Endotoxic shock is a disease process caused by a severe underlying infection. If left unchecked, this process may progress to refractory hypotension, multiple organ system failure, and death. Other than the cardiovascular response and its associated hypotension, abnormalities of the renal, hepatic, pulmonary, and hematologic systems are common during endotoxemia. The development of multiple organ failure contributes significantly to morbidity and mortality. In addition, oxygen-derived free radicals contribute to the cellular and tissue injury associated with endotoxin-induced inflammation. Heme oxygenase (HO)-1 is a cytoprotective enzyme that is induced by stimuli associated with oxidative stress. HO-1 degrades heme (a potent oxidant) to generate carbon monoxide (CO, a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron. Due to properties of HO-1 and its products, it is believed that HO-1 may play an important role in protecting cells and tissues in the settings of increased oxidative stress, such as during endotoxemia. Studies from our laboratory using HO-1 null (-/-) mice confirmed this hypothesis by showing that endotoxemia produced increased oxidative stress, end-organ damage, and death in mice lacking HO-1 compared with wild-type mice. This detrimental outcome did not correlate with the blood pressure response, as HO-1-/- mice had a significantly higher systolic blood pressure in the setting of increased mortality. These data led us to hypothesize that the upregulation of HO-1, and its subsequent cytoprotective effects (outweighing the potential vasodiIatory/hypotensive effects), may play an important role in preventing the pathophysiology of endotoxic shock. Thus, the goals of this proposal are 1) to determine whether vascular overexpression of HO-1 may have beneficial consequences in endotoxin-induced tissue injury and death by using a vasculai smooth muscle cell-targeted promoter to generate transgenic mice, 2) to elucidate the role of HO-1 in bone marrow-derived inflammatory cells versus parenchymal cells during endotoxin-induced end-organ damage and death, and 3) to further identify DNA sequences (cis-acting elements) and their cognate DNA-binding proteins (trans-acting factors), that in conjunction with the architectural transcription factor HMG-I/Y, are important for regulating HO-1 transcription during an inflammatory stimulus
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