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

1992 ◽  
Vol 263 (6) ◽  
pp. H1901-H1906 ◽  
Author(s):  
M. D. Menger ◽  
S. Pelikan ◽  
D. Steiner ◽  
K. Messmer
Keyword(s):  
Striated Muscle ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Microvascular Permeability ◽  
Leukocyte Rolling ◽  
Reactive Oxygen Metabolites ◽  
Oxygen Metabolites ◽  
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.

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

1992 ◽  
Vol 263 (6) ◽  
pp. H1892-H1900 ◽  
Author(s):  
M. D. Menger ◽  
D. Steiner ◽  
K. Messmer
Keyword(s):  
Shear Rate ◽  
Striated Muscle ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Capillary Density ◽  
Wall Shear Rate ◽  
Reactive Oxygen Metabolites ◽  
Capillary Perfusion ◽  
No Reflow ◽  
Oxygen Metabolites

“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.

Attenuation of postischemic microvascular disturbances in striated muscle by hyperosmolar saline dextran

1992 ◽  
Vol 263 (5) ◽  
pp. H1411-H1416 ◽  
Author(s):  
D. Nolte ◽  
M. Bayer ◽  
H. A. Lehr ◽  
M. Becker ◽  
F. Krombach ◽  
...  
Keyword(s):  
Striated Muscle ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Hypovolemic Shock ◽  
Fluorescein Isothiocyanate ◽  
Saline Control ◽  
Therapeutic Effects ◽  
Leukocyte Rolling ◽  
Capillary Perfusion ◽  
Dorsal Skinfold Chamber

The underlying mechanisms of the beneficial therapeutic effects of small-volume resuscitation with hyperosmolar solutions for treatment of hypovolemic shock are still poorly understood. Using the dorsal skinfold chamber model and intravital fluorescence microscopy, we investigated the effects of hyperosmolar saline dextran on ischemia-reperfusion injury in striated skin muscle of awake normovolemic golden hamsters. Test solutions (4 ml/kg body wt i.v.) were administered 2 min before reperfusion after 4 h of pressure-induced ischemia. In animals receiving 0.9% saline (control), we observed a drastic enhancement of leukocyte rolling along and sticking to the endothelium of postcapillary venules 0.5 h after reperfusion. Postischemic leukocyte rolling and sticking were significantly reduced when animals were treated with 7.2% saline alone (HSS), 10% Dextran 60 in 0.9% saline (HDS), or 10% Dextran 60 in 7.2% saline (HHS). In control animals, capillary perfusion was reduced to approximately 60% of preischemic values 0.5 h after reperfusion. Concomitantly, leakage of the macromolecule fluorescein isothiocyanate-dextran (5 mg in 0.1 ml saline i.v., M(r) 150,000) into the perivascular space increased from 0% before ischemia to approximately 12% at 0.5 h reperfusion. In contrast, when animals were treated with HSS, HDS, or HHS before reperfusion, capillary perfusion decreased to a significantly minor extent of approximately 15%, and macromolecular leakage was slightly increased to approximately 5%. Our results suggest that hyperosmolar saline dextran effectively attenuates postischemic microvascular disturbances elicited by ischemia-reperfusion, presumably through reduction of postischemic leukocyte-endothelium interaction and capillary swelling.

Reactive oxygen species mediate modification of glycocalyx during ischemia-reperfusion injury

2006 ◽  
Vol 290 (6) ◽  
pp. H2247-H2256 ◽  
Author(s):  
Ivan Rubio-Gayosso ◽  
Steven H. Platts ◽  
Brian R. Duling
Keyword(s):  
Reactive Oxygen Species ◽  
Binding Sites ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Control Site ◽  
Oxygen Species ◽  
Heparin Binding ◽  
Heparin Binding Domain

The glycocalyx (Gcx) is a complex and poorly understood structure covering the luminal surface of endothelial cells. It is known to be a determinant of vascular rheology and permeability and may be a key control site for the vascular injuries caused by ischemia-reperfusion (I/R). We used intravital-microscopy to evaluate the effects of I/R injury on two properties of Gcx in mouse cremasteric microvessels: exclusion of macromolecules (anionic-dextrans) and intracapillary distribution of red blood cells (RBC). In this model, the Gcx is rapidly modified by I/R injury with an increase in 70-kDa anionic-dextran penetration without measurable effect on the penetration of 580-kDa anionic-dextran or on RBC exclusion. The effects of I/R injury appear to be mediated by the rapid production of reactive oxygen species (ROS) because they are ameliorated by the addition of exogenous superoxide dismutase-catalase. Intravenous application of allopurinol or heparin also inhibited the effects of I/R injury, and we interpret efficacy of allopurinol as evidence for a role for xanthine-oxidoreductase (XOR) in the response to I/R injury. Heparin, which is hypothesized to displace XOR from a heparin-binding domain in the Gcx, reduced the effects of I/R. The effects of I/R injury were also partially prevented or fully reversed by the intravascular infusion of exogenous hyaluronan. These data demonstrate: 1) the liability of Gcx during I/R injury; 2) the importance of locally produced ROS in the injury to Gcx; and 3) the potential importance of heparin-binding sites in modulating the ROS production. Our findings further highlight the relations between glycosaminoglycans and the pathophysiology of Gcx in vivo.

Oxidant Mechanisms in Glomerular Injury

Physiology ◽  
1988 ◽  
Vol 3 (6) ◽  
pp. 254-257
Author(s):  
SV Shah
Keyword(s):  
Reactive Oxygen ◽  
In Vivo Studies ◽  
Reactive Oxygen Metabolites ◽  
Glomerular Injury ◽  
Oxygen Metabolites

An increasing body of evidence derived from both in vitro and in vivo studies utilizing leukocyte-dependent and leukocyte-independent models of glomerulonephritis suggests an important role for reactive oxygen metabolites in glomerular pathophysiology.

Hypoxic reperfusion attenuates postischemic microvascular injury

1989 ◽  
Vol 256 (1) ◽  
pp. H315-H319 ◽  
Author(s):  
R. J. Korthuis ◽  
J. K. Smith ◽  
D. L. Carden
Keyword(s):  
Skeletal Muscle ◽  
Molecular Oxygen ◽  
Vascular Resistance ◽  
Ischemia Reperfusion ◽  
Autologous Blood ◽  
Reactive Oxygen ◽  
Reactive Oxygen Metabolites ◽  
Solvent Drag ◽  
Arterial Po2 ◽  
Oxygen Metabolites

The results of several recent studies have demonstrated that reactive oxygen metabolites are responsible for a major portion of ischemia/reperfusion (I/R) injury in skeletal muscle. Presumably, the cytotoxic oxidants are produced during reperfusion when molecular oxygen (the source of the reactive oxygen metabolites) is reintroduced to the tissues. The purpose of this study was to test the hypothesis that molecular oxygen must be provided at reperfusion to produce I/R injury in skeletal muscle. Isolated, maximally vasodilated (papaverine) canine gracilis muscles were reperfused, after 4 h of inflow occlusion, from reservoirs containing autologous blood equilibrated with either 95% O2-5% CO2 or 95% N2-5% CO2 gas mixtures. Arterial PO2 fell from approximately 120 mmHg to less than 3-5 mmHg, during the use of nitrogen. The solvent drag reflection coefficient for total plasma proteins (sigma f) and total vascular resistance was determined for the following conditions: control (no ischemia), reperfusion with oxygenated blood after 4 h ischemia; and reperfusion (after 4 h ischemia), first with anoxic blood and then oxygenated blood. Reperfusion with oxygenated blood, after 4 h of ischemia, significantly reduced solvent drag reflexion coefficient (sigma f) from 0.93 +/- 0.02 to 0.63 +/- 0.02, indicating a dramatic increase in vascular permeability. Total vascular resistance increased from 6.1 +/- 1.1 mmHg.ml-1.min.100 g during the preischemic period to 12.9 +/- 3.0 mmHg.ml-1.min.100 g during normoxic reperfusion. In muscles reperfused with anoxic blood, sigma f averaged 0.82 +/- 0.06, whereas vascular resistance increased by 56 +/- 13%.(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver

1991 ◽  
Vol 260 (3) ◽  
pp. G355-G362 ◽  
Author(s):  
H. Jaeschke ◽  
A. Farhood
Keyword(s):  
Reperfusion Injury ◽  
Kupffer Cell ◽  
Kupffer Cells ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Oxidant Stress ◽  
Plasma Concentrations ◽  
Reactive Oxygen ◽  
Reperfusion Period

The hypothesis that Kupffer cells and infiltrating neutrophils generate reactive oxygen in the hepatic sinusoids and may contribute to ischemia-reperfusion injury in the liver was investigated in a model of partial no-flow ischemia and reperfusion in male Fischer rats in vivo. During the reperfusion period of 60 min, plasma concentrations of glutathione disulfide (GSSG; index of oxidant stress) increased from 1.62 +/- 0.20 microM glutathione (GSH) equivalents to maximal values of 11.82 +/- 1.45 (45 min ischemia), 24.19 +/- 2.35 (60 min ischemia), and 70.20 +/- 7.8 (120 min ischemia). The basal tissue GSSG content in the postischemic lobes (0.19 +/- 0.02 nmol GSH eq/mg protein) increased by 50-100%. Although the number of neutrophils in liver and lung increased by 3- to 10-fold during reperfusion, there was no positive correlation between the number of neutrophils and the GSSG concentrations measured in plasma or tissue. However, activation of Kupffer cells with high doses of retinol or with Propionibacterium acnes significantly enhanced plasma GSSG levels, while inactivation of Kupffer cells with methyl palmitate or gadolinium chloride significantly attenuated the increase of plasma GSSG. Inactivation of Kupffer cells protected the liver significantly against ischemia-reperfusion injury. It is concluded that Kupffer cells are the predominant source of reactive oxygen formed during the initial reperfusion period and that Kupffer cell activity (including reactive oxygen formation) contributes to reperfusion injury in the liver in vivo.

scholarly journals Xanthine oxidase and neutrophil infiltration in intestinal ischemia

1986 ◽  
Vol 251 (4) ◽  
pp. G567-G574 ◽  
Author(s):  
M. B. Grisham ◽  
L. A. Hernandez ◽  
D. N. Granger
Keyword(s):  
Superoxide Dismutase ◽  
Xanthine Oxidase ◽  
Reduced Glutathione ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Neutrophil Infiltration ◽  
Mucosal Injury ◽  
Ischemia And Reperfusion ◽  
Reactive Oxygen Metabolites ◽  
Oxygen Metabolites

A growing body of experimental data indicates that reactive oxygen metabolites such as superoxide, hydrogen peroxide, and hydroxyl radical may mediate the mucosal injury produced by reperfusion of ischemic intestine. Xanthine oxidase has been proposed as the primary source of these reduced O2 species because pretreatment with xanthine oxidase inhibitors such as allopurinol or pterin aldehyde prevent postischemic mucosal injury. Another potential source of oxygen radicals is the inflammatory neutrophil. To ascertain whether neutrophils could play a role in the pathogenesis of ischemia-reperfusion injury in the small bowel we examined the effect of ischemia and reperfusion on neutrophil infiltration and tissue levels of reduced glutathione, superoxide dismutase, and catalase. Our studies demonstrate that reperfusion of ischemic intestines results in a dramatic increase (1,800%) in neutrophil infiltration and a concurrent loss of reduced glutathione and superoxide dismutase of 60 and 30%, respectively. Catalase activity was unaffected by ischemia-reperfusion. Pretreatment with allopurinol or administration of superoxide dismutase prevented the influx of neutrophils and retarded the drop in reduced glutathione levels. These results suggest a relationship among xanthine oxidase-generated oxy radicals, neutrophil extravasation, and mucosal damage. We propose that ischemia and reperfusion results in xanthine oxidase-generated, superoxide-dependent accumulation of inflammatory neutrophils in the mucosa where neutrophil-derived reactive oxygen metabolites mediate and/or exacerbate intestinal injury.

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