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Biomedical subjects

M D Menger

Publications and source records attributed to M D Menger.

At least 235 records · Page 13Linked to original sources
PubMed1993

[Microcirculation of skeletal muscle after ischemia and reperfusion].

The postischemic reperfusion-damage in the microcirculation of skeletal muscle is characterized by 1) heterogenous capillary perfusion with capillary perfusion deficiency ("no reflow"), 2) microvascular accumulation of leukocytes, which adhere to the endothelium of postcapillary venules, and 3) increase of vessel permeability with swelling of endothelial cells and with interstitial edema. Two models of pathomechanism may be differentiated: The capillary perfusion-deficiency of the no-reflow phenomenon prolongs the duration of ischemia extending the period of postischemic reperfusion and induces the tissue-damage by further decrease of tissue-pH, by loss of energy rich phosphates and by a deficit of oxygen supply to tissue. On the other hand, reperfusion with consecutive reentry of molecular oxygen into the microvasculature provokes the formation of oxygen-radicals and the accumulation of leukocytes adhering to the endothelium of postcapillary venules ("reflow-paradox"). The activated white blood cells release additional oxygen-radicals and deliver aggressive mediators, such as proteases, cytokines and eicosanoids, which have chemotactic influence on leukocytes. This results in a vicious circle in which oxygen-radicals and mediators are responsible for the augmentation of postischemic tissue-damage. Prophylactic isovolemic hemodilution to a hematocrit of 30% with dextran 60 reduces the postischemic capillary perfusion deficiency (no reflow); therapy with "oxygen radical scavengers" and xanthinoxydase-inhibitors reduces accumulation/adherence of leukocytes as well as the damage to the endothelial lining with increased microvascular permeability (reflow-paradox). Intermittent reperfusion/reoxygenation influences both components of postischemic microcirculation damage and is therefore a simple clinical approach for reducing the ischemia/reperfusion-syndrome in elective surgery.

Animals↗
PubMed1993

Impact of leukocyte adhesion on myocardial ischemia/reperfusion injury: conceivable mechanisms and proven facts.

Leukocyte activation, adhesion, and emigration serve a protective role during a well-contained inflammatory response. However, under certain pathologic conditions such as endotoxemia, inflammatory bowel disease, and ischemia-reperfusion injury, leukocytes may turn against the host and aggravate--rather than prevent--tissue damage. Numerous experimental studies have been performed during the last decade to investigate the pathophysiologic role of leukocyte accumulation and adhesion during ischemia/reperfusion injury of various organs, in particular of the myocardium. Most of the latter studies investigated whether the consequences of experimental myocardial infarction could be attenuated by interventions aimed at the inhibition of chemotactic leukocyte infiltration or adhesion (or both) to microvascular endothelial cells. Although many promising results were reported, the consequent step towards an introduction of these strategies into experimental or even routine clinical management of patients with myocardial infarction has so far not been undertaken. In this manuscript, the authors try to give an overview on the state of the art of "antileukocyte" strategies in myocardial ischemia-reperfusion injury and to offer explanations for incongruent data obtained with diverse experimental approaches (animal species, treatment modalities, surgical and anesthesiologic artifacts, techniques for morphologic and functional evaluation of tissue damage). The authors conclude that long-term preclinical studies on suitable animal models, thoroughly investigating the positive and negative effects of antileukocyte interventions on the functional consequences of myocardial ischemia-reperfusion injury, are mandatory before the first clinical trial can be advocated.

Animals↗
PubMed1993

Involvement of 5-lipoxygenase products in cigarette smoke-induced leukocyte/endothelium interaction in hamsters.

Although cigarette smoke (CS) has been identified as an independent risk factor for atherogenesis and sudden cardiac death, the underlying pathomechanism has not been clarified. A common factor of both atherogenesis and ischemia/reperfusion damage associated with myocardial infarction is the adhesion of circulating leukocytes to the vascular endothelium. Searching for the mechanism by which CS exerts its deleterious effects on the cardiovascular system, we used a dorsal skinfold chamber model in hamsters for intravital microscopy to examine the effect of CS on the interaction of fluorescently stained leukocytes with the microvascular endothelium in striated muscle. Exposure of awake animals (n = 7) for 5 minutes to the mainstream smoke of one cigarette (2R1 research cigarette) elicited rolling and subsequent adhesion of circulating leukocytes to the endothelium of both arterioles and postcapillary venules with a maximum 30 minutes after CS-exposure. In order to test a putative mediator role of the chemotactic and adhesion-promoting leukotrienes in this event, we pretreated another group of 7 animals with MK-886, a potent and specific inhibitor of leukotriene biosynthesis (20 mumol/kg body weight, iv, 30 minutes prior to CS exposure). While no inhibitory effect was seen on CS-induced leukocyte rolling along the microvascular endothelium. MK-886 pretreatment significantly attenuated leukocyte adhesion to arterioles (5.2 +/- 13.7 cells/mm2 vs. 54.1 +/- 54.8 in control animals. P < 0.01) and venules (37.0 +/- 33.6 cells/mm2 vs. 161.6 +/- 91.1 in control animals, P < 0.01), 30 minutes after CS exposure, suggesting a key mediator role of leukotrienes in this event. We propose that the stimulation of leukocyte/endothelium interaction by CS may provide the pathophysiologic basis for--or at least contribute to--its deleterious effects on cardiovascular mortality and morbidity. The identification of the mediator role of leukotrienes in this event may open the way to novel pharmacologic and dietary approaches for the prophylaxis of CS-induced cardiovascular pathology.

Animals↗
PubMed1993

[Microcirculation of the liver in hemorrhagic shock in the rat and its significance for energy metabolism and function].

INTRODUCTION: Shock induced microcirculatory failure is proposed to be causative for the impairment of hepatic function, which contributes to the development of multiple organ failure. In order to quantify the interrelation between hepatic microcirculatory disturbances and organ dysfunction, we have analyzed hepatic microcirculation (in vivo microscopy), energy metabolism (ketone body ratio) and liver excretory function (bile flow) during hemorrhagic shock in rats. METHODS: Under chloralose anesthesia and mechanical ventilation Sprague-Dawley rats (n = 6) were laparotomized and the left liver lobe was exteriorized for in vivo fluorescence microscopy. Sinusoidal perfusion was assessed after i.v. injection of Na-fluorescein (2 mumol.kg-1), in vivo staining of white blood cells by Rhodamin-6G (0.1 mumol.kg-1 i.v.) enabled for analysis of leukocyte-endothelium interaction. Erythrocyte flux was measured by means of laser Doppler flowmetry. Hepatic function was estimated by measurement of bile flow via cannulation of the common bile duct. Ketone body ratio (acetoacetate/beta-hydroxybutyrate, Ac-Ac/beta-OHB) was measured spectrophotometrically from arterial blood and served as indicator of hepatic energy metabolism (n = 12). After baseline recordings hemorrhagic shock (MAP: 40 mmHG) was induced by blood withdrawal and maintained for a total of 2 h. Measurements were performed during baseline as well as 1 h and 2 h after induction of hemorrhage. RESULTS: After 1 h and 2 h of hemorrhagic shock sinusoidal perfusion was found markedly impaired (p < 0.05) from 100% (baseline) to 78.3 +/- 2.4% and 60.9 +/- 13.4%, accompanied by a significant fall of erythrocyte flux to 52 +/- 2% and 46 +/- 4% (p < 0.05). Leukocyte velocity was significantly (p < 0.05) reduced both in sinusoids and in postsinusoidal venules, while leukocyte adherence to the endothelial lining cells was found increased (sinusoids: 183.2 +/- 55.6% and 178.8 +/- 39.0% (p < 0.05); postsinusoidal venules: 232.4 +/- 43.1% and 297.6 +/- 65.8% (p < 0.05)). In addition, 2 h of hemorrhagic shock caused an increase of beta-OHB, while Ac-Ac levels remained unchanged. This resulted in a significant reduction of ketone body ratio. Concomitantly, bile production was significantly decreased from 20.8 +/- 2.9 microliters.min-1 during control to 6.1 +/- 1.0 microliter.min-1 after 2 h of shock (p < 0.05). The alteration of energy metabolism and the impairment of bile flow correlated significantly (p < 0.01) with the extent of microcirculatory disturbances. CONCLUSION: Liver microcirculation in hemorrhagic shock is characterized by sinusoidal perfusion failure with a reduction of erythrocyte flux, leukocyte velocity and enhancement of leukocyte adherence to the microvascular endothelial lining. Correlation of the impairment of energy metabolism and liver dysfunction with these microcirculatory disturbances may indicate their crucial role in the development of shock-induced organ failure.

Animals↗
PubMed1992

Angiogenesis, microvascular architecture, microhemodynamics, and interstitial fluid pressure during early growth of human adenocarcinoma LS174T in SCID mice.

To date, most quantitative information on tumor angiogenesis, microcirculation, and transport has been derived from rodent tumors grown in transparent chamber preparations. In this paper we present a chamber technique adapted to immunodeficient mice for the study of human tumor xenografts. Microcirculatory parameters in severe combined immunodeficient mice bearing a dorsal skin fold chamber preparation were quantified using intravital microscopy and image analysis. The take rate of the human colon adenocarcinoma LS174T in the chamber preparation was 100%, and the tumor area doubling time was 6.5 days. Three days following implantation of 2 x 10(5) tumor cells onto the striated skin muscle, capillary sprouts were noted in the tumor cell mass. Microvasculature in the tumors was established after 10 days. Capillary density, vessel diameter, red blood cell velocity, and blood flow rates in individual microvessels measured on days 10, 14, 18, and 22 showed no statistical difference in the striated muscle (capillaries) and subcutaneous tissue (arterioles and venules) of the skin of tumor-free animals (N = 6), whereas these parameters increased slightly, but not significantly, in the LS174T tumors (N = 7). Mean interstitial fluid pressure (+/- SD) in these small tumors was 4.6 +/- 1.7 mmHg (N = 4) on day 10 and 5.1 +/- 0.9 mmHg (N = 4) on day 22 and significantly elevated compared to that in the subcutaneous and skin tissue (-0.9 +/- 0.8 mmHg) (N = 4) (P < 0.001). To our knowledge, this is the first model enabling intravital microscopic studies of human tumor xenografts in a transparent chamber preparation in severe combined immunodeficient mice. Studies on angiogenesis, microcirculation, and transport using such a preparation should provide new insights into microcirculation-mediated mechanisms for cancer treatment.

Adenocarcinoma↗
PubMed1992

Assessment of hepatic phagocytic activity by in vivo microscopy after liver transplantation in the rat.

Phagocytic activity of sinusoidal lining cells was studied in 32 livers of male Lewis rats by in vivo fluorescence microscopy with epiillumination. Normal livers (group 1, n = 8) were compared with orthotopic syngeneic liver grafts 90 min after reperfusion after a period of cold storage in University of Wisconsin solution for 17 hr (group 2, n = 10) or 24 hr (group 3, n = 14). After bolus injection of fluorescence-labeled latex particles (3 x 10(8)/kg; diameter = 1.1 micron), zonal distribution and kinetics of adherence of latex beads were quantified by off-line video analysis. Hepatocellular function was estimated by the rate of bile production and biliary concentrations of bile acids. In normal livers 50%, 37% and 13% of injected latex beads adhered in zones 1, 2 and 3, respectively, whereas in transplanted livers a more homogeneous distribution was found (group 2: 37%, 41%, 22%; group 3: 37%, 39%, 24%; p less than 0.01 vs. controls by analysis of variance). Kinetic analysis of phagocytic activity showed no significant difference between group 1 (88% adherence of visible latex beads 3 min after injection) and group 2 (90% adherence). However, after long-term preservation in group 3, sinusoidal adherence was significantly faster (96.4% adherence; p less than 0.001). Bile secretion in group 2 was lower than in controls and severely depressed in group 3 (group 1: 1.1 +/- 0.07 microliter/min/gm liver [mean +/- S.E.M.]; group 2: 0.8 +/- 0.07; group 3: 0.1 +/- 0.04; p less than 0.001) without significant changes in bile acid concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1992

Distribution pattern of capillary and venular red blood cell velocity following ischemia-reperfusion in striated muscle.

Ischemia-reperfusion induced changes in distribution pattern of RBC-velocity of nutritive capillaries and postcapillary venules was analyzed in striated muscle using intravital fluorescence microscopy in awake hamsters. Four hours of ischemia to striated muscle contained in the dorsal skinfold preparation (n = 10) revealed a significant (p < 0.01) decrease of capillary, but only a slight decrease of mean venular RBC-velocity during the entire reperfusion period. However, analysis of distribution pattern of single values revealed a shift of the histograms to the left, including pronounced skewness as mean values approached zero. This characteristic phenomenon may be due to an increase of microvascular hematocrit and/or decrease in deformability of red blood cells during ischemia-reperfusion. Beside other factors, the impairment of flow properties and flow conditions of the blood may contribute to the development of microvascular reperfusion injury.

Animals↗
PubMed1992

Influence of cryopreservation on viability and nutritional microcirculation of islets of Langerhans.

Isolated pancreatic islets of Syrian golden hamsters were cryopreserved for 1 and 10 weeks, respectively. Following thawing islet mass was found more than 90%. Analysis of viability of these islets by dithizone staining revealed 94 +/- 4% (1 week cryopreservation) and 96 +/- 3% (10 weeks cryopreservation) positively stained islets. After implantation into dorsal skin-fold chambers of syngeneic animals, intravital fluorescence microscopy (5% FITC-dextran, i.v.) showed a regular microvascular network 10 days after implantation. The total diameter of the microvascular network was found similar in cryopreserved islets (day 10: 420.8 +/- 55.2 microns (1 week preservation) and 406.5 +/- 25.2 (10 weeks preservation)) as compared to non-preserved controls (day 10: 411.7 +/- 53.9 microns). Therefore we conclude that cryopreservation of hamster islet isografts for 1 and 10 weeks, respectively, does not alter viability as well as the potential for revascularization. Cryopreservation seems to be an adequate technique for long time storage prior to free transplantation.

Animals↗
PubMed1992

In vivo assessment of neovascularization and incorporation of prosthetic vascular biografts.

Neovascularization plays a major role in prosthetic vascular graft healing. New developments in manufacturing biomaterials have encouraged the use of biological and biosynthetic materials for both arterial replacement and bypass procedures. We have analyzed in vivo the process of neovascularization and incorporation of biolized bovine carotid artery (Solco P), a biological material, and the composite of ovine collagen and polyester mesh (Omniflow), a biosynthetic material. The synthetic fabric polytetrafluorethylene (e-PTFE), which is widely used in cardiovascular surgery, served as control. Using the dorsal skinfold chamber of the Syrian golden hamster as site for implantation (n = 15), angiogenesis and neovascularization were analyzed quantitatively by means of intravital fluorescence microscopy. In each chamber a piece (approximately 1 mm2) of each of the three vascular grafts was implanted. Five days after implantation neovascularization was ascertained in 90% of the Omniflow grafts, while only 40% of the PTFE and 20% of the Solco P implants revealed new ingrowing microvessels. On day 10 the density of newly formed microvessels was significantly higher (p less than 0.01) in Omniflow grafts (263.5 +/- 24.1 cm-1) as compared to PTFE (134.2 +/- 20.8 cm-1) and Solco P (153.2 +/- 32.0 cm-1). In addition, the biosynthetic composite revealed a larger extension of neovascularization into the perigraft tissue, and 12 days after implantation these grafts were most tightly incorporated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Capillary blood perfusion during postischemic reperfusion in striated muscle.

Monitoring of nutritive blood flow in muscle is of particular importance to reconstructive surgeons, since ischemia/reperfusion in striated muscle is known to result in postischemic microvascular perfusion failure. Laser Doppler flowmetry has recently been introduced as an easy-to-use, noninvasive technique for continuous monitoring of microvascular tissue perfusion. Despite its popularity, there exists a great deal of controversy as to what actually generates the laser Doppler signal recorded from a given tissue. Intravital microscopy is a technique for direct visualization of the nutritional circulation in tissue. By using intravital microscopy, direct measurements of blood perfusion in individual segments of the nutritional microcirculation can be made. In 22 Syrian golden hamsters we performed laser Doppler flowmetry and intravital microscopy measurements in muscle tissue prior to and during reperfusion after 4 hours of tourniquet ischemia using the dorsal skinfold chamber model. Intravital microscopy (n = 10) revealed a heterogeneous capillary perfusion during the early reperfusion phase with a decrease (p less than 0.01) in functional capillary density to 49.4 +/- 17.0 percent of control. No recovery was observed after 24 hours of reperfusion. Laser Doppler flowmetry (n = 12) showed a parallel reduction of capillary red blood cell flux during the early perfusion phase to 43.9 +/- 22.6 percent of control values (p less than 0.01), and no recovery was observed after 24 hours of reperfusion. However, the laser Doppler flowmetry technique was not able to detect the capillary perfusion inhomogeneities shown by intravital microscopy. Postischemic reperfusion in striated muscle is characterized by a decrease in functional capillary density and a heterogeneous capillary perfusion. Laser Doppler flowmetry is a useful tool for monitoring microvascular tissue perfusion, although in striated muscle of the hamster it must be considered that accurate nutritional "capillary" flow readings can be grossly overestimated if larger vessels, such as arterioles and collecting venules, are contained in the measuring field of the laser Doppler probe.

Animals↗
PubMed1992

The impact of arterialization on hepatic microcirculation and leukocyte accumulation after liver transplantation in the rat.

This study investigated the influence of hepatic arterialization on early graft function, microcirculation, and leukocyte-endothelial interaction after syngeneic orthotopic liver transplantation in Lewis rats. Livers were preserved for 17 hr in UW solution and transplanted without rearterialization (group 1: n = 10) or with immediate arterial reconstruction (group 2: n = 10). Graft function was analyzed by bile flow; microcirculation was assessed by laser Doppler flowmetry (LDF) and intravital microscopy (IVM). In addition, flow behavior of leukocytes was quantified by IVM after i.v. injection of the WBC marker acridine orange. Improved graft function in group 2 was indicated by increased bile production during the observation period of 90 min after reperfusion (7.18 +/- 0.62 vs. 3.63 +/- 0.63 ml/100 g liver [mean +/- SEM] P < 0.001). In arterialized grafts LDF values increased by 22.9 +/- 3.8% upon reperfusion of the hepatic artery (P = 0.004). Arterialization increased WBC velocities in sinusoids (group 1: 0.29 +/- 0.02 mm/sec, group 2: 0.34 +/- 0.01 mm/sec, P < 0.001) and postsinusoidal venules (0.43 +/- 0.05 vs. 0.64 +/- 0.05 mm/sec, P = 0.029). In addition, the number of nonperfused midzonal sinusoids decreased significantly (8.5 +/- 2.2% of all sinusoids analyzed vs. 4.2 +/- 1.3%, P = 0.048). However, the marked sinusoidal and venular WBC adherence observed 1 hr after reperfusion was not altered by arterialization. It is concluded that arterial reconstruction in rat liver transplantation improves microvascular perfusion and graft function but this improvement does not relate to WBC accumulation within the graft. We propose that studies on hepatic preservation and postischemic reperfusion in the rat should be based on the physiological model of dual vascularization.

Animals↗
PubMed1992

Microvascular ischemia-reperfusion injury in striated muscle: significance of "no reflow".

"No reflow" has been implicated as prominent phenomenon in microvascular injury associated with ischemia-reperfusion (I/R). The objectives of this study were 1) to elucidate the significance of no reflow in microvascular I/R injury of striated muscle and 2) to determine whether reactive oxygen metabolites play a role in the development of postischemic no reflow. By use of the hamster dorsal skinfold preparation and intravital microscopy, microvascular perfusion of capillaries and postcapillary venules of striated muscle was quantitatively assessed before and 30 min, 2 h, and 24 h after 4 h of tourniquet-induced ischemia. I/R was characterized by a significant reduction (P < 0.01) in functional capillary density to 35% of baseline values during initial reperfusion, with incomplete recovery after 24 h (n = 9). In addition, capillary perfusion was found to be extremely heterogeneous, and wall shear rate in postcapillary venules was significantly decreased (P < 0.01). Treatment with either superoxide dismutase (SOD; n = 9) or allopurinol (n = 9) resulted in maintenance of capillary density of 60% of baseline (P < 0.05). Furthermore, I/R-induced capillary perfusion inhomogeneities and decrease of wall shear rate in venules were attenuated significantly (P < 0.01) by SOD and allopurinol. Thus part of capillary perfusion disturbances during I/R in striated muscle may be caused by increased postcapillary vascular resistance, probably mediated by reactive oxygen metabolites. However, the fact that in SOD- and allopurinol-treated animals 40% of the capillaries were still found to be nonperfused indicates that mechanisms other than oxygen radicals play an important role in the development of postischemic no reflow.

Allopurinol↗
PubMed1992

Microvascular ischemia-reperfusion injury in striated muscle: significance of "reflow paradox".

Ischemia-reperfusion (I/R)-induced microvascular injury is characterized by capillary "no-reflow" and reflow-associated events, termed "reflow paradox," including leukocyte-endothelium interaction and increase in microvascular permeability. The major objectives of this study were 1) to elucidate the significance of reflow paradox after 4 h of tourniquet-induced ischemia in striated muscle and 2) to determine the role of reactive oxygen metabolites in the pathogenesis of reflow paradox-dependent microcirculatory alterations. By use of in vivo fluorescence microscopy in a striated muscle preparation of hamsters, leukocyte-endothelium interaction in postcapillary venules and macromolecular extravasation from capillaries and venules were quantified before ischemia and after 30 min, 2 h, and 24 h of reperfusion. I/R elicited marked enhancement (P < 0.01) of leukocyte rolling during initial reperfusion and a 20-fold increase of leukocyte adherence (P < 0.01) lasting for the entire postischemic reperfusion period (n = 7). These phenomena were accompanied by significant leakage (P < 0.01) of macromolecules from capillaries and in particular from postcapillary venules (n = 9). Both superoxide dismutase (SOD, 20 mg/kg body wt, n = 7) and allopurinol (50 mg/kg body wt, n = 7) were effective in attenuating I/R-induced leukocyte rolling and adherence. In addition, microvascular leakage was significantly reduced by allopurinol (n = 9) and completely abolished by SOD (n = 9) (P < 0.01). These results support the concept that reactive oxygen metabolites contribute to I/R-induced reflow paradox, resulting in leukocyte accumulation, adherence, and increase in microvascular permeability.

Allopurinol↗