Moreover, in LPS-treated PARK2-/- lungs, the sequestration/activation of neutrophils and release of inflammatory cytokines (IL-6, TNF-ɑ) are significantly reduced. The BAL levels of soluble VCAM-1 and ICAM-1 are also decreased in LPS-treated PARK2-/- mice compared to WT. In cultured human lung endothelial cells, down-regulation of parkin by siRNA 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 pro-inflammatory signaling, and indicate that it may play a critical role in acute inflammation.