Biomedical subjects

P Kubes

Publications and source records attributed to P Kubes.

At least 109 records · Page 6Linked to original sources

PubMed1994

Regulation of stimulated integrin surface expression in human neutrophils by tyrosine phosphorylation.

The control of the adhesive properties of human neutrophils is an essential element of their defense function. One level at which this control is exerted involves the upregulation of the surface expression of beta 2-integrins. In this study, we have examined the potential involvement of tyrosine phosphorylation in the latter process. Two inhibitors of tyrosine kinases with differing modes of action, erbstatin and herbimycin A, were found to inhibit the expression of CD11b and CD18 stimulated by chemotactic factors (fMet-Leu-Phe or leukotriene B4) or growth factors (tumor necrosis factor alpha). This inhibition was not shared by an inactive analog of erbstatin or by the protein kinase C inhibitor Ro 31-8330. Erbstatin also inhibited the unveiling of activation-specific neoepitopes detected by antibody CBRM1/5. Pretreatment of neutrophils (but not of endothelial cells) with erbstatin inhibited the stimulation of neutrophils' adherence to endothelial cells induced by fMet-Leu-Phe. Augmentation of tyrosine phosphorylation by inhibiting tyrosine phosphatases using hydroperoxyvanadate led to an increased surface expression of CD11b and CD18 and enhanced the adhesion of neutrophils to endothelial cells. Finally, the leumedin NPC 15669, which had previously been shown to inhibit stimulated CD11b expression and neutrophil adherence to endothelial cells and to exhibit anti-inflammatory properties in various in vivo models of inflammation, inhibited the stimulation of tyrosine, phosphorylation induced by fMet-Leu-Phe. Taken together, these data establish a strong correlation between tyrosine phosphorylation and integrin upregulation in stimulated human neutrophils.

Antigens, CD↗

PubMed1994

Histamine induces leukocyte rolling in post-capillary venules. A P-selectin-mediated event.

The objective of this study was to systematically assess the molecular mechanisms and kinetics of histamine-induced leukocyte rolling in rat mesenteric venules using intravital microscopy. A complicating factor in these studies is surgical preparation-induced leukocyte rolling (spontaneous rolling), which leads to a lack of effect of histamine on this parameter. Therefore, we identified the source of the surgery-induced leukocyte rolling (partial mast cell degranulation) and established that pretreatment of animals with sodium cromoglycate (connective tissue mast cell stabilizer) inhibited spontaneous leukocyte rolling. Superfusion of the mast cell-stabilized rat mesentery with histamine caused a profound increase in leukocyte rolling which persisted for the entire hour of experimentation. Diphenhydramine (H1-receptor antagonist) but not cimetidine (H2-receptor antagonist) prevented the rise in histamine-induced leukocyte rolling. An anti-P-selectin Ab but not an anti-CD18 Ab reversed the histamine-induced leukocyte rolling in a dose-dependent fashion. In this model of low base line rolling, exposure of the mesentery to the chemotactic agent platelet-activating factor did not induce leukocyte rolling or adhesion. However, co-administration of histamine with platelet-activating factor did indeed promote leukocyte adhesion suggesting that the presence of at least one effector of P-selectin is a minimal requirement for chemotactically-stimulated leukocytes to adhere to postcapillary venules. This study demonstrates for the first time that histamine induces leukocyte rolling via a P-selectin-dependent mechanism in vivo. This is a prolonged, H1 receptor-mediated event that may contribute significantly to the early phase of inflammation.

Animals↗

PubMed1994

Reductions in physiologic shear rates lead to CD11/CD18-dependent, selectin-independent leukocyte rolling in vivo.

In this study, we tested the hypothesis that reducing shear rates in postcapillary venules causes CD18-dependent, selectin-independent leukocyte rolling. Intravital microscopy was used to assess shear rate-dependent leukocyte rolling in 25- to 40-microns rat mesenteric venules. Pretreatment of animals with 25 mg/kg fucoidin, a carbohydrate moiety that binds to and inhibits selectin function, essentially abolished the number of spontaneously rolling leukocytes. When shear rates were reduced by 50% (from 438 +/- 36 s-1 to 222 +/- 19 s-1) in the presence of fucoidin, leukocyte rolling increased fourfold, suggesting a selectin-independent mechanism of leukocyte rolling. Administration of CL26, an anti-CD18 antibody, prevented the leukocyte rolling associated with reduced shear rates. A second objective was to determine if the integrin-mediated leukocyte rolling at reduced shear rates would lead to firm adhesion of leukocytes in the presence of a chemotactic stimulus. Animals were pretreated with fucoidin and 100 nmol/L platelet-activating factor (PAF) was superfused over the mesentery. Fucoidin prevented leukocyte rolling and subsequent PAF-induced adhesion at normal shear rates; however, when shear rates were reduced by 50%, a significant CD18-dependent increase in leukocyte rolling (10-fold) and adhesion (5-fold) was noted within 15 minutes. These data raise the possibility that, at lower shear rates, as is the case in various inflammatory conditions, selectin-independent, CD18-dependent leukocyte rolling and subsequent adhesion can occur in postcapillary venules.

Animals↗

PubMed1994

Nitric oxide synthesis inhibition increases epithelial permeability via mast cells.

In this study, we assessed the involvement of mast cells and mast cell-derived mediators in the enhanced epithelial permeability associated with nitric oxide synthesis inhibition. Permeability of the small bowel was assessed by measuring the clearance of a small marker (51Cr-labeled EDTA) from blood to lumen in the presence of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). L-NAME caused a very rapid (10 min) increase in epithelial permeability, reaching peak values (sixfold increase) within 20 min. Two mast cell stabilizers, doxantrazole and lodoxamide, greatly attenuated the rise in mucosal permeability. Rat mast cell protease II activity (marker of mucosal mast cell degranulation) was increased significantly only in the plasma of L-NAME-treated animals. Chronic dexamethasone administration depleted rats of mucosal mast cells and also prevented the L-NAME-induced rise in mucosal permeability. The increase in epithelial permeability was mediated by a number of mediators: platelet-activating factor caused the early rise in epithelial permeability, and histamine caused the later increase in epithelial permeability. Superoxide dismutase attenuated the L-NAME-induced rise in epithelial permeability, suggesting an important and continuous role for superoxide. Transepithelial flux of 51Cr-EDTA across rat intestinal epithelial cell monolayers did not increase in the presence of L-NAME, suggesting that inhibition of nitric oxide does not directly cause epithelial permeability alterations, whereas the in vivo data implicate a potential role for the mast cell. In conclusion, nitric oxide synthesis inhibition activates mast cells in the mucosa and consequently increases epithelial permeability.

Animals↗

PubMed1994

Mast cells contribute to ischemia-reperfusion-induced granulocyte infiltration and intestinal dysfunction.

The objective of this study was to determine whether ischemia-reperfusion (I/R) of the small bowel activated mast cells and, if so, to determine whether this event contributed to granulocyte infiltration and mucosal barrier dysfunction. Autoperfused segments of the jejunum were exposed to 30 min of ischemia followed by 60 min of reperfusion. Epithelial permeability was assessed by the clearance of 51Cr-labeled EDTA from plasma to lumen. Plasma rat mast cell protease II (RMCP II) was measured and used as an index of mucosal mast cell degranulation, whereas myeloperoxidase (MPO) activity was used as an index of granulocyte infiltration. I/R caused a significant increase in plasma RMCP II levels, MPO activity, and epithelial permeability. The mucosal mast cell stabilizer doxantrazole prevented the I/R-induced increase in all three parameters. The connective tissue mast cell stabilizer ketotifen had no effect. To determine whether oxidants were involved in mast cell degranulation, some animals were pretreated with superoxide dismutase and catalase. This regimen completely abolished the I/R-induced rise in plasma RMCP II levels and attenuated mucosal MPO activity and epithelial permeability. Selective inhibitors of two mast cell-derived mediators, platelet-activating factor and histamine, did not attenuate the rise in epithelial permeability. These data suggest that oxidant-induced mucosal mast cell degranulation is a key event in the granulocyte infiltration and tissue dysfunction associated with reperfusion of the ischemic intestine.

Animals↗

PubMed1994

Molecular mechanisms involved in superoxide-induced leukocyte-endothelial cell interactions in vivo.

Intravital microscopy was used to monitor leukocyte adherence, flux, rolling velocity, and number of rolling leukocytes (flux/velocity) in venules 25-40 microns in diameter. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX/XO), was infused into the mesenteric circulation in untreated animals or in animals pretreated with either catalase (a hydrogen peroxide scavenger), WEB-2086 [a platelet-activating factor (PAF) receptor antagonist], or monoclonal antibodies directed against adhesion molecules CD18 (CL26) or P-selectin (PB1.3). HX/XO infusion caused a decrease in leukocyte rolling velocity and an increase in the number of rolling and adherent leukocytes. WEB-2086 prevented the increase in leukocyte adhesion and markedly increased leukocyte rolling velocity. PB1.3 abolished the HX/XO-associated rise in the flux of rolling leukocytes and proportionally decreased the number of adherent leukocytes. CL26 abolished HX/XO-induced leukocyte adhesion and also reduced the number of rolling leukocytes. In conclusion, P-selectin mediates the increased leukocyte flux induced by superoxide, whereas PAF and CD18 modulate leukocyte adhesion. PAF also reduces leukocyte rolling velocity, possibly as a result of CD18, but not P-selectin.

Animals↗

PubMed1994

NO donors prevent integrin-induced leukocyte adhesion but not P-selectin-dependent rolling in postischemic venules.

The objective of this study was to examine the effect of nitric oxide (NO) donors on polymorphonuclear leukocyte (PMN) interactions in the microvasculature of postischemic tissue and to compare the antiadhesive properties of NO donors with the responses observed after immunoneutralization of three key adhesion glycoproteins (CD11/CD18, intercellular adhesion molecule-1, and P-selectin). Rolling and firm adhesion (adherence) of leukocytes and shear rate were monitored in cat mesenteric venules subjected to 60 min of ischemia (blood flow reduced to 20% of control), followed by 60 min of reperfusion. Immediately before reperfusion, the mesentery was superfused with a NO donor (3-morpholinosydonimine-N-ethyl-carbamide or spermine-NO) or a monoclonal antibody (MAb) against an adhesion glycoprotein that was administered intravenously. In untreated animals, a profound influx in rolling PMNs was observed during reperfusion that was subsequently followed by increased firm adhesion. The anti-P-selectin antibody completely abolished the rise in the flux of rolling PMNs, whereas the anti-CD18 antibody prevented firm adhesion. Both NO donors attenuated ischemia/reperfusion-induced leukocyte adhesion to a level comparable with that observed after administration of a MAb against CD11/CD18 without affecting PMN rolling. The antiadhesive effect of the NO donors could not be attributed solely to an improvement of venular wall shear rate. In vitro data did not reveal a direct effect of NO donors on the expression of CD18 or neutrophil adhesion to endothelial cells. These observations suggest that NO donors may provide protection from tissue injury by preventing PMN adhesion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils.

The objective of the present study was to determine whether prolonged inhibition of nitric oxide synthesis in endothelial cells increased the surface adhesion of these cells for neutrophils. Human umbilical vein endothelial cells (HUVECs) were grown to confluence in 48-well microtiter plates. Exposure of HUVECs to the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) did not cause neutrophil adhesion at 1 hour but increased adhesion at 4 hours in a dose-dependent manner. The increased adhesion was prevented with L-arginine or nitric oxide donors but not an analogue of cGMP. The increased adhesion was inhibited by monoclonal antibodies directed against the beta 2-integrin CD18 and endothelial cell adhesion molecule ICAM-1. Platelet-activating factor (PAF) receptor antagonist WEB 2086 also prevented the L-NAME-induced neutrophil adhesion. Intracellular oxygen radical scavengers (dimethyl sulfoxide, butylated hydroxytoluene, and alpha, alpha'-dipyridyl), the iron chelator desferrioxamine, and the mitochondrial inhibitor azide inhibited the L-NAME-induced neutrophil adhesion, whereas extracellular oxygen radical scavengers (superoxide dismutase and catalase) had no effect. HUVECs were loaded with 2',7'-dichlorodihydrofluorescein diacetate, and oxidation to the fluorescent dichlorodihydrofluorescein (DCHF) was monitored. Fluorescence was enhanced in the L-NAME-treated HUVECs throughout the 4-hour incubation, an event inhibitable by an antioxidant and azide. The magnitude of the intracellular oxidation of DCHF was equivalent to approximately 0.8 mumol/L H2O2. These data suggest that prolonged nitric oxide synthesis inhibition in HUVECs causes an oxidant- and PAF-associated rise in adhesion on the surface of these endothelial cells for neutrophils.

Antigens, CD↗

PubMed1994

Ischemia/reperfusion-induced granulocyte influx is a multistep process mediated by mast cells.

OBJECTIVE: The influx of polymorphonuclear leukocytes (PMNs) that occurs at the onset of reperfusion of postischemic tissue is a multistep mechanism that includes initial rolling of PMNs, a progressive reduction in PMN rolling velocity, and ultimately PMN adhesion and emigration. In this study we assessed whether mast cells play a role in reperfusion-induced PMN recruitment with emphasis on PMN rolling, adhesion, and emigration. METHODS: Cat small intestinal venules were visualized using intravital microscopy during control, 60 min of ischemia (intestinal blood flow 20% of control), and 60 min of reperfusion in untreated and cromolyn- (mast cell stabilizer) pretreated animals. RESULTS: Between 1 and 5 min of reperfusion, there was a very dramatic rise in PMN rolling which persisted for the next 60 min. In cromolyn-pretreated animals, the flux of rolling PMNs increased in the very early (5 min) reperfusion period, but by 10 min the number of rolling leukocytes was significantly reduced, an event that persisted for the next 60 min. PMNs rolled at a velocity of 40% of control values for the first 10 min of reperfusion without a change in hemodynamic values but returned toward control values by 60 min of reperfusion. An identical velocity profile was observed for the cromolyn-treated animals. In untreated animals, PMN adhesion and emigration was significantly increased throughout the reperfusion period, whereas the cromolyn-pretreated animals had reduced adhesion (60 min of reperfusion) and a reduced rate of emigration throughout the reperfusion period. CONCLUSION: Interstitial mast cells contribute significantly to the multistep recruitment (rolling, adhesion, and emigration) of PMNs from blood to postischemic tissues and raise the possibility that antiallergy agents such as cromolyn may be a useful form of therapy in the postischemic intestine.

Animals↗

PubMed1994

Time course of nitric oxide production and epithelial dysfunction during ischemia/reperfusion of the feline small intestine.

The objective of this study was to correlate nitric oxide production with time of reperfusion of the post-ischemic feline small intestine. Epithelial permeability, quantitated as blood-to-lumen clearance of 51Cr-EDTA, following 1 hr of ischemia and 4 hr of reperfusion of the small intestine, increased approximately 10-fold. This increase was further augmented by L-NAME infusion between 60 and 120 min but not at 240 min. Ca(2+)-dependent nitric oxide synthase activity was reduced by approximately 50% at 3 and 4 hr of reperfusion, whereas Ca(2+)-independent nitric oxide synthase activity was undetectable throughout the experiment. Administration of L-arginine at the start of reperfusion attenuated the reperfusion-induced epithelial barrier dysfunction for the first 120 min but not at 180 or 240 min. Continuous infusion of a nitric oxide donor (CAS 754) following 1 hr of reperfusion reduced epithelial permeability at 4 hr of reperfusion. In conclusion, a reduction in nitric oxide production was observed with time of reperfusion, possibly due to reduced nitric oxide synthase levels.

Animals↗

PubMed1994

The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion.

The accumulation of leukocytes in inflamed tissue results from adhesive interactions between leukocytes and endothelial cells within the microcirculation. These adhesive interactions and the excessive filtration of fluid and protein that accompanies an inflammatory response are largely confined to one region of the microvasculature: postcapillary venules. The nature and magnitude of the leukocyte-endothelial cell adhesive interactions that take place within postcapillary venules are determined by a variety of factors, including expression of adhesion molecules on leukocytes and/or endothelial cells, products of leukocyte (superoxide) and endothelial cell (nitric oxide) activation, and the physical forces generated by the movement of blood along the vessel wall. The contribution of different adhesion molecules to leukocyte rolling, adherence, and emigration in venules is discussed. Emerging views on potential endogenous antiadhesion molecules produced by endothelial cells as well as the influence of alterations in shear rate on leukocyte adhesion are addressed. Finally, the pathophysiological significance of the microvascular responses to inflammation are discussed in terms of adhesion-directed strategies for the treatment of different cardiovascular diseases and circulatory disorders.

Animals↗

PubMed1993

Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels.

The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil-neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

Animals↗

PubMed1993

Inhibition of platelet-activating factor-induced leukocyte adhesion in vivo by a leumedin.

Leumedins are a class of amino acid derivatives which have been reported to exert anti-inflammatory properties through a mechanism related to their ability to inhibit the expression of adhesion molecules on leukocytes. In the present study, the ability of an orally active leumedin (NPC 17923) to inhibit leukocyte adherence stimulated by platelet-activating factor was examined using an in vivo intravital microscopy preparation of mesenteric venules in the rat. Oral pretreatment with NPC 17923 (100 mg/kg) markedly increased the ratio of white blood cell velocity to red blood cell velocity, indicating that less force was required to displace a white blood cell from the vascular endothelium. NPC 17923 also significantly inhibited the adherence of white blood cells to the endothelium during the superfusion with platelet-activating factor. While not significantly affecting vessel diameter under basal conditions, vessels were significantly larger in NPC 17923-pretreated rats during the superfusion with platelet-activating factor. These results are consistent with the hypothesis that the anti-inflammatory properties of leumedins are at least in part due to effects on leukocyte adherence, but may also be in part attributable to effects on vascular tone.

4-Aminobenzoic Acid↗

PubMed1993

Neutrophil-mediated proteolysis. Differential roles for cathepsin G and elastase.

In this study, we assessed the underlying mechanisms by which proteinases released from activated neutrophils mediate fibronectin degradation. Purified human neutrophils (1 x 10(6)) were incubated for 1 hr with 1 microM PMA in the absence or presence of different proteinase inhibitors in 96-well microtiter plates that were coated with 125I-labeled fibronectin (FN). PMA-activated neutrophils caused 85% of FN to be degraded (versus 5% under control conditions). A selective inhibitor of elastase (L658,758), a monoclonal antibody directed against human neutrophilic elastase, and plasma all reduced the neutrophil-mediated FN degradation by 60%. A monoclonal antibody directed against the neutrophil adhesion glycoprotein CD11/CD18 increased the antiproteolytic effect of plasma to 70% but had no effect on the other anti-elastase agents, suggesting that the subjacent space formed by adherent neutrophils restricted to a small degree plasma derived antiproteinases. Agents that blocked cathepsin G or cathepsin G and elastase completely prevented the proteolysis associated with PMA-stimulated neutrophils, suggesting that the actions of elastase may be dependent on the presence of biologically active cathepsin G.

Amino Acid Chloromethyl Ketones↗

PubMed1993

Mediators of leukocyte adhesion in rat mesenteric venules elicited by inhibition of nitric oxide synthesis.

BACKGROUND: Inhibitors of nitric oxide production promote leukocyte adherence and emigration in postcapillary venules. The objective of this study was to determine if the enhanced leukocyte adherence and emigration associated with inhibition of NO production involves inflammatory agents such as platelet-activating factor (PAF) and leukotriene B4 (LTB4) and/or phospholipase A2 (PLA2). METHODS: The rat mesentery was superfused with the inhibitor of NO production NG-nitro-L-arginine methyl ester (L-NAME) either alone or in combination with WEB2086 (PAF receptor antagonist), SC41930 (LTB4 receptor antagonist), or quinacrine (PLA2 inhibitor). The number of adherent and emigrated leukocytes, leukocyte rolling velocity, erythrocyte velocity, venular blood flow, and shear rate were monitored in mesenteric venules. RESULTS: L-NAME alone induced a dramatic increase in leukocyte adherence (10-fold) and emigration (4-fold). Treatment with SC41930 significantly reduced, whereas either WEB2086 or quinacrine completely abolished, the increased leukocyte adherence and emigration induced by L-NAME. CONCLUSIONS: These observations suggest that the increased leukocyte adherence and emigration associated with inhibition of NO synthesis involves PLA2 activation and is mediated by PAF and LTB4.

Animals↗

PubMed1993

Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells.

Recent work has demonstrated that inhibition of nitric oxide production with various nitric oxide synthesis inhibitors (L-NAME, L-NMMA) initiate leukocyte adhesion to postcapillary venules. The objective of this study was to elucidate the mechanism (or mechanisms) that promote the L-NAME-induced leukocyte response. Intravital microscopy was used to examine 25-40 microns venules in the rat mesentery. Nitric oxide synthesis was inhibited with L-NAME and leukocyte adhesion was observed over the first 60 min. The fourfold increase in leukocyte adhesion was independent of alterations in venular red blood cell velocity. The adhesion was superoxide-mediated inasmuch as superoxide dismutase (SOD) abolished the rise in leukocyte adhesion associated with nitric oxide synthesis inhibition. Ketotifen, a mast cell stabilizer, also abolished the rise in leukocyte adhesion induced by L-NAME. Histology revealed that mast cell degranulation occurred only in animals treated with L-NAME but not in animals pretreated with SOD or ketotifen. This observation suggests that mast cells become activated in the absence of nitric oxide production and superoxide contributes to the mast cell activation. The L-NAME-induced leukocyte adhesion could be reproduced by infusing hypoxanthine/xanthine oxidase (a superoxide generating system) or compound 48/80 (an activator of mast cells) and both responses were attenuated by ketotifen. These data suggest that inhibition of nitric oxide synthesis results in a superoxide and mast cell-dependent leukocyte adhesion.

Animals↗

PubMed1993

Polymorphonuclear leukocyte--endothelium interactions: a role for pro-inflammatory and anti-inflammatory molecules.

The movement of polymorphonuclear leukocytes (PMNs) from the mainstream of blood to the extravascular space is a characteristic feature of the inflammatory response. This process requires that the PMN initially contacts the endothelium, then adheres firmly to the vessel wall, and finely migrates out of the microvasculature. Each of these events requires signals or pro-inflammatory molecules that direct the PMN to the potential site of inflammation. These molecules include histamine, which appears to be of importance in the initial recruitment of PMNs, leukotriene B4, which promotes PMN adhesion, and platelet-activating factor, which may contribute to both the adhesion process as well as the migration through the endothelial barrier. Although many other pro-inflammatory molecules have been identified, including the cytokines and complement, the three aforementioned molecules are used in this review as paradigms of the varying functions that pro-inflammatory molecules have in the inflammatory process. There is a growing body of evidence that in addition to the many pro-inflammatory agents found in the body there are a number of important anti-inflammatory molecules, including nitric oxide, prostacyclin, and adenosine. Each of these molecules possess important properties that serve to interrupt or protect against the ongoing inflammatory process. The anti-inflammatory potential of these endogenous molecules is discussed.

Animals↗

PubMed1993

Ischemia-reperfusion in feline small intestine: a role for nitric oxide.

The objective of this study was to assess whether nitric oxide synthesis inhibition affects intestinal barrier function after ischemia-reperfusion of the feline small bowel. Local intra-arterial infusion of the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 25 nmol.ml-1.min-1) was performed in autoperfused segments of cat ileum for 60 min after 90 min of ischemia and 60 min of reperfusion. Epithelial permeability was quantitated by measuring blood-to-lumen clearance of 51Cr-labeled EDTA, and microvascular dysfunction was assessed by measuring the clearance of protein from the vasculature into the interstitium. 125I-labeled albumin clearance from blood to lumen and histology were performed to further characterize the extent of intestinal dysfunction after reperfusion of the postischemic intestine in the presence and absence of L-NAME. Ischemia-reperfusion-induced mucosal and microvascular permeability increases were dramatically augmented by L-NAME infusion, and this effect was reversed by infusion of L-arginine (125 nmol.ml-1.min-1). Initiating L-arginine (but not D-arginine) infusion alone 10 min before reperfusion provided protection against ischemia-reperfusion-induced mucosal barrier dysfunction; however, this was not associated with a reduction in endogenous levels of L-arginine during ischemia-reperfusion. These data suggest that basal nitric oxide production is important in minimizing mucosal and microvascular barrier dysfunction associated with reperfusion of postischemic intestine.

Animals↗