Release of bacterial endotoxin (lipopolysaccharide, LPS) into the circulation occurs in sepsis, as well as after major trauma and surgery. Sepsis alone affects more than 500,000 patients per year in the United States, nearly half of which die. LPS triggers a systemic inflammatory response and multi-organ dysfunction due to cellular activation of both immune and non-myeloid cells. Endotoxemia-induced myocardial dysfunction is an important determinant of morbidity and mortality in sepsis; it and related mechanisms have also been associated with the pathophysiology of heart failure and cardiopulmonary bypass. New information detailed in the present proposal and from other investigators indicates that both receptor mediated and direct intracellular trafficking of LPS are likely to be responsible for stimulating the intracellular signaling cascades, perturbation of cellular functions, and gene transcription events that are responsible for LPS-induced cellular injury. These effects occur quite rapidly (30-60 min) and include decreased myocardial contractility, abnormal calcium regulation, oxygen wastage, abnormal mitochondrial transport, and free radical production. These abnormalities coincide with initiation of multiple signaling pathways and the transport of LPS to intracellular sites including mitochondria, Golgi, and the contractile apparatus. This project using myocytes in culture and isolated perfused hearts, will test three hypotheses: 1) that LPS activates Toll-like receptors and related signal transduction proteins; 2) that membrane association and intracellular transport of LPS are responsible for signaling and functional effects; and 3) that LPS or LPS-activated signal transduction pathways cause mitrochondrial dysfunction. Given the potential diversity of the mechanism of LPS signal initiation and the pleiotropic nature of subsequent cellular responses, defining the earliest mechanisms of LPS signaling is essential to the design of specific and effective treatment strategies. Furthermore, the results from these studies are likely to apply not only endotoxin but also to host responses to other foreign pathogen products, and, in a more general sense, to understanding the role of stimulation of innate and adaptive immunity in various forms of myocardial injury.
Showing the most recent 10 out of 25 publications
