Potter, Richard - University of Western Ontario - Department of Medical Biophysics

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Scientist, Lawson Health Research Institute Assistant Professor, Department of Medical Biophysics, University of Western Ontario Assistant Professor, Department of Surgery, University of Western Ontario My laboratory was established in 1993 in collaboration with the Division of Vascular Surgery at the London Health Science Centre and is dedicated to the study of clinically relevant problems associated with the circulatory system. Utilizing a multi-disciplinary approach, studies are undertaken to further our understanding of the mechanisms leading to circulatory dysfunction and organ injury resulting from the reperfusion of previously ischemic organs (i.e, ischemia and reperfusion), or as a consequence of remote organ injury following severe trauma or sepsis.

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Hepatic Injury During SIRS: Role of Leukocytes and Kupffer Cells The systemic inflammatory response syndrome (SIRS) associated with severe trauma, or sepsis accounts for the majority of deaths within Intensive Care Units. Our overall goal is to test mechanisms leading to the initiation of remote injury to extrapulmonary organs during this syndrome. We have shown that intestinal injury occurs following either a distant focus of inflammation (Surgery 1996; 120:547-53) or infection (J. Surg. Res. 1996; 61:190-196). Since the liver is an essential organ for the detoxification of intestinal blood, we need to know if liver injury occurs concurrently with intestinal injury and what mechanisms may promote such injury. Hypotheses being studied include: 1. Hepatocyte injury and reduced microvascular blood flow leading to altered hepatic function occurs early in the development of the systemic inflammatory response syndrome following a distant focus of inflammation. 2. Cytokines, such as tumor necrosis factor alpha, trigger the onset of liver injury by induction of apoptosis and activation of macrophages (ie., Kupffer cells). 3. Progression of liver injury during SIRS results as a consequence of leukocyte mediated injury. 2. Mechanisms Leading to Delayed Microvascular and Parenchymal Protection Following Ischemic Preconditioning We have shown that restoration of blood flow to previously ischemic organs result in reduced microvascular perfusion, and significant tissue injury (J. Surg. Res. 1995; 59:521-526; Microvasc. Res. 1996; 51: 275-287). Recently, we showed that ischemic preconditioning of skeletal muscle, using brief periods of ischemia and reperfusion, provided protection against a subsequent prolonged ischemic event, 24 hours following the PC stimulus (Am. J. Physiol (Heart and Circ), 1998; 275(1)). However, such delayed protection was limited to the preservation of microvascular perfusion (i.e., no concurrent tissue protection). This unique observation suggested that the mechanisms providing protection to microvascular perfusion may be different to those leading to parenchymal protection. We will test several hypotheses regarding the role of nitric oxide and scavengers of reactive oxygen metabolites to establish the importance of these compounds in the differential protection afforded 24 hours following PC. Such hypotheses include: 1. Nitric oxide is an important prerequisite for the expression of the delayed benefits afforded by ischemic preconditioning. 2. The delayed benefits of ischemic preconditioning is not limited to preserved microvascular perfusion, as suggested by our previous work, but extends to the protection of the microvascular endothelium with such protection characterized by reduced cellular injury and microvascular permeability following prolonged ischemia. 3. The expression of parenchymal protection, 24 hours following ischemic preconditioning, is related to the oxidative capacity of the tissue, and thus the potential to produce scavengers of reactive oxygen metabolites. 4. The delayed benefits of ischemic preconditioning are, in part, the result of the reduced conversion of nitric oxide to peroxynitrite.