The Journal of surgical research
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Antioxidants are potent radical scavengers that protect against endotoxemia and septic shock in animal models. Using a rat model of peritonitis sepsis induced by cecal incision we studied the effect of the free radical scavenger dimethyl sulfoxide (DMSO) on hepatic nuclear factor kappa B (NF-kappa B) activation, hepatic intercellular adhesion molecule 1 (ICAM-1) gene expression, serum tumor necrosis factor alpha (TNF) formation, and serum glucose concentration. Five groups of rats (N = 5) were treated as follows: (1) untreated control (Untreated), (2) sham operated with laparotomies (Sham), (3) pretreated with 6 ml/kg DMSO followed by sham operation (DMSO/Sham), (4) cecal incision (Sepsis), and (5) pretreated with DMSO followed by cecal incision (DMSO/Sepsis). ⋯ At 3 h postcecal incision, DMSO inhibited sepsis-induced hepatic NF-kappa B activation and hepatic ICAM-1 gene expression to control levels and suppressed serum TNF by 75%. In the late (6 h) septic phase, DMSO inhibited NF-kappa B activation (32%), ICAM-1 gene expression (27%), and TNF formation (71%). These findings suggest that the protective mechanism of antioxidants in septic rats may be partly due to the inhibition of NF-kappa B activation and NF-kappa B-mediated events.
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Nitric oxide (NO), cGMP, and cAMP affect the synthesis, metabolism, and cellular effects each other. We wanted to study how cGMP and cAMP interact to affect the induced synthesis of NO in response to interleukin-1 beta (IL-1 beta) in rat pulmonary artery smooth muscle cells. To further dissect the relative contributions of each cyclic nucleotide, and to detect any possible "crossover" effect of one cyclic nucleotide activating the other protein kinase, we tested how pharmacological inhibition of cGMP-dependent and cAMP-dependent protein kinases (PKG and PKA, respectively) affected responses. ⋯ Both cAMP and cGMP augment cytokine induction of NO synthesis through activation of PKA: cAMP does so directly; cGMP, through a crossover stimulation of PKA.
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Acute respiratory distress syndrome (ARDS) is seen in a variety of clinical settings in critically ill patients. ARDS has been defined as a clinical syndrome characterized by progressive hypoxemia, tachypnea, and generalized patchy bilateral pulmonary infiltrates in the absence of cardiac failure. Furosemide has been shown to improve pulmonary gas exchange and intrapulmonary shunt in animal models of ARDS by preferential perfusion of nonedematous lung units. We hypothesized that continuous dose furosemide would improve lung injury during resuscitation from oleic acid-induced lung injury in canines. ⋯ Continuous dose furosemide therapy improves LIS, PO2/FIO2, and Qs/Qt and decreases PEEP requirements in this oleic acid model of ARDS.
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Effects of lisofylline (1-(5-R-hydroxyhexyl)-3,7-dimethylxanthine), a functional inhibitor of phosphatidic acid (PA) generation derived from de novo synthesis, on neutrophil function were examined in a porcine sepsis model. Hanford minipigs (18-25 kg) were randomly separated into six groups of six animals each: (1) saline control group; (2) sepsis control group, infused with Pseudomonas aeruginosa (1 x 10(6) colony-forming units/kg/min) for 2 h; (3) lisofylline control group, given a 25 mg/kg bolus of lisofylline 30 min prior to time zero, followed by a continuous infusion of 10 mg/kg/h throughout the study; (4) lisofylline pretreatment sepsis group, given lisofylline 30 min prior to sepsis, (5) lisofylline 1-h post-treatment sepsis group, and (6) lisofylline 2-h post-treatment sepsis group. All animals were studied for 6 h. ⋯ Sepsis caused neutropenia, pretreatment produced neutrophilia, and 1-h post-treatment caused the neutropenia to recover to control levels. Interestingly, toward the end of the 6-h period, the neutrophil count was higher in the lisofylline control group than in the saline control groups. Thus, the inhibition of PA generation from de novo synthesis during sepsis not only can selectively downregulate some neutrophil functions but can also reverse neutropenia.
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We studied the hepato-splanchnic vascular response and changes in O2 extraction capabilities to a reduction in blood flow following endotoxemia. Fourteen anesthetized and mechanically ventilated dogs were divided into two groups of seven each. Group 1 received 2 mg/kg of E. coli endotoxin, and group 2 served as a control. ⋯ Whole body DO2crit at the onset of organ O2 supply dependency was similar under control (9.4 +/- 1.9 mL/kg. min for whole body, 10.3 +/- 4.7 mL/kg. min for liver, and 10.0 +/- 2.6 mL/kg. min for intestine) and endotoxic conditions (13.6 +/- 3.2 mL/kg. min for whole body, 15.6 +/- 2.7 mL/kg. min for liver, and 15.4 +/- 8.7 mL/kg. min for intestine). We conclude that fluid-resuscitated endotoxic shock in dogs is characterized by blood flow redistribution within the liver and intestine. Microvascular depression may be more severe in the liver than in the intestinal mucosa, although the whole body, the liver, and the intestine became O2 supply-dependent simultaneously.