An uncontrolled cytokine storm in lungs leads to detrimental effects such as neutrophil influx, capillary leakage, tissue edema, and organ failure often manifested as pneumonia-induced acute lung injury (ALI). Lysophosphatidic acid receptor 1 (LPA1) is a pro-inflammatory G protein coupled receptor, which induces pro- inflammatory cytokine release through G?-mediated signaling and interaction with endotoxin receptor, CD14. LPA1 has been implicated in the pathogenesis of lung inflammatory disorders. Knockdown or inhibition of LPA1 attenuates endotoxin- or bleomycin-induced lung injury and sepsis. We discovered that LPA1 stability is regulated in the ubiquitin-lysosome system. Ubiquitin-specific protease 11 (USP11) deubiquitinates and stabilizes LPA1, thus promoting LPA1-modulated pro-inflammatory effects. Knockdown of USP11 reduces LPA1 stability and attenuates both LPA- and LPS-induced lung inflammation. This is the first to demonstrate that destabilizing LPA1 reduces lung inflammation, and deubiquitinating enzyme contributes to the pathogenesis of lung injury. We have developed a small blocking peptide (LDPep) to interrupt the interaction between LPA1 and USP11, which specifically reduces LPA1 protein level, without altering expression of other LPA receptors and USP11 target proteins. LDPep post-treatment lessens endotoxin-induced lung injury and sepsis shock. This project will explore a novel therapeutic approach for treating inflammatory disorders like ALI and sepsis. Execution of these studies will lay the groundwork for a significant mechanistic advance in the molecular regulation of pro-inflammatory responses during severe infection. Results from these studies can serve as the basis for further development of pharmacologic agents that destabilize LPA1, thereby reducing severity of inflammatory diseases such as lung injury and sepsis.
Local infection by pathogen (such as P. aeruginosa)-induced acute lung injury is a highly virulent pathogen etiologically linked to high morbidity and mortality during fulminant infection. These studies will be the first to elucidate that the role of de-ubiquitinating enzyme and G protein-coupled receptor stability in the pathogenesis of lung injury. A new developed LPA1 destabilizing peptide specifically reduces LPA1 stability and lessens endotoxin-induced lung injury. These studies will be critical in developing novel therapeutics by a small molecule blocking peptide to lessen the severity of lung inflammatory injury.
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