Sepsis is a disease process representing the systemic response to severe infection. Infections of the abdomen, chest, genitourinary tract, and primary bloodstream account for more than 80% of sepsis cases, and the incidence of these infections and sepsis continues to rise. Until the late 1980s, sepsis was considered by many to be near-synonymous with gram-negative endotoxemia. However, in the early 1990s, it became more and more obvious that the concept of sepsis can arise from microbial infections in the absence of endotoxin. Interestingly, gram-negative sepsis has diminished over the years to an incidence of 25-30% in 2000, while gram-positive and polymicrobial infections account for 30-50% and 25% respectively. The infectious process systemically activates immune cells of the host, including neutrophils and macrophages, which trigger a pro-inflammatory response that contributes to eradication of the invading organism(s). If this pathogen is not eradicated, sepsis may progress to severe sepsis (sepsis plus organ dysfunction) and septic shock (severe sepsis plus refractory hypotension and circulatory failure), which frequently leads to death. Heme oxygenase (HO)-1 is a cytoprotective enzyme that is induced by stimuli associated with inflammation and oxidative stress. HO-1 catalyzes the degradation of Heme, a potent oxidant, to generate biliverdin, iron and carbon monoxide (CO). Biliverdin is converted to bilirubin, a potent endogenous antioxidant, with recently recognized anti-inflammatory properties. Iron is sequestered by ferritin, which has additional antioxidant effects. CO has numerous biological functions, including anti- inflammatory properties, and shares many similarities with nitric oxide (NO), such as its ability to modulate vascular tone by increasing cGMP levels. Recent work from our laboratory demonstrates that in the absence of HO-1, mice develop multiple organ dysfunction associated with increased oxidative stress during endotoxemia. Moreover, data from bone marrow transplant experiments suggest that parenchymal expression of HO-1 is critical for the prevention of organ dysfunction. Our previous proposal focused on endotoxemia, but with the emergence of polymicrobial and gram-positive organisms leading to sepsis, we are proposing to advance our investigations into infectious models of sepsis. At the present time, much less is known about the role of HO-1 in controlling the systemic infectious response that occurs during sepsis. Thus, the overall goal of this competitive renewal is to elucidate the role of HO-1 in sepsis related to either polymicrobial or single organism insults. We hypothesize that HO-1 will play a critical role in the microbial response, and subsequent pathophysiology, of sepsis in mice. To test our hypothesis, we propose three specific aims:
Aim 1) investigate the importance of HO-1 in mediating the microbial response during sepsis, 2) elucidate the mechanism responsible for the protective role of HO-1 against bacteremia, and 3) further investigate the regulation of transcription factors critical for inflammatory control of HO-1 gene expression, and explore the regulation of the human HO-1 promoter and 5'-flanking sequences. ? ? ?
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