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D N Granger

Publications and source records attributed to D N Granger.

At least 145 records · Page 8Linked to original sources
PubMed1997

Molecular mechanisms of anoxia/reoxygenation-induced neutrophil adherence to cultured endothelial cells.

The objectives of this study were to (1) determine the time course of neutrophil adhesion to monolayers of human umbilical vein endothelial cells (HUVECs) that were exposed to 60 minutes of anoxia followed by 30 to 600 minutes of reoxygenation and (2) define the mechanisms responsible for both the early (minutes) and late (hours) hyperadhesivity of postanoxic HUVECs to human neutrophils. The results clearly demonstrate that anoxia/reoxygenation (A/R) leads to a biphasic increase in neutrophil adhesion to HUVECs, with peak responses occurring at 30 minutes (phase 1) and 240 minutes (phase 2) after reoxygenation. Oxypurinol and catalase inhibited phase-1 adhesion, suggesting a role for xanthine oxidase and H2O2. In comparison, platelet activating factor (PAF) contributed to both phases of neutrophil adhesion. Anti-intercellular adhesion molecule-1 (ICAM-1) and anti-P-selectin antibodies (monoclonal antibodies [mAbs]) attenuated phase-1 neutrophil adhesion, consistent with roles for constitutively expressed ICAM-1 and enhanced surface expression of preformed P-selectin. Phase-2 neutrophil adhesion was attenuated by an anti-E-selectin mAb, indicating a dominant role of this adhesion molecule in the late phase response. Pretreatment with actinomycin D and cycloheximide or with competing ds-oligonucleotides containing the nuclear factor-kappa B or activator protein-1 cognate DNA sequences significantly attenuated phase-2 response, suggesting a role for de novo macromolecule synthesis. Surface expression of ICAM-1, P-selectin, and E-selectin on HUVECs correlated with the phase-1 and -2 neutrophil adhesion responses. Collectively, these findings indicate that A/R elicits a two-phase neutrophil-endothelial cell adhesion response that involves transcription-independent and transcription-dependent surface expression of different endothelial cell adhesion molecules.

Azepines↗
PubMed1997

Differential up-regulation of circulating soluble and endothelial cell intercellular adhesion molecule-1 in mice.

Although circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1) are frequently used as an indicator of the severity of different immune, inflammatory, or neoplastic diseases, little is known about the factors that govern plasma sICAM-1 concentration and its relationship to the membranous form of ICAM-1 (mICAM-1) expressed on vascular endothelial cells. Plasma sICAM-1 concentration (measured by enzyme-linked immunosorbent assay) and mICAM-1 expression (measured using the dual radiolabeled monoclonal antibody technique) in different vascular beds (eg, lung, small intestine, and spleen) were monitored in wild-type (C57BL) and ICAM-1-deficient mice, before and after administration of tumor necrosis factor (TNF)-alpha. In wild-type mice, TNF-alpha elicited time-dependent increases in lung and intestine mICAM-1 (plateau achieved at 12 hours), with a corresponding increase in plasma sICAM-1 (peaked at 5 hours and then declined). The initial increases in mICAM-1 and pulmonary leukocyte sequestration (measured as lung myeloperoxidase activity) induced by TNF-alpha preceded any detectable elevation in sICAM-1. In ICAM-1-deficient mice, plasma sICAM-1 was reduced by approximately 70%, with > 95% reductions of mICAM-1 in lung and intestine, and > 75% reduction in splenic accumulation of anti-ICAM-1 antibody. Although TNF-alpha doubled plasma sICAM-1 in ICAM-1-deficient mice, mICAM-1 was unaffected in all tissues. Either splenectomy or pretreatment with cycloheximide resulted in an attenuated TNF-induced increase in sICAM-1, without affecting mICAM-1 expression. These findings indicate that plasma sICAM-1 concentration does not accurately reflect the level of ICAM-1 expression on endothelial cells in different vascular beds.

Animals↗
PubMed1997

Hepatic ischemia/reperfusion affects leukocyte rolling and velocity.

Mechanisms of injury in hepatic ischemia/reperfusion injury are poorly defined. Leukocytes are thought to be important in the final mechanism of hepatic damage. We intend to show the time course of abnormal leukocyte activity in the liver after ischemia/reperfusion (I/R) injury. Left lobar hepatic ischemia was induced for 20 min in anesthetized C57B1-6 mice. Measurements were taken at control, reperfusion, and matching sham times (no ischemia) of 2, 5, 12, and 24 h. Measurements were taken using rhodamine and fluorescein enhanced intravital microscopy. Post sinusoidal venules were evaluated for numbers of rolling leukocytes, leukocyte saltation, and leukocyte velocity. Data are expressed as number of rolling leukocytes per 100 microns venule length (2 min). Statistical analysis was by ANOVA. The number of rolling leukocytes at 5, 12, and 24 h of reperfusion (p < 0.001) was significantly higher than control and sham-operated animals. Leukocyte velocities were significantly slower in the 12 h I/R group when compared to sham animals (p < 0.001). These data show that there are definable and quantifiable changes in leukocyte kinetics in the liver after ischemia/reperfusion. These changes, which lasted for 24 h, are likely due to upregulation of various endothelial cell adhesion molecules. Delineation of these mechanisms may be important in disease states such as shock, sepsis, and hepatic transplantation.

Analysis of Variance↗
PubMed1996

Diabetes exacerbates inflammatory responses to ischemia-reperfusion.

BACKGROUND: Diabetes is associated with an increased incidence of ischemic organ damage. The objectives of present study were to compare the leukocyte-endothelial cell adhesive interactions and albumin leakage response of mesenteric venules to ischemia-reperfusion between control rats, rats with streptozotocin-induced diabetes, and rats with hyperglycemia induced by glucose infusion and to define the molecular determinants of the leukocyte accumulation elicited by ischemia-reperfusion in diabetic rats. METHODS AND RESULTS: Under baseline conditions, lower venular shear rates and an increased number of rolling leukocytes were noted in diabetic rats, whereas the number of adherent and emigrated leukocytes did not differ from that in control rats. Spontaneous albumin leakage from mesenteric venules was markedly increased in diabetic rats but not in hyperglycemic nondiabetic rats. Ischemia-reperfusion elicited significantly larger increases in leukocyte adhesion and emigration and albumin leakage in diabetic rats. Acute elevation of glucose levels did not modify the microvascular responses to ischemia-reperfusion compared with control rats. Antibodies directed against CD11/CD18, intercellular adhesion molecule-1 (ICAM-1), or P-selectin but not L-selectin significantly decreased the number of adherent and emigrated leukocytes after ischemia-reperfusion in diabetic rats. However, none of the antibodies significantly attenuated the increased albumin leakage response to ischemia-reperfusion in diabetic rats. CONCLUSIONS: These results indicate that diabetes mellitus is associated with exaggerated leukocyte-endothelial cell adhesion and albumin leakage responses to ischemia-reperfusion. The enhanced leukocyte accumulation in response to ischemia-reperfusion is mediated by CD11/CD18-ICAM-1 interactions (firm adhesion) and P-selectin (rolling). The exaggerated albumin leakage response to ischemia-reperfusion in diabetics is not mediated by the recruited inflammatory cells.

Albumins↗
PubMed1996

Neutrophils generate oxygen free radicals in rat mesenteric microcirculation after abdominal irradiation.

BACKGROUND & AIMS: Oxygen free radicals have been invoked as mediators of tissue injury in gastrointestinal diseases. This study determines whether oxygen radicals are generated in the mesenteric microvasculature after abdominal irradiation and defines the cellular source of these radicals. METHODS: Leukocyte adherence and emigration in mesenteric venules were measured using intravital microscopy at 2 or 6 hours after abdominal irradiation. Oxygen radical production was measured using the oxidant-sensitive fluorochrome dihydrorhodamine 123 (DHR-123). RESULTS: Relative to control microvessels, irradiated venules exhibited a significant increase in adherent leukocytes 2 hours after irradiation, whereas both adherent and emigrated leukocytes were increased at 6 hours. An increased oxidation of DHR-123 was noted within venules at 2 hours after irradiation, with a more marked response, associated with leukocytes emigrated into the interstitium, observed at 6 hours after irradiation. Treatment with an anti-CD18 antibody blocked irradiation-induced leukocyte adherence and emigration and prevented the DHR-123 oxidation, normally observed at 6 hours, with a partial attenuation of DHR-123 oxidation at 2 hours. Neither the leukocyte-independent component of DHR-123 oxidation nor the leukocyte recruitment normally observed at 2 hours postirradiation was blunted by the xanthine oxidase inhibitor allopurinol. CONCLUSIONS: These findings indicate that activated leukocytes represent the major source of oxidants generated in the mesentery after abdominal irradiation.

Abdomen↗
PubMed1996

Inhibition of white blood cell adhesion at reperfusion decreases tissue damage in postischemic striated muscle.

PURPOSE: To determine the impact of white blood cell (WBC)-endothelium adhesion on tissue damage in the setting of ischemia-reperfusion injury in striated muscle. METHODS: The cremaster muscle of four groups of anesthetized Sprague-Dawley rats was subjected to 4 hours of global, warm (37 degrees C) ischemia and 2 hours of reperfusion. At reperfusion two groups of animals received intravenous injections of monoclonal antibodies directed against either CD11b/CD18 (1B6) or ICAM-1 (1A29). The remaining two groups of animals received saline injections (NoRx) or nonreactive IgG1. In vivo light microscopic techniques were used to determine WBC adherence (number of WBCs per 100 microns postcapillary venules) at different intervals of reperfusion. Muscle viability was assessed with computer-assisted image analysis by measuring the optical intensity of transilluminated muscles after incubation with nitroblue tetrazolium. RESULTS: Our results (mean +/- SEM) demonstrate a significant increase in the number of adherent WBCs relative to baseline (8.0 +/- 0.5) after 4 hours of global ischemia in animals receiving NoRx or IgG1. The significant increase occurred at 30 minutes of reperfusion (17.6 +/- 0.6 and 17.4 +/- 0.4 for NoRx or IgG1, respectively) and was sustained for the duration of the experiment. This increase in adherence was attenuated by 1B6 and 1A29 (12.2 +/- 2.2 and 12.4 +/- 0.8, respectively; p < 0.05 compared with NoRx and IgG1). The decrease in WBC adhesion was associated with a decrease in reperfusion injury to the muscle, as indicated by lower optical intensity values for the 1B6 and 1A29 groups (123 +/- 3 and 129 +/- 2) compared with the NoRx and IgG1 groups (151 +/- 2 and 158 +/- 4). CONCLUSIONS: Our data support an important role for WBCs in the pathogenesis of ischemia-reperfusion injury. Interfering with the WBC-endothelium interactions by using monoclonal antibodies directed against WBCs and endothelial cell adhesion molecules may help to limit ischemia-reperfusion injury.

Animals↗
PubMed1996

Extract of Helicobacter pylori induces neutrophils to injure endothelial cells and contains antielastase activity.

BACKGROUND & AIMS: Previous studies indicate that a water extract of Helicobacter pylori promotes leukocyte adhesion and emigration as well as endothelial barrier disruption (increased vascular protein leakage) in rat mesenteric venules. The aims of this study were to assess whether H. pylori extract-activated neutrophils disrupt endothelial cell monolayers and to identify the mechanisms involved in this process. METHODS: Human neutrophils were incubated with monolayers of human umbilical vein endothelial cells (HUVECs) in the presence or absence of H. pylori extract. RESULTS: H. pylori extract-activated human neutrophils produced endothelial cell detachment from HUVEC monolayers, the severity of which was dependent on the duration of exposure. Endothelial cell detachment was prevented by a monoclonal antibody directed against CD11/CD18 on neutrophils or a monoclonal antibody against intercellular adhesion molecule 1 on endothelial cells. HUVEC monolayer disruption was also prevented by superoxide dismutase, catalase, and a monoclonal antibody against elastase. Further studies indicated that H. pylori extract was capable of inhibiting human neutrophil elastase. The antielastase activity was not diminished by oxidants. CONCLUSIONS: These studies indicate that H. pylori extract-activated human neutrophils can disrupt HUVEC monolayers only when human neutrophils are allowed to adhere to HUVECs and may provide an explanation for the H. pylori extract-induced, neutrophil-dependent vascular protein leakage observed in vivo. The possibility that H. pylori releases antiproteases may explain, in part, why this bacterium is so virulent.

Antibodies, Monoclonal↗
PubMed1996

Portal hypertension enhances endotoxin-induced intercellular adhesion molecule 1 up-regulation in the rat.

BACKGROUND & AIMS: Liver disease or portosystemic shunting enhances th e sensitivity to endotoxin. The aim of this study was to investigate whether intercellular adhesion molecule 1 (ICAM-1) expression in response to endotoxin may be dysregulated in an animal model of portal hypertension. METHODS: Portal hypertension was induced by partial portal vein ligation. Sham-operated animals served as controls. ICAM-1 expression was measured using radiolabeled antibodies under baseline conditions or 5 hours after treatment with either endotoxin or recombinant tumor necrosis factor (TNF). Immunoreactive plasma TNF was also measured. RESULTS: Under baseline conditions, ICAM-1 expression in all organs studied was similar in portal-hypertensive and sham-operated rats. ICAM-1 up-regulation after a high dose of endotoxin (5 mg/kg) was similar in both groups of animals. However, portal-hypertensive animals showed a significantly higher ICAM-1 expression in response to low doses of endotoxin (0.1-10 microgram/kg). The response to a low (but not a high) dose of recombinant TNF was also significantly enhanced in portal-hypertensive animals. In addition, portal-hypertensive rats had higher plasma TNF levels after treatment with endotoxin or recombinant TNF. CONCLUSIONS: Portal hypertension induces an exaggerated ICAM-1 up-regulation in response to endotoxin, which is related to an increased production and decreased clearance of the cytokine.

Analysis of Variance↗
PubMed1996

Leukocyte adhesion and hepatic microvascular responses to intestinal ischemia/reperfusion in rats.

BACKGROUND & AIMS: Although it has been reported that gut ischemia/reperfusion (I/R) elicits neutrophil-dependent liver dysfunction, little is known about the kinetics of leukocyte accumulation in the hepatic microcirculation after gut I/R. The aim of this study was to determine the temporal relationship between leukocyte sequestration and oxidative stress in rat liver after occlusion (30 minutes) and reperfusion (60 minutes) of the superior mesenteric artery and assess the effects of neutrophil depletion or immunoneutralization of either intercellular adhesion molecule 1 (ICAM-1) or the leukocyte adhesion glycoprotein CD11/CD18 on the hepatic microvascular responses to gut I/R. METHODS: Leukocyte accumulation, number of nonperfused sinusoids, and autofluorescence of reduced nicotinamide adenine dinucleotide (NADH) were monitored using intravital videomicroscopy both before and after gut I/R. RESULTS: The number of adherent leukocytes in both midzonal and pericentral regions after gut I/R was elevated. Autofluorescence of NADH increased after reperfusion (indicating hypoxia), particularly in the pericentral region. Neutrophil depletion or antibodies to either ICAM-1 or CD11/CD18 blunted the gut I/R-induced increases in NADH autofluorescence in the pericentral region, leukocyte adherence, and nonperfused sinusoids. CONCLUSIONS: Leukocytes accumulate in the liver after gut I/R via interaction of CD11/CD18 and ICAM-1. The leukocytes appear to mediate an oxidative stress, occurring in proximity to nonperfused sinusoids, that may contribute to liver injury.

Animals↗
PubMed1996

The cellular and molecular basis of gastric mucosal defense.

The association between colonization of the stomach by Helicobacter pylori and peptic ulcer disease has stimulated a renewal of interest in the factors that render the gastric mucosa resistant to injury induced by endogenous secretions and ingested toxins. Mucosal defense consists of a complex network of components that function in concert with one another. This network includes: 1) the extramucosal components such as acid, mucus, surface-active phospholipids, and bicarbonate; 2) the epithelium itself; 3) the microcirculation and sensory afferent neurons beneath the epithelium; 4) the mucosal immune system; and 5) the ability of the mucosa to undergo repair. In the past two decades, an enormous amount has been learned about the cellular and molecular basis of the various components of mucosal defense, including a better understanding of the chemical substances that coordinate mucosal responses to injury. In this paper, we review the factors that contribute to mucosal defense, the cellular and molecular mechanisms through which mucosal defense is modulated, and the chemical mediators that play key roles in this process.

Animals↗
PubMed1996

Role of interleukin 8 on leucocyte-endothelial cell adhesion in intestinal inflammation.

BACKGROUND: An important action of interleukin 8 (IL8) is stimulation of granulocytes. The object of this study was to assess the contribution of IL8 to the leucocyte-endothelial cell interactions associated with intestinal inflammation in the rat. METHODS: Two indomethacin injections (48 and 24 hours prior to the experiments) induced a longlasting ileitis in rats. The number of adherent and emigrated leucocytes, leucocyte rolling velocity, and shear rate were monitored in normal and inflamed mesenteric postcapillary venules. Some animals received a monoclonal antibody (MAb) against IL8 or CD11b/CD18 at 24 and 12 hours prior to the experiment. RESULTS: Indomethacin elicited a seven-fold increase in leucocyte adherence and a 5.4-fold increase in leucocyte emigration, while leucocyte rolling velocity was reduced by nearly 80%. The indomethacin induced increases in leucocyte adherence and emigration were significantly reduced (by 57% and 67%, respectively) while leucocyte rolling velocity was increased (to 63% of control) by the IL8-specific MAb. The level of inhibition seen with the IL8 MAb was similar to that associated with administration of a MAb directed against the leucocyte adhesion molecule CD11b/CD18. CONCLUSIONS: IL8 contributes to the leucocyte-endothelial cell interactions elicited in mesenteric venules by indomethacin.

Animals↗
PubMed1996

Role of leukocyte beta 2-integrin in PAF-induced shock and intestinal injury.

Leukocyte adhesion and diapedesis, critical steps in the inflammatory process, depend on the expression of integrin CD11b/CD18. In this study, we examined the preventive effect of monoclonal antibodies (MAb) against CD11b (1B6), CD11a, or CD18 (CL26) on platelet-activating factor (PAF)-induced bowel injury. Young male Sprague-Dawley rats were anesthetized and injected with either of two doses of PAF (2.5 or 3 micrograms/kg iv) to induce transient hypotension and irreversible shock. Some rats wee also injected intravenously with 1B6 (anti-CD11b), anti-CD11a, CL26 (anti-CD18), or combined anti-CD11a and 1B6, 30 min before PAF. Animals receiving a low dose of PAF developed mild hypotension, hemoconcentration, increased intestinal myeloperoxidase, and bowel injury after 1 h. These effects were completely prevented by pretreatment with 1B6. A high dose of PAF induced irreversible shock and gross intestinal necrosis. Both CL26 and 1B6 were partially effective in attenuating PAF-induced bowel injury. Addition of anti-CD11a to 1B6 in the treatment further ameliorated the systemic adverse effects of PAF and intestinal injury. However, focal minor injury still developed. Anti-CD11a alone, fucoidin, or anti-P-selectin was ineffective. Rats depleted of neutrophils were also largely protected from the adverse effects of PAF at high doses, although minor intestinal injury often persisted. We conclude that leukocyte beta 2-integrins play an important role in PAF-induced hypotension, leukopenia, hemoconcentration, and intestinal necrosis, and that CD11b/CD18 is the main adhesion molecule involved in the pathogenesis of injury. However, CD11/CD18- and neutrophil-independent pathways exist for mediating PAF-induced bowel injury, although their role is probably a minor one.

Animals↗
PubMed1996

Microvascular dysfunction induced by nonsteroidal anti-inflammatory drugs: role of leukocytes.

The objectives of this study were to determine whether 1) the leukocyte-endothelial cell adhesion observed in venules exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) is accompanied by enhanced albumin extravasation, and 2) leukocytes mediate this endothelial cell barrier dysfunction. Intravital video microscopy was used to monitor leukocyte-endothelial cell adhesion and the leakage of fluorescein isothiocyanate-labeled albumin in rat mesenteric venules exposed to either indomethacin or aspirin. Both NSAIDs induced the recruitment of adherent and emigrated leukocytes with temporally related increases in albumin leakage. Agents that effectively decreased or prevented the NSAID-induced leukocyte adherence/emigration (leukotriene B4 receptor antagonist or adhesion molecule-specific monoclonal antibodies) also blocked the corresponding albumin leakage response. These findings indicate that adherent and/or emigrating leukocytes mediate the early endothelial cell barrier dysfunction elicited by NSAIDs.

Animals↗
PubMed1996

Endotoxin stimulates lymphocyte-endothelial interactions in rat intestinal Peyer's patches and villus mucosa.

Although lymphocyte-endothelial cell interactions represent a key step in controlling the recruitment of lymphocytes into gut-associated tissues, its dynamic process in microvessels of lymphoid (Peyer's patches) and nonlymphoid (villus) regions of the small bowel remains poorly understood. We monitored the migration of fluorescence-labeled T lymphocytes into normal and lipopolysaccharide (LPS)-inflamed rat intestinal microvessels using intravital microscopy. In Peyer's patches, T lymphocytes selectively adhered to postcapillary venules, although such selectivity was not observed in submucosal venules of villi. T lymphocytes exhibited rolling behavior followed by firm adhesion in microvessels of both the Peyer's patches and the villi, with both types of adhesive interaction being mediated by alpha 4-integrins. The enhanced rolling and adherence of lymphocytes observed in Peyer's patches and submucosal venules of villi of LPS-treated rats were preceded by a reduction in shear rate and were mediated largely by alpha 4-integrins and partly by beta 2-integrins. In capillaries of intestinal mucosa, lymphocyte adherence occurred without rolling and was independent of alpha 4-integrins. LPS also significantly increased adherence of lymphocytes to villus capillaries, which was not mediated by either alpha 4- or beta 2-integrin. These observations demonstrate significant heterogeneity of lymphocyte-endothelial cell interactions within different regions of the intestinal mucosa.

Animals↗
PubMed1996

Mechanisms underlying enhanced capillary filtration induced by platelet-activating factor.

Fluid filtration rate with respect to surface area (Jv/S) from rat mesenteric capillaries was measured before and after platelet-activating factor (PAF) superfusion, a model of acute inflammation. Jv/S increased from a baseline value of 0.015 +/- 0.003 to 0.033 +/- 0.003 micron/s (n = 7 rats, P < 0.01) during PAF superfusion. Measurements of arteriolar pressure with a servo-nulling pressure system suggest that the dominant factor causing the increase in Jv/S during PAF superfusion is increased capillary permeability, rather than an increase in pressure. Jv/S did not increase when PAF superfusion was preceded by administration of the radical-scavenging enzymes catalase and superoxide dismutase, implicating a role for oxygen radicals in the PAF-induced capillary filtration. In another series of studies, three experiments were performed, i.e., PAF superfusion alone or PAF superfusion plus treatment with either a soluble form of sialyl-Lewisx oligosaccharide (SLex) or a nonbinding form of SLex (SLN). These experiments revealed that the increased Jv/S normally elicited by PAF is significantly blunted by administration of soluble SLex but not by the control oligosaccharide SLN. The results of this study invoke a role for oxygen free radicals and selectins (ligands for SLex) in the enhanced capillary fluid filtration elicited by PAF.

Animals↗
PubMed1996

Neutrophil enhancement of reperfusion-induced capillary fluid filtration associated with hypercholesterolemia.

Fluid filtration rate (Jv/S) from individual mesenteric capillaries in normocholesterolemic and hypercholesterolemic rats was measured before and after 30 min each of ischemia and reperfusion (I/R). The median I/R-induced increase in Jv/S (I/R vs. baseline) was 44% in normocholesterolemic rats (n = 11) and 97% in hypercholesterolemic rats (n = 11). A positive correlation slope of 0.20% per mg/dl resulted when the percent Jv/S increase vs. plasma cholesterol concentration (P = 0.02) was plotted, demonstrating that hypercholesterolemia enhances the capillary response to I/R. Because microvascular pressure did not change significantly after I/R in either group of rats, the increments in Jv/S likely reflect increased capillary permeability. In hypercholesterolemic rats rendered neutropenic with antineutrophil serum, I/R did not elicit a significant increase in Jv/S, suggesting that activated neutrophils mediate the exaggerated endothelial barrier dysfunction associated with hypercholesterolemia.

Animals↗
PubMed1996

Role of mast cells in oxidized low-density lipoprotein-induced microvascular dysfunction.

Previous studies demonstrated that human low-density lipoprotein (LDL) oxidized with Cu2+ promotes leukocyte-endothelial cell adhesion, mast cell degranulation, and albumin extravasation in rat mesentery. The objective of this study was to determine whether the mast cell degranulation elicited by oxidized LDL accounts for the accompanying microvascular responses. Leukocyte rolling, adherence, and emigration, fluorescein isothiocyanate-albumin leakage, and mast cell degranulation were monitored in rat mesentery before and during local intra-arterial infusion of either normal LDL (nLDL) or copper-oxidized LDL (CuLDL). Infusion of CuLDL, but not nLDL, elicited significant increases in leukocyte rolling, adherence and emigration, albumin leakage, and mast cell degranulation. Pretreatment with the mast cell-stabilizing agent ketotifen or superfusion of the mesenteric microcirculation with iodoxamide significantly reduced CuLDL-induced mast cell degranulation. The mast cell stabilization was accompanied by attenuated leukocyte-endothelial cell adhesion and albumin leakage responses to CuLDL. The results of this study indicate that 1) CuLDL-induced microvascular dysfunction (albumin leakage) involves the activation of mast cells, and 2) the protective action of mast cell stabilizers may be related to their ability to blunt CuLDL-induced leukocyte-endothelial cell interactions in postcapillary venules.

Animals↗