Sepsis remains a major cause of morbidity and mortality. Typically, 50% of all sepsis cases start as an infection in the lungs. Sepsis is accompanied by multiple organ dysfunction, cytokine storm, and disseminated coagulation syndrome. These processes directly involve vascular endothelial cells. Although inflammation, dysregulated coagulation, and alterations in endothelial permeability are recognized factors of septic acute lung injury (ALI), the endogenous mediators and cellular mechanisms orchestrating processes of endothelial inflammatory activation and coagulation in septic conditions remain poorly understood. In pilot studies we identified truncated oxidized phospholipids (TR-OxPLs) in the inflamed lungs using Mass Spectrometry-based phospholipidomics approach. Our exciting preliminary data show that TR-OxPLs markedly exacerbated lung dysfunction and impaired vascular endothelial barrier in cell and animal models of septic ALI. Using pneumonia-related models of ALI induced by live Staphylococcus aureus (S. au, USA300 CA-MRSA clinical strain 923) or heat-killed S. au (HKSA) this translational study will employ for the first time the quantitative phospholipidomics approach to identify specific TR-OxPLs elevated during ALI and elucidate their role as factors exacerbating inflammation and dysregulating coagulation cascade. We hypothesize that increased generation of TR-OxPLs during sepsis augments lung injury by inducing expression of NLRP3 inflammasome activator, thioredoxin interacting protein (TXNIP); and by suppressing the expression of vascular anticoagulant, Tissue Factor Pathway Inhibitor (TFPI). Altogether, these events lead to activation of inflammatory signaling, dysregulated coagulation, inflammatory cell infiltration in the lung, and organ damage.
Aim -1 will determine the spectrum of TR-OxPL generated in the lungs of S. au-challenged animals.
Aim -2 will study the impact of TR- OxPL generated in S. au-induced septic conditions on the severity of lung injury.
Aim -3 will study molecular mechanisms of TR-OxPL-induced exacerbation of septic inflammation and coagulation.
Aim -4 will test new mechanism-based strategies to alleviate TR-OxPLs generation and their pathologic consequences in S. au- induced septic ALI.
Sepsis remains a major cause of morbidity and mortality, however development of effective therapies for sepsis treatment represents a major challenge. Using preclinical models of lung inflammation caused by live methicillin-resistant Staphylococcus aureus (USA300 clinical strain 923) and inactivated Staphylococcus aureus particles to recapitulate sterile septic conditions after antibiotic treatment, this study will investigate the changes in the spectrum of lung phospholipid oxidation products and their effects on molecular pathways exacerbating vascular endothelial inflammation and coagulation and thus, defining the severity of acute lung injury. These studies may uncover new approaches for treatment of sepsis and other diseases associated with increased vascular leakage and inflammation.
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