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Biomedical subjects

M P Fink

Publications and source records attributed to M P Fink.

At least 19 recordsLinked to original sources
PubMed2001

Extremely low doses of tissue factor pathway inhibitor decrease mortality in a rabbit model of septic shock.

OBJECTIVE: We sought to determine the lowest dose of recombinant human tissue factor pathway inhibitor (TFPI) that can provide protection from lethality in a rabbit model of septic shock. METHODS: Sepsis was induced in New Zealand white rabbits by intraperitoneal implantation of 7.0 ml of a solution containing hemoglobin (4.8 g/dl), porcine mucin (6 g/dl), and 0.8-1.4 x 10(4) viable Escherichia coli (strain O:18 K+). Gentamicin (5 mg/kg) was administered 4 h following surgery, and this dose was repeated every 12 h for 3 days. Beginning 4 h following the induction of sepsis, animals were treated with a bolus (1 ml) plus a continuous infusion (100 ml over 24) of either TFPI (various doses) or its vehicle. Four different doses of TFPI were studied, and each experiment included a contemporaneous control group. The primary outcome parameter was survival time. Results were analyzed using the Wilcoxen log rank test. RESULTS: The average survival time for rabbits treated with the highest dose of TFPI tested (50 microg/kg bolus and 0.5 microg/kg per minute infusion) was 118 h, as compared to 81 h in vehicle-treated controls). The average survival time for septic rabbits treated with a much lower dose of TFPI (100 ng/kg bolus and 1.0 ng/kg per minute infusion) was 119 h as compared to 57 h in surviving vehicle-treated controls. Treatment with an even lower dose of TFPI (10 ng/kg bolus and 0.1 ng/kg per minute infusion) still produced a marginally significant prolongation of average survival time (80 h) relative to contemporaneously studied controls (47 h). When the dose of TFPI was decreased still further (1.0 ng/kg bolus and 0.01 ng/kg per minute infusion), average survival times were not significantly different between TFPI-treated and vehicle-treated rabbits (77 and 51 h, respectively). CONCLUSIONS: Delayed infusion with remarkably low doses of recombinant human TFPI prolongs survival in a rabbit model of antibiotic-treated Gram-negative bacterial sepsis. In planning human trials of TFPI as an adjuvant treatment for sepsis it may be reasonable to use much lower doses of the agent than were heretofore contemplated.

Animals↗
PubMed2001

Cytopathic hypoxia. Mitochondrial dysfunction as mechanism contributing to organ dysfunction in sepsis.

Several lines of evidence support the notion that cellular energetics are deranged in sepsis, not on the basis of inadequate tissue perfusion, but rather on the basis of impaired mitochondrial respiration and/or coupling; that is, organ dysfunction in sepsis may occur on the basis of cytopathic hypoxia. If this concept is correct, then the therapeutic implications are enormous. Efforts to improve outcome in patients with sepsis by monitoring and manipulating cardiac output, systemic Do2, and regional blood flow are doomed to failure. Instead, the focus should be on developing pharmacologic strategies to restore normal mitochondrial function and cellular energetics.

Adenosine Triphosphate↗
PubMed2001

Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.

OBJECTIVE: Pyruvate has been shown to be protective in numerous in vitro and in vivo models of oxidant-mediated cellular or organ system injury. Unfortunately, the usefulness of pyruvate as a therapeutic agent is abrogated by its very poor stability in solution. In an effort to take advantage of the ability of pyruvate to scavenge reactive oxygen species while avoiding the problems associated with the instability of pyruvate in solution, we sought to determine whether a simple derivative, ethyl pyruvate, would be protective in an animal model of reactive oxygen species-mediated tissue injury, namely mesenteric ischemia and reperfusion in rats. DESIGN: Prospective, randomized trial. SETTING: Animal research center. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Under general anesthesia, rats were subjected to 60 mins of mesenteric ischemia followed by 60 mins of reperfusion. Controls (n = 6) received intravenous lactated Ringer's solution according this dosing schedule: 1.5 mL/kg bolus before ischemia, 3.0 mL/kg bolus before resuscitation, and 1.5 mL.kg-1.hr-1 by continuous infusion. Two experimental groups received similar volumes of either pyruvate (n = 6 each) or ethyl pyruvate (n = 9) solution made up exactly like lactated Ringer's solution except for the substitution of either pyruvate or ethyl pyruvate for lactate, respectively. MEASUREMENTS AND MAIN RESULTS: To obtain tissues for assessing mucosal permeability and histology, five 10-cm long segments of small intestine were obtained at the following time points: baseline, after 30 and 60 mins of ischemia, and after 30 and 60 mins of reperfusion. Mucosal permeability to fluorescein isothiocyanate dextran (molecular weight 4000 Da) was assessed ex vivo by using an everted gut sac method. Compared with controls, treatment of rats with either pyruvate solution or ethyl pyruvate solution significantly ameliorated the development of intestinal mucosal hyperpermeability during the reperfusion. Treatment with ethyl pyruvate solution also significantly decreased the extent of histologic mucosal damage after mesenteric reperfusion. CONCLUSIONS: Treatment with Ringer's ethyl pyruvate solution ameliorated structural and functional damage to the intestinal mucosa in a rat model of mesenteric ischemia/reperfusion. Ethyl pyruvate solution warrants further evaluation as a novel therapeutic agent for preventing oxidant-mediated injury in various disease states.

Animals↗
PubMed2001

Ringer's ethyl pyruvate solution: a novel resuscitation fluid.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of the structural and functional alterations to tissues that are associated with a variety of pathological processes, including: sepsis and septic shock, thermal injury, doxorubicin-induced cardiomyopathy, hemorrhagic shock, and mesenteric ischemia/reperfusion (I/R) injury. Pyruvate (CH3COCOO-), a small molecule that is normally regarded as a key intermediate in the oxidative or anaerobic metabolism of glucose, is also a potent and effective ROS scavenger. Unfortunately, the usefulness of pyruvate as a therapeutic agent is abrogated by its very poor stability in solution. In an effort to take advantage of the ability of pyruvate to scavenge ROS while avoiding the problems associated with the instability of pyruvate in solution, we have developed a novel resuscitation fluid, which consists of a simple derivative of pyruvic acid, ethyl pyruvate, dissolved in a calcium-containing balanced salt solution. We call this solution Ringer's Ethyl Pyruvate Solution (REPS), and have shown in preliminary studies that treatment with REPS can improve outcome in a variety of animal models of critical illness.

Animals↗
PubMed2001

Cytopathic hypoxia in sepsis: a true problem?

It is increasingly apparent that organ dysfunction in sepsis is caused, at least in part, by an acquired intrinsic derangement in cellular oxidative adenosine triphosphate (ATP) production. We have termed this phenomenon "cytopathic hypoxia". Although several different but mutually compatible mechanisms might account for the development of cytopathic hypoxia in sepsis, recent data from our laboratory point to activation of the nuclear enzyme, poly-ADP-ribosyl polymerase (PARP), as being the most important.

Adenosine Diphosphate↗
PubMed2000

Roundtable conference on tissue oxygenation in acute medicine, Brussels, Belgium, 14-16 March 1998.

* Nutritional tissue perfusion and tissue metabolic demand are heterogeneously distributed. * Oxygen diffusion occurs preferentially at the precapillary arteriolar level. * Determination of adequacy of tissue oxygenation requires local organ measurements. * While there remains considerable variability in individual RBC transfusion practices, a recent clinical trial questioned the efficacy of RBC transfusion to hemoglobin concentrations greater than 80 gm/l in patients without heart disease [63]. * RBC substitutes, including cell-free hemoglobin solutions and PFC solutions are efficacious, yet may exhibit a number of direct vascular effects.

Belgium↗
PubMed2000

Mesenteric dysfunction after cardiopulmonary bypass: role of complement C5a.

BACKGROUND: We investigated the effects of cardiopulmonary bypass (CPB) on ileal homeostasis, and the influence of functional inhibition of complement C5a on CPB-induced mesenteric injury. METHODS: Pigs were perfused on CPB for 1 hour and then perfused off CPB for an additional 2 hours. Antiporcine C5a monoclonal antibody (C5a MAb) was administered 20 minutes before onset of CPB to 6 pigs; 6 controls received saline vehicle. Total complement activity, ileal myeloperoxidase, and indices of ileal integrity were examined. RESULTS: Treatment with C5a MAb ameliorated CPB-induced abnormalities in endothelium-dependent relaxation to ADP and substance P, and the hypercontractile response to phenylephrine of ileal microvessels (88 to 168 microm). Ileal myeloperoxidase activity [units/g protein] was 41 +/- 11 in the C5a MAb group, compared to 83 +/- 13 in the saline group (19 +/- 10 base line). Total hemolytic complement activity was similar in the C5a MAb and saline groups (0.6 +/- 0.2 and 0.7 +/- 0.2 CH50 units). During CPB, ileal mucosal blood flow and mucosal pH, edema formation, and epithelial permeability deteriorated similarly in saline and C5a MAb groups. Inducible nitric oxide synthase (iNOS) mRNA expression was similar before and after CPB. CONCLUSIONS: CPB is associated with significant physiologic alterations in mucosal perfusion, epithelial permeability, edema formation, and blood flow regulation. Inhibition of C5a limits neutrophil-mediated impairment of ileal microvascular regulation after bypass, but does not improve extravascular mesenteric dysfunction after CPB.

Animals↗
PubMed2000

Polarized transport of hydrophilic compounds across rat colonic mucosa from serosa to mucosa is temperature dependent.

BACKGROUND & AIMS: In both clinical and experimental studies, intestinal epithelial barrier function is routinely assessed by measuring mucosal permeability to various hydrophilic compounds. We performed experiments to determine whether permeation of several hydrophilic compounds across rat colonic mucosa is polarized. METHODS: Sheets of colonic mucosa, stripped of the underlying seromuscular coats, were mounted in Ussing chambers. RESULTS: The rates of permeation across colonic mucosa by numerous hydrophilic compounds (fluorescein isothiocyanate [FITC]-dextrans with molecular weights of 4000 [FD4] and 70,000 [FD70] daltons, fluorescein disulfonic acid [FS], lucifer yellow [LY], lactulose, and mannitol) were several times greater in the serosal-to-mucosal (S-->M) direction than in the opposite direction. Increased S-->M permeation by FD4, lactulose, and mannitol was evident at 37 degrees C, but not at 4 degrees C. Efflux of FD4 and FS in the S-->M direction was dose-dependently inhibited by verapamil, an inhibitor of the P-glycoprotein efflux system. Indomethacin, an anion transporter inhibitor, showed no effect on the S-->M permeation of FD4, FD70, FS, or LY. Adding an excess of unlabeled dextran (mol wt, 10,000 daltons) dose-dependently decreased the S-->M efflux of FD4, but not FS or LY. CONCLUSIONS: The transport across rat colonic mucosa of a number of hydrophilic substances, including some compounds that are commonly used to measure intestinal permeability in clinical practice, is greater in the S-->M than in the M-->S direction. S-->M transport of these hydrophilic solutes is temperature dependent, suggesting that the process is an active one. S-->M transport of FD4 may occur via a process that manifests some degree of substrate specificity for polysaccharides.

Animals↗
PubMed2000

Hypoxic signal transduction in critical illness.

Derangements in tissue perfusion occur during critical illness, and the resulting deficit in oxygen delivery may play an important role in the pathogenesis of hemorrhagic and septic shock. Cells and organisms have developed a variety of adaptive strategies to maintain adequate energy production to maintain normal cellular function under hypoxic conditions. Recent studies from our laboratory suggest that certain proinflammatory cytokines, which are likely to be elaborated during or after shock, can interfere with the ability of cells to adapt to hypoxia, and thereby contribute to the development of organ system dysfunction.

Critical Illness↗
PubMed2000

Lisofylline ameliorates intestinal and hepatic injury induced by hemorrhage and resuscitation in rats.

OBJECTIVE: We sought to determine whether treatment with lisofylline (LSF) preserves intestinal barrier function in rats subjected to hemorrhagic shock and resuscitation (HS/R). SETTING: Research laboratory at a major university teaching hospital. DESIGN: Rats were bled to a mean arterial pressure of 30 mm Hg and maintained at that pressure for 90 mins. One group (n = 8) was treated with LSF (bolus doses of 15 mg/kg at 45 and 89 min plus infusion at 10 mg x kg(-1) x hr(-1)), whereas another group (n = 8) received only the lactated Ringer's solution (LRS) vehicle. At 90 mins, the animals were resuscitated with shed blood and LRS (55 mL x kg(-1) x hr(-1)). Intestinal mucosal permeability was determined by measuring the mucosal-to-serosal clearance of fluorescein isothiocyanate dextran (molecular weight = 4 kDa) into everted gut sacs. MEASUREMENTS AND MAIN RESULTS: Intestinal and hepatic blood flow (assessed by laser Doppler flowmetry) was greater in LSF-treated rats. Treatment with LSF ameliorated the development of histologic evidence of mucosal damage and hyperpermeability. Rats treated with LSF had lower plasma concentrations of the intracellular hepatic enzyme, aspartate aminotransferase. After 90 mins of resuscitation, concentrations of adenosine triphosphate in intestinal and hepatic tissue were greater in LSF-treated as compared with LRS-treated rats, but concentrations of the endogenous antioxidant, glutathione, in intestinal and hepatic tissue, although lower than in rats not subjected to HS/R, were similar in the two treatment groups. CONCLUSION: Treatment with LSF ameliorated HS/R-induced derangements in intestinal structure and function and hepatic injury, possibly by preserving microvascular perfusion and tissue adenosine triphosphate concentrations.

Animals↗
PubMed2000

Ischemic preconditioning ameliorates ischemia- and reperfusion-induced intestinal epithelial hyperpermeability in rats.

We hypothesized that ischemic preconditioning (IPC) would ameliorate ischemia (I) and reperfusion (R)-induced intestinal mucosal hyperpermeability and that this effect would be diminished by lowering local adenosine concentrations using adenosine deaminase (ADA). The small intestine of anesthetized rats (group 1; n = 6) was divided into six 10-cm segments (A1-F1) each perfused by a different set of mesenteric branches. Segments D1-F1 were subjected to 3 cycles of IPC (2 min I/5 min R). Segments A1, B1, and C1 were excised at baseline, after 60 min of I (160), and after 60 min of I followed by 60 min of R (160/R60), respectively. Segment D1 was excised immediately after the last cycle of IPC, E1 was excised at 160 after IPC, and F1 was excised at 160/R60 after IPC. In group 2 (n = 6), the intestine was divided into five 10-cm vascularly isolated segments (A2-E2). Segment A2 was resected at baseline. The lumen of the remaining segments was filled with ADA (32 U/50 cm). Segment B2 was removed at the end of the experiment having been exposed to ADA for 150 min (ADA150). Segments C2, D2, and E2 were subjected to IPC. Segment C2 was excised immediately thereafter. Segments D2 and E2 were excised at 160 and 160/R60, respectively. Intestinal permeability to fluorescein isothiocyanate-labeled dextran (molecular weight 4000 D) was assessed ex vivo by using an everted gut sac method. IPC ameliorated intestinal hyperpermeability induced by 160 (43.0+/-7.6 vs. 70.4+/-8.3 nLmin/cm2; P = 0.024) and 160/R60 (20.2+/-3.7 vs. 69.5+/-10.8 nL/min/cm2; P= 0.003). IPC prevented ischemia-induced reduction in villus height. Treatment with ADA partially reversed the protective effect of IPC on the changes in permeability and villus height induced by I/R. We conclude that IPC partially protects against mucosal barrier dysfunction in rats subjected to mesenteric I/R. Adenosine is a mediator of IPC in the gut mucosa, but other factors also may be important.

Adenosine↗