Microvascular perfusion deficits are not a prerequisite for mucosal injury in septic rats

1999 ◽  
Vol 276 (4) ◽  
pp. G933-G940 ◽  
Author(s):  
R. R. Nevière ◽  
M. L. Pitt-Hyde ◽  
R. D. Piper ◽  
W. J. Sibbald ◽  
R. F. Potter
Keyword(s):  
Cell Injury ◽  
Mucosal Injury ◽  
Endotoxin Tolerance ◽  
Capillary Density ◽  
Microvascular Perfusion ◽  
Myeloperoxidase Activity ◽  
Capillary Perfusion ◽  
Ileal Mucosa ◽  
Mucosal Permeability ◽  
Perfusion Deficits

Our major objective was to investigate whether injury to the mucosa of the small intestine occurred in a normotensive model of sepsis and whether such injury was associated with microvascular perfusion deficits. Using fluorescence intravital microscopy, we show direct evidence of cell injury within the mucosa (pneumonia 12.4 ± 2.6 cells/field, sham 2.2 ± 0.7 cells/field), whereas use of51Cr-labeled EDTA showed evidence of increased mucosal permeability (pneumonia 1.90 ± 0.67 ml · min−1 · 100 g−1; sham 0.24 ± 0.04 ml · min−1 · 100 g−1), 48 h following induction of pneumonia. Despite such injury the capillary density in the ileal mucosa and submucosa of pneumonic rats (1,027 ± 77 and 1,717 ± 86 mm2) was not significantly different compared with sham (998 ± 63 and 1,812 ± 101 mm2). However, a modest albeit significant decrease in capillary perfusion was measured in the muscularis layer of pneumonia (11.0 ± 1.3 mm) compared with sham (13.9 ± 0.63 mm) and appeared to be associated with leukocyte entrapment. Pretreatment using low doses of endotoxin to induce endotoxin tolerance not only increased muscularis capillary density but reduced the number of leukocytes trapped within the microvasculature, decreased myeloperoxidase activity within the ileum in pneumonic rats, and prevented mucosal injury. In conclusion, we have shown that pneumonia results in remote injury to the mucosa of the ileum and that such injury was not associated with concurrent mucosal perfusion deficits.

Antithrombin reduces leukocyte adhesion during chronic endotoxemia by modulation of the cyclooxygenase pathway

2000 ◽  
Vol 279 (1) ◽  
pp. C98-C107 ◽  
Author(s):  
J. N. Hoffmann ◽  
B. Vollmar ◽  
D. Inthorn ◽  
F. W. Schildberg ◽  
M. D. Menger
Keyword(s):  
Endothelial Cell ◽  
Leukocyte Adhesion ◽  
Repeated Administration ◽  
Capillary Density ◽  
Cell Interaction ◽  
Multiple Organ ◽  
Microvascular Perfusion ◽  
Leukocyte Adherence ◽  
Capillary Perfusion ◽  
Endothelial Cell Interaction

Antithrombin (AT) is known as the most important natural inhibitor of thrombin activity and has been shown to improve distinct clinical parameters during the course of septic (endotoxin)-induced multiple organ dysfunction. We hypothesized that AT acts by inhibiting leukocyte activation and microvascular injury via the promotion of endothelial release of PGI2, and therefore, we studied the effects of AT on leukocyte/endothelial cell interaction and microvascular perfusion during endotoxemia. In a skinfold preparation of Syrian hamsters, severe endotoxemia was induced by repeated administration of endotoxin intravenously [lipopolysaccharide (LPS), Escherichia coli, 2 mg/kg] at 0 and 48 h. AT (250 IU/kg) was administered intravenously at 0, 24, and 48 h ( n = 6, AT group). In control animals ( n = 5, control), LPS was given without AT supplementation. By intravital fluorescence microscopy, leukocyte-endothelial cell interaction and functional capillary density (FCD; measure of capillary perfusion) were analyzed during a 72-h period after the first LPS injection. AT significantly attenuated LPS-induced arteriolar and venular leukocyte adherence after both the first and the second LPS injection [ P < 0.01, measures analysis of variance (MANOVA)]. In parallel, AT was effective in preventing LPS-induced depression of FCD after the first and the second LPS administration ( P < 0.05, MANOVA). By pretreatment with the cyclooxygenase inhibitor indomethacin ( n = 6), effects of AT on leukocyte adherence and FCD were found completely abolished. Thus our study indicates that AT exerts its beneficial effects in endotoxemia by reducing leukocyte-endothelial cell interaction and microvascular perfusion failure probably via liberation of prostacyclin from endothelial cells.

Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock

2002 ◽  
Vol 283 (1) ◽  
pp. G212-G221 ◽  
Author(s):  
Runkuan Yang ◽  
David J. Gallo ◽  
Jeffrey J. Baust ◽  
Takashi Uchiyama ◽  
Simon K. Watkins ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Colonic Mucosa ◽  
Ethyl Pyruvate ◽  
Parent Compound ◽  
Mucosal Injury ◽  
Nuclear Factor Κb ◽  
Organ Injury ◽  
Mesenteric Lymph Nodes ◽  
Ileal Mucosa ◽  
Mucosal Permeability

Administration of pyruvate, an effective scavenger of reactive oxygen species, has been shown to be salutary in numerous models of redox-mediated tissue or organ injury. Pyruvate, however, is unstable in solution and, hence, is not attractive for development as a therapeutic agent. Herein, ethyl pyruvate, which is thought to be more stable than the parent compound, was formulated in a calcium-containing balanced salt solution [Ringer ethyl pyruvate solution (REPS)] and evaluated in a murine model of hemorrhagic shock and resuscitation (HS/R). Resuscitation with REPS instead of Ringer lactate solution (RLS) significantly improved survival at 24 h and abrogated bacterial translocation to mesenteric lymph nodes and the development of increased ileal mucosal permeability to FITC-labeled dextran (4,000 Da) at 4 h. Mice treated with REPS instead of RLS also had lower circulating levels of alanine aminotransferase at 4 h. Treatment with REPS instead of RLS decreased activation of nuclear factor-κB in liver and colonic mucosa after HS/R and also decreased the expression of inducible nitric oxide synthase, tumor necrosis factor, cyclooxygenase-2, and interleukin-6 mRNA in liver, ileal mucosa, and/or colonic mucosa. These data support the view that resuscitation with REPS modulates the inflammatory response and decreases hepatocellular and gut mucosal injury in mice subjected to HS/R.

Effects of erythrocyte flexibility on microvascular perfusion and oxygenation during acute anemia

2007 ◽  
Vol 293 (2) ◽  
pp. H1206-H1215 ◽  
Author(s):  
Pedro Cabrales
Keyword(s):  
Exchange Transfusion ◽  
Capillary Density ◽  
Microvascular Perfusion ◽  
Capillary Perfusion ◽  
Noninvasive Methods ◽  
Isovolemic Hemodilution ◽  
Rbc Membrane ◽  
Arterial Blood ◽  
Glutaraldehyde Solution ◽  
Fresh Rbcs

Responses to exchange transfusion using red blood cells (RBCs) with normal and reduced flexibility were studied in the hamster window chamber model during acute moderate isovolemic hemodilution to determine the role of RBC membrane stiffness in microvascular perfusion and tissue oxygenation. Erythrocyte stiffness was increased by 30-min incubation in 0.02% glutaraldehyde solution, and unreacted glutaraldehyde was completely removed. Filtration pressure through 5-μm pore size filters was used to quantify stiffness of the RBCs. Anemic conditions were induced by two isovolemic hemodilution steps using 6% 70-kDa dextran to a hematocrit (Hct) of 18% (moderate hemodilution). The protocol continued with an exchange transfusion to reduce native RBCs to 75% of baseline (11% Hct) with either fresh RBCs (RBC group) or reduced-flexibility RBCs (GRBC group) suspended in 5% albumin at 18% Hct; a plasma expander (6% 70-kDa dextran; Dex70 group) was used as control. Systemic parameters, microvascular perfusion, capillary perfusion [functional capillary density (FCD)], and oxygen levels across the microvascular network were measured by noninvasive methods. RBC deformability for GRBCs was significantly decreased compared with RBCs and moderate hemodilution conditions. The GRBC group had a greater mean arterial blood pressure (MAP) than the RBC and Dex70 groups. FCD was substantially higher for RBC (0.81 ± 0.07 of baseline) vs. GRBC (0.32 ± 0.10 of baseline) and Dex70 (0.38 ± 0.10 of baseline) groups. Microvascular tissue Po2 was significantly lower for Dex70 and GRBC vs. RBC groups and the moderate hemodilution condition. Results were attributed to decreased oxygen uploading in the lungs and obstruction of tissue capillaries by rigidified RBCs, indicating that the effects impairing RBC flexibility are magnified at the microvascular level, where perfusion and oxygenation may define transfusion outcome.

Effect of nitric oxide on capillary hemodynamics and cell injury in the pancreas duringPseudomonaspneumonia-induced sepsis

2004 ◽  
Vol 286 (1) ◽  
pp. H340-H345 ◽  
Author(s):  
Barbara Tribl ◽  
Ryon M. Bateman ◽  
Stephanie Milkovich ◽  
William J. Sibbald ◽  
Christopher G. Ellis
Keyword(s):  
Nitric Oxide ◽  
Cell Injury ◽  
Capillary Density ◽  
Functional Capillary Density ◽  
Microvascular Perfusion ◽  
Cellular Damage ◽  
Supply Rate ◽  
Injury Model ◽  
Nitrite Nitrate ◽  
Plasma Nitrite

Sepsis-induced nitric oxide (NO) overproduction has been implicated in a redistribution of flow from the pancreas making it vulnerable to ischemic injury in septic shock. To test this hypothesis in a remote injury model of normotensive sepsis, we induced Pseudomonas pneumonia in the rat and used intravital video microscopy (IVVM) of the pancreas to measure functional capillary density, capillary hemodynamics [red blood cell (RBC) velocity, lineal density, and supply rate], and lethal cellular damage (propidium iodine staining) at 6 and 24 h after the induction of pneumonia. With pneumonia, plasma nitrite/nitrate [[Formula: see text]] levels were doubled by 21 h ( P < 0.05). To assess the effect of NO overproduction on microvascular perfusion, N6-(1-iminoethyl)-l-lysine (l-NIL) was administered to maintain [Formula: see text] levels at baseline. Pneumonia did cause a decrease in RBC velocity of 23% by 6 h, but by 24 h RBC velocity and supply rate had increased relative to sham by 22 and 38%, respectively ( P < 0.05). l-NIL treatment demonstrated that this increase was due to NO overproduction. With pneumonia, there was no change in functional capillary density and only modest increases in cellular damage. We conclude that, in this normotensive pneumonia model of sepsis, NO overproduction was protective of microvascular perfusion in the pancreas.

ICAM-1 and P-selectin expression in a model of NSAID-induced gastropathy

1998 ◽  
Vol 274 (2) ◽  
pp. G246-G252 ◽  
Author(s):  
Z. Morise ◽  
S. Komatsu ◽  
J. W. Fuseler ◽  
D. N. Granger ◽  
M. Perry ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Critical Role ◽  
Mucosal Blood Flow ◽  
Gastric Mucosal Blood Flow ◽  
Mucosal Injury ◽  
Gastric Mucosal Injury ◽  
Intercellular Adhesion Molecule ◽  
Sprague Dawley ◽  
Intercellular Adhesion Molecule 1 ◽  
Mucosal Permeability

A growing body of experimental evidence suggests that neutrophilic polymorphonuclear leukocyte (PMN)-endothelial cell interactions play a critical role in the pathophysiology of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The objective of this study was to directly determine whether the expression of endothelial cell adhesion molecules is enhanced in a model of NSAID-induced gastropathy. Gastropathy was induced in male Sprague-Dawley rats via oral administration of indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearance of 51Cr-EDTA (mucosal permeability), and histological analysis (epithelial necrosis) were used as indexes of gastric mucosal injury. Gastric mucosal vascular expression of intercellular adhesion molecule 1 (ICAM-1) or P-selectin were determined at 1 and 3 h after Indo administration using the dual radiolabeled monoclonal antibody (MAb) technique. For some experiments, a blocking MAb directed at either ICAM-1 (1A29) or P-selectin (RMP-1) or their isotype-matched controls was injected intravenously 10 min before Indo administration. We found that P-selectin expression was significantly increased at 1 h but not 3 h after Indo administration, whereas ICAM-1 expression was significantly increased at both 1 and 3 h after Indo treatment. The blocking ICAM-1 and P-selectin MAbs both inhibited Indo-induced increases in lesion score, mucosal permeability, and epithelial cell necrosis. However, the Indo-induced gastropathy was not associated with significant PMN infiltration into the gastric mucosal interstitium, nor did Indo reduce gastric mucosal blood flow. We propose that NSAID-induced gastric mucosal injury may be related to the expression of P-selectin and ICAM-1; however, this mucosal injury does not appear to be dependent on the extravasation of inflammatory cells or mucosal ischemia.

Dexmedetomidine Attenuates the Microcirculatory Derangements Evoked by Experimental Sepsis

2015 ◽  
Vol 122 (3) ◽  
pp. 619-630 ◽  
Author(s):  
Marcos L. Miranda ◽  
Michelle M. Balarini ◽  
Eliete Bouskela
Keyword(s):  
Blood Gases ◽  
Capillary Density ◽  
Sepsis Syndrome ◽  
In Vivo Studies ◽  
Experimental Sepsis ◽  
Leukocyte Rolling ◽  
Capillary Perfusion ◽  
Arterial Blood ◽  
Baseline Values

Abstract Background: Dexmedetomidine, an α-2 adrenergic receptor agonist, has already been used in septic patients although few studies have examined its effects on microcirculatory dysfunction, which may play an important role in perpetuating sepsis syndrome. Therefore, the authors have designed a controlled experimental study to characterize the microcirculatory effects of dexmedetomidine in an endotoxemia rodent model that allows in vivo studies of microcirculation. Methods: After skinfold chamber implantation, 49 golden Syrian hamsters were randomly allocated in five groups: (1) control animals; (2) nonendotoxemic animals treated with saline; (3) nonendotoxemic animals treated with dexmedetomidine (5.0 μg kg−1 h−1); (4) endotoxemic (lipopolysaccharide 1.0 mg/kg) animals treated with saline; and (5) endotoxemic animals treated with dexmedetomidine. Intravital microscopy of skinfold chamber preparations allowed quantitative analysis of microvascular variables and venular leukocyte rolling and adhesion. Mean arterial blood pressure, heart rate, arterial blood gases, and lactate concentrations were also documented. Results: Lipopolysaccharide administration increased leukocyte rolling and adhesion and decreased capillary perfusion. Dexmedetomidine significantly attenuated these responses: compared with endotoxemic animals treated with saline, those treated with dexmedetomidine had less leukocyte rolling (11.8 ± 7.2% vs. 24.3 ± 15.0%; P &lt; 0.05) and adhesion (237 ± 185 vs. 510 ± 363; P &lt; 0.05) and greater functional capillary density (57.4 ± 11.2% of baseline values vs. 45.9 ± 11.2%; P &lt; 0.05) and erythrocyte velocity (68.7 ± 17.6% of baseline values vs. 54.4 ± 14.8%; P &lt; 0.05) at the end of the experiment. Conclusions: Dexmedetomidine decreased lipopolysaccharide-induced leukocyte–endothelial interactions in the hamster skinfold chamber microcirculation. This was accompanied by a significant attenuation of capillary perfusion deficits, suggesting that dexmedetomidine yields beneficial effects on endotoxemic animals’ microcirculation.

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.

Plasma viscosity regulates systemic and microvascular perfusion during acute extreme anemic conditions

2006 ◽  
Vol 291 (5) ◽  
pp. H2445-H2452 ◽  
Author(s):  
Pedro Cabrales ◽  
Amy G. Tsai
Keyword(s):  
Flow Distribution ◽  
Capillary Density ◽  
High Viscosity ◽  
Plasma Viscosity ◽  
Functional Capillary Density ◽  
Microvascular Perfusion ◽  
Arterial Blood ◽  
Chamber Model ◽  
Kidney Liver ◽  
Window Chamber

The hamster window chamber model was used to study systemic and microvascular hemodynamic responses to extreme hemodilution with low- and high-viscosity plasma expanders (LVPE and HVPE, respectively) to determine whether plasma viscosity is a factor in homeostasis during extreme anemic conditions. Moderated hemodilution was induced by two isovolemic steps performed with 6% 70-kDa dextran until systemic hematocrit (Hct) was reduced to 18% ( level 2). In a third isovolemic step, hemodilution with LVPE (6% 70-kDa dextran, 2.8 cP) or HVPE (6% 500-kDa dextran, 5.9 cP) reduced Hct to 11%. Systemic parameters, cardiac output (CO), organ flow distribution, microhemodynamics, and functional capillary density, were measured after each exchange dilution. Fluorescent-labeled microspheres were used to measure organ (brain, heart, kidney, liver, lung, and spleen) and window chamber blood flow. Final blood and plasma viscosities after the entire protocol were 2.1 and 1.4 cP, respectively, for LVPE and 2.8 and 2.2 cP, respectively, for HVPE (baseline = 4.2 and 1.2 cP, respectively). HVPE significantly elevated mean arterial pressure and CO compared with LVPE but did not increase vascular resistance. Functional capillary density was significantly higher for HVPE [87% (SD 7) of baseline] than for LVPE [42% (SD 11) of baseline]. Increases in mean arterial blood pressure, CO, and shear stress-mediated factors could be responsible for maintaining organ and microvascular perfusion after exchange with HVPE compared with LVPE. Microhemodynamic data corresponded to microsphere-measured perfusion data in vital organs.

Role of leukocytes in indomethacin-induced small bowel injury in the rat

1994 ◽  
Vol 266 (2) ◽  
pp. G239-G246 ◽  
Author(s):  
H. M. Chmaisse ◽  
J. S. Antoon ◽  
P. R. Kvietys ◽  
M. B. Grisham ◽  
M. A. Perry
Keyword(s):  
Small Bowel ◽  
Morphological Changes ◽  
Mucosal Injury ◽  
Bowel Injury ◽  
Rat Jejunum ◽  
Small Bowel Injury ◽  
Mucosal Permeability ◽  
Quantitative Histology ◽  
51Cr Edta

This study assesses the role of neutrophils in indomethacin-induced small bowel injury and determines the influence of intestinal pH on the magnitude of this injury. Rat jejunum was perfused via the lumen with buffer, and mucosal injury was assessed by blood-to-lumen clearance of 51Cr-EDTA and quantitative histology. Reduction in luminal pH from 7.4 to 6.0 in the presence of indomethacin (1.0 mg/ml) increased 51Cr-EDTA clearance from 2.0 +/- 0.1 to 6.5 +/- 0.3 microliter.min-1.g-1. Indomethacin caused a reduction in villus length, an increase in villus width, and an increase in lesion score. Depletion of neutrophils with antiserum largely prevented the increase in 51Cr-EDTA clearance and morphological changes. Intravenous indomethacin given at a dose to mimic therapeutic plasma levels (1 mg/kg iv) had no significant effect on 51Cr-EDTA clearance but caused similar morphological changes to those observed following intraluminal administration. The data suggest that neutrophils play a role in acute indomethacin injury and that the drug given intravenously can cause morphological changes without necessarily altering mucosal permeability to 51Cr-EDTA.

Plasma viscosity regulates capillary perfusion during extreme hemodilution in hamster skinfold model

1998 ◽  
Vol 275 (6) ◽  
pp. H2170-H2180 ◽  
Author(s):  
Amy G. Tsai ◽  
Barbara Friesenecker ◽  
Michael McCarthy ◽  
Hiromi Sakai ◽  
Marcos Intaglietta
Keyword(s):  
Molecular Weight ◽  
Shear Stress ◽  
Capillary Density ◽  
High Viscosity ◽  
Plasma Viscosity ◽  
Capillary Perfusion ◽  
Low Viscosity ◽  
Arterial Blood ◽  
Wall Shear ◽  
Stress Dependent

Effect of increasing blood viscosity during extreme hemodilution on capillary perfusion and tissue oxygenation was investigated in the awake hamster skinfold model. Two isovolemic hemodilution steps were performed with 6% Dextran 70 [molecular weight (MW) = 70,000] until systemic hematocrit (Hct) was reduced by 65%. A third step reduced Hct by 75% and was performed with the same solution [low viscosity (LV)] or a high-molecular-weight 6% Dextran 500 solution [MW = 500,000, high viscosity (HV)]. Final plasma viscosities were 1.4 and 2.2 cP (baseline of 1.2 cP). Hct was reduced to 11.2 ± 1.1% from 46.2 ± 1.5% for LV and to 11.9 ± 0.7% from 47.3 ± 2.1% for HV. HV produced a greater mean arterial blood pressure than LV. Functional capillary density (FCD) was substantially higher after HV (85 ± 12%) vs. LV (38 ± 30%) vs. baseline (100%).[Formula: see text] levels measured with Pd-porphyrin phosphorescence microscopy were not statistically changed from baseline until after the third hemodilution step. Wall shear rate (WSR) decreased in arterioles and venules after LV and only in arterioles after HV. Wall shear stress (WSR × plasma viscosity) was substantially higher after HV vs. LV. Increased mean arterial pressure and shear stress-dependent release of endothelium-derived relaxing factor are possible mechanisms that improved arteriolar and venular blood flow and FCD after HV vs. LV exchange protocols.

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