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T Shuman

Publications and source records attributed to T Shuman.

6 recordsLinked to original sources
PubMed1994

Eosinophil 15-lipoxygenase is a leukotriene A4 synthase.

5-Lipoxygenase is the first committed enzyme in the leukotriene biosynthetic pathway and is known to catalyze not only the first oxygenation of arachidonate to form 5(S)-hydroperoxyeicosatetraenoic acid (5(S)-HPETE), but also dehydration of this intermediate into leukotriene A4 (LTA4) by an activity termed leukotriene A4 synthase. Inhibition of cytosolic 5-lipoxygenase prepared from human blood granulocytes with zileuton (100 microM) was virtually complete, but LTA4 synthase activity was only inhibited by 47%. Structural characterization of eicosanoids synthesized in these preparations revealed an abundance of 15-lipoxygenase metabolites including 15-HETE when arachidonate was used as substrate and 5(S),15(S)-dihydroxy-6,8,11,13(E,E,Z,Z)-eicosatetraenoic acid when 5(S)-HPETE was used as substrate. When neutrophils were prepared that contained less than 1% eosinophil contamination, zileuton was found to almost completely inhibit all 5-lipoxygenase, as well as LTA4 synthase products. Immunochemical analysis of the supernatants from purified neutrophils and eosinophils confirmed the previous observation that neutrophils do not express 15-lipoxygenase. Incubation of 5(S)-HPETE with recombinant mammalian 15-lipoxygenase resulted in the formation of 6-trans-LTB4 and 6-trans-12-epi-LTB4 as LTA4 products, as well as the 12-lipoxygenase product 5(S),12(S)-diHPETE. The mechanism of action of 15-lipoxygenase acting as an LTA4 synthase is proposed to involve removing the pro-R hydrogen atom at carbon-10 of 5(S)-HPETE, which is antarafacial to the hydroperoxy group to yield LTA4.

Arachidonate 15-Lipoxygenase↗
PubMed1992

Injury in nonischemic lung after unilateral pulmonary ischemia with reperfusion.

We developed an in vivo intact canine model to study pulmonary ischemia-reperfusion (IR) injury. The surgical approach simulates that of unilateral lung transplantation but is free of technical difficulties and other factors related to lung preservation. Serial measurements of regional pulmonary blood flow (rPBF), extravascular density (EVD), and transcapillary protein flux were made with the quantitative imaging technique of positron emission tomography. Eleven experimental and six control animals were studied. After 2 h of warm ischemia followed by reperfusion, no significant change occurred in rPBF despite significantly increased EVD, which was greater on the ischemic than on the nonischemic side. Protein flux, measured as a rate constant, was also greater on the ischemic than on the nonischemic side (median 181 x 10(-4)/min, range 104-619, vs. median 90, range 33-132) immediately after reperfusion. Both sides were also significantly different from control values (median 37, range 21-57). On both sides, protein flux decreased over time and at 5 h after reperfusion was not different from that of controls. Data from the control animals showed that these findings in the experimental animals were not due to surgical technique, deterioration in the surgical preparation, or hyperperfusion of the nonischemic lung. Thus IR injury of one lung can lead to similar, but less severe, injury in the contralateral lung. Because injury in the nonischemic lung develops only after reperfusion of the ischemic lung, injury to the nonischemic lung is probably humorally mediated. The model is a useful and relevant method for studying the physiological consequences of pulmonary IR injury.

Animals↗
PubMed1992

Inflammation and oxygen free radical formation during pulmonary ischemia-reperfusion injury.

In a companion study, we showed that 2 h of warm unilateral lung ischemia followed by reperfusion resulted in bilateral tissue injury, indicated by increases in extravascular density (EVD) and permeability, measured as the pulmonary transcapillary escape rate (PTCER) for radiolabeled transferrin. EVD and PTCER measurements were obtained with the quantitative imaging technique of positron emission tomography (PET). In the current study, we evaluated this increase in EVD histologically and correlated EVD and PTCER with measurements of oxidant-reactive sulfhydryls (RSH) in plasma as a marker of oxygen free radical (OFR) formation. Histologically edema, leukocyte infiltration, and hemorrhage were all present on the ischemic side, but only after reperfusion, whereas only neutrophil infiltration was observed on the nonischemic side. Histology scores correlated with EVD (r = 0.81) and PTCER (r = 0.75), but permeability was abnormal at times even in the absence of neutrophil infiltration. Plasma RSH concentration from the ischemic lung decreased significantly (P less than 0.05) during pulmonary ischemia (i.e., before reperfusion) and returned to baseline on reperfusion. The degree of RSH oxidation did not correlate with the severity of injury as measured by PET or histology. Thus pulmonary ischemia-reperfusion injury is characterized by inflammation, hemorrhage, edema, and OFR formation. Injury occurred after reperfusion, not after ischemia alone. In addition, injury to the contralateral nonischemic lung suggests a neutrophil-independent circulating mediator of injury.

Animals↗
PubMed1986

Free radical scavengers and myocardial preservation during transplantation.

The efficacy of oxygen radical scavengers in preservation of left ventricular (LV) function after prolonged hypothermic global ischemia was investigated in a model of orthotopic cardiac transplantation in sheep. Group 1 hearts (N = 8) received hypothermic crystalloid cardioplegic solution, and were harvested and stored at 4 degrees C in balanced electrolyte solution for six hours prior to transplantation. Group 2 (N = 9) received identical treatment with the addition of 30,000 units of superoxide dismutase to the cardioplegic solution and the administration of 60,000 units of superoxide dismutase coincident with reperfusion. All animals were weaned from cardiopulmonary bypass. Preischemic and postischemic LV function was determined using sonomicrometry and a micromanometer-tipped LV catheter. Coronary blood flow was determined using standard microsphere techniques, and platelet deposition was assayed with autologous platelets labeled with indium 111. Lipid peroxidation products were measured using thiobarbituric acid assay. LV performance was significantly better (p less than .05) in Group 2 hearts when assessed by the slope of the end-systolic pressure-volume relationship and the stroke work versus end-diastolic volume relationship. There was better preservation of endocardial blood flow in the group receiving superoxide dismutase compared with controls (p less than .05). Platelet deposition, as determined by the tissue to blood ratio of scintigraphic counts, was greater (p less than .05) in controls compared with the group receiving superoxide dismutase. In addition, thiobarbituric acid reactive species were significantly less (p less than .05) in Group 2 versus Group 1 hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1972

Income.

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