Biomedical subjects

P Kubes

Publications and source records attributed to P Kubes.

At least 127 records · Page 7Linked to original sources

PubMed1993

Nitric oxide donors reduce the rise in reperfusion-induced intestinal mucosal permeability.

Recent data have demonstrated that inhibition of nitric oxide synthesis exacerbated the mucosal injury associated with reperfusion of the postischemic intestine. In this study, using a feline 1-h intestinal ischemia followed by reperfusion model, we tested the possibility that exogenous sources of nitric oxide may prevent the reperfusion-induced mucosal barrier disruption and examined the mechanisms involved. Mucosal barrier integrity was assessed by determining 51Cr-EDTA clearance from blood to lumen. Intestinal blood flow and resistance were also determined. Reperfusion after 1 h of ischemia significantly increased 51Cr-EDTA clearance (0.05 +/- 0.01 to 0.35 +/- 0.07 ml.min-1.100 g-1) and decreased intestinal blood flow by 50%. Exogenous sources of nitric oxide including SIN-1, CAS-754, and nitroprusside as well as exogenous L-arginine all reduced reperfusion-induced mucosal barrier dysfunction without improving intestinal blood flow. Inhibition of endogenous nitric oxide with NG-nitro-L-arginine methyl ester between 1 and 2 h of reperfusion further augmented the rise in mucosal permeability associated with ischemia-reperfusion. Addition of the permeable analogue of guanosine 3',5'-cyclic monophosphate, 8-bromoguanosine 3',5'-cyclic monophosphate, improved reperfusion-induced intestinal blood flow significantly but did not provide protection against mucosal barrier disruption associated with the first hour of ischemia-reperfusion. Exogenous sources of nitric oxide can reduce reperfusion-induced mucosal barrier dysfunction independent of alterations in intestinal blood flow.

Animals↗

PubMed1993

Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury.

A number of recent studies have demonstrated that neutrophil adherence to the vascular endothelium is a critical early event in the pathogenesis of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Although a role in this process for the leukocyte adhesion molecule, CD11/CD18, has been demonstrated, the involvement of endothelial adhesion molecules has not previously been examined. Therefore, using monoclonal antibodies directed against a number of endothelial adhesion molecules (ICAM-1, P-selectin, E-selectin), we studied the role of these molecules in the production of mucosal injury after indomethacin administration and in indomethacin-induced leukocyte adherence. As previously shown in the rabbit, anti-CD18 markedly reduced (by 75%) the severity of damage induced by indomethacin in the rat. Moreover, this antibody completely prevented indomethacin-induced leukocyte adherence. Similarly, anti-ICAM-1 significantly attenuated (by 74%) the severity of indomethacin-induced gastric injury while also markedly reducing leukocyte adherence (by 83%). Anti-P-selectin and anti-E-selectin produced only small (approximately 35%), but statistically significant, reductions of mucosal injury, but only anti-P-selectin significantly affected indomethacin-induced leukocyte adherence (by approximately 50%). These results demonstrate that indomethacin-induced leukocyte adherence and mucosal injury are dependent on the expression of CD18 and ICAM-1. P-selectin also appears to play a small, but important, role in these processes, whereas the role of E-selectin remains equivocal. These studies support the hypothesis that interactions at the leukocyte-endothelium interface are critical in the pathogenesis of NSAID-induced mucosal injury, and this interface may represent a rational target for therapies aimed at preventing this form of injury.

Animals↗

PubMed1993

Nitric oxide prevents leukocyte adherence: role of superoxide.

The objective of this study was to determine whether the antiadhesive effects of NO for leukocytes are related to its ability to scavenge superoxide in vivo. Intravital microscopy was used to monitor leukocyte adherence and flux as well as velocity and number of rolling leukocytes in 25- to 40-microns venules. The superoxide-generating system, hypoxanthine and xanthine oxidase (HX-XO), was infused into the mesenteric circulation in untreated animals and in animals pretreated with either superoxide dismutase (SOD) or the NO donor, SIN 1. In another series of studies, the mesenteric preparation was superfused with either platelet-activating factor (PAF) or leukotriene B4 (LTB4) followed by the administration of either SIN 1 or SOD. HX-XO infusion caused a significant increase in the number of rolling and adherent leukocytes (responses that were entirely inhibited by SOD or SIN 1). SOD and SIN 1 both attenuated the PAF-induced but not the LTB4-induced leukocyte adherence. The observation that both SOD and SIN 1 inhibit leukocyte adhesion only under conditions associated with superoxide formation (HX-XO and PAF, but not LTB4) strongly suggests that the antiadhesion properties of NO are related to its ability to inactivate the superoxide anion.

Animals↗

PubMed1993

Nitric oxide-induced microvascular permeability alterations: a regulatory role for cGMP.

This study evaluated the physiological effects of compounds that alter guanosine 3',5'-cyclic monophosphate (cGMP) on the increase in vascular protein clearance induced by nitric oxide (NO) synthesis inhibition in the feline small intestine. A lymphatic vessel draining the small bowel was cannulated; vascular protein clearance and intestinal blood flow were measured. N omega-nitro-L-arginine methyl ester (L-NAME), the NO inhibitor, was infused (0.5 mumol/min) into the superior mesenteric artery. Vascular protein clearance increased approximately 4.6-fold, whereas blood flow decreased to 50% of control. Elevation of cGMP by 1) cytosolic guanylate cyclase activation with a NO donor (SIN 1) or 2) a cGMP analogue, 8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP) completely prevented the rise in microvascular permeability associated with L-NAME. Moreover, these compounds reduced (almost 90%) baseline vascular protein clearance, whereas inhibition of cytosolic guanylate cyclase with methylene blue significantly increased this parameter. Atrial natriuretic factor (ANF) has been reported to increase tissue cGMP levels and microvascular permeability. In this study, ANF did indeed increase intestinal microvascular permeability however this occurred independent of changes in intestinal cGMP levels. These data support a role for cGMP associated with NO-induced microvascular permeability alterations and raise the possibility that ANF has a cGMP-independent effect on microvascular permeability within the intestine.

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PubMed1993

Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage.

The mechanisms by which nitric oxide modulates microvascular albumin exchange were investigated by monitoring leukocyte-endothelial cell adhesion and fluorescein isothiocyanate-albumin leakage in rat mesenteric venules exposed to NG-nitro-L-arginine methyl ester (L-NAME). L-NAME elicited an initial rapid increase followed by a slower rate of albumin accumulation in the interstitial space. The initial phase of albumin leakage preceded the L-NAME-induced leukocyte adherence and emigration, whereas the magnitude of the albumin leakage observed in the later phase of L-NAME exposure was highly correlated with the number of adherent and emigrated leukocytes in the same segment of venule. Monoclonal antibodies (MAbs) directed against adhesion molecules CD11/CD18, ICAM-1, or P-selectin, but not a nonbinding MAb, attenuated the albumin leakage induced by L-NAME. WEB2086, a platelet activating factor antagonist, and 8-bromoguanosine 3',5'-cyclic monophosphate (8-br-cGMP) reduced the leukocyte adherence and emigration as well as the increased albumin leakage. Only 8-br-cGMP and the P-selectin MAb attenuated the platelet-leukocyte aggregation elicited by L-NAME. Phalloidin, which promotes endothelial junctional integrity, inhibited both the early and late phases of albumin leakage. Overall, these findings suggest that the increased albumin leakage observed in postcapillary venules after inhibition of nitric oxide production involves a mechanism that includes a role for cGMP, platelet activating factor, leukocyte-endothelial cell adhesion, and the endothelial cell cytoskeleton.

Albumins↗

PubMed1992

Colchicine and methotrexate reduce leukocyte adherence and emigration in rat mesenteric venules.

Colchicine and methotrexate are commonly used in the treatment of gout and rheumatoid arthritis, respectively; however the mechanism(s) of action of these drugs remain(s) unknown. The objective of this study was to determine whether colchicine and methotrexate can modify the adhesion and emigration of leukocytes in postcapillary venules that are exposed to inflammatory mediators such as platelet-activating factor (PAF) and leukotriene B4 (LTB4). The rat mesentery was prepared for in vivo microscopic observation. Venules with internal diameters ranging between 25 and 35 microns were selected for study. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 sec) and emigrated leukocytes were measured during superfusion of the mesentery with bicarbonate-buffered saline (BBS). Repeat measurements of adhesive and hemodynamic parameters were obtained between 50 and 60 min of superfusion with either 100 nM PAF or 20 nM LTB4 added to the superfusate. In some experiments, 1 microM of either colchicine or methotrexate was added to the superfusate containing either PAF or LTB4. Both PAF and LTB4 caused increases in leukocyte adherence and emigration and reductions in leukocyte rolling velocity and venular shear rate. Colchicine effectively prevented all of the adhesive and hemodynamic alterations induced by both inflammatory mediators, while methotrexate was largely effective in preventing the responses elicited by PAF, but not LTB4. These results indicate that the therapeutic actions of colchicine and methotrexate may result from the ability of these agents to interfere with the adhesion and emigration of leukocytes from postcapillary venules.

Animals↗

PubMed1992

Granulocyte turnover in the feline intestine.

The objective of this study was to determine the turnover rate of the extravascular pool of granulocytes in different regions of the feline gastrointestinal tract. Leukocyte emigration from the vasculature was prevented over a 48-h period by repeated intravenous injections of a monoclonal antibody (MAb IB4) directed against the leukocyte adhesion glycoprotein complex CD11/CD18. Tissue-associated myeloperoxidase (MPO) activity was used to monitor the total tissue granulocyte pool at 0.5, 12, 24, and 48 h after MAb IB4 administration. The mucosal layer of the duodenum, jejunum, ileum, and colon exhibited different kinetics of granulocyte clearance, with average life-spans (t1/2) ranging between 6.9 (colon) and 10.4 h (duodenum). Granulocyte clearance rates of 0.5 x 10(6) and 2.4 x 10(6) cells/h/g tissue were estimated (from measured values of t1/2 and tissue granulocyte pool) for the small bowel and colonic mucosae, respectively. The submucosal layer of the intestine exhibited a biphasic reduction in tissue MPO activity following immunoneutralization of CD11/CD18, with an initial t1/2 < or = 0.5 h followed by a t1/2 of 36-60 h. The initial rapid decline in tissue MPO suggests that a significant fraction of granulocytes in the submucosa is localized in a readily exchangeable pool (e.g., marginated cells within the vasculature). The results of this study indicate that the average life-span of resident granulocytes varies significantly between different regions of the gastrointestinal tract, with the intestinal mucosa exhibiting a t1/2 comparable to that previously reported for circulating feline neutrophils (approximately 8 h).

Animals↗

PubMed1992

Ischemia/reperfusion-induced feline intestinal dysfunction: importance of granulocyte recruitment.

Although previous studies have reported that neutrophils play an important role in mediating the microvascular injury observed after reperfusion of ischemic intestine, the contribution of these phagocytic cells to the mucosal dysfunction remains unclear. Three series of experiments consisting of an untreated group, a short-term monoclonal antibody (MAb) IB4 treatment group (MAb IB4 given on the day of the experiment), and a long-term MAb IB4 treatment group (3-day pretreatment with MAb IB4) were performed using autoperfused segments of cat ileum exposed to 3 hours of ischemia followed by 1 hour of reperfusion. Mucosal myeloperoxidase activity, an index of mucosal granulocyte levels, increased from 12 to 25 U/g wet wt in the untreated group. In the short-term MAb IB4 experiments, baseline values were very similar to those of the untreated group but no increase in myeloperoxidase activity was observed after ischemia/reperfusion. Long-term pretreatment with MAb IB4 reduced baseline values of myeloperoxidase activity to approximately 1 U/g wet wt; the values remained at this level throughout the experiment. The permeability of the mucosal barrier was quantitated by measuring blood-to-lumen clearance to 51Cr-ethyl-enediaminetetraacetic acid (EDTA). The water absorptive capacity of the intestine was also measured. In the untreated group, mucosal permeability to 51Cr-EDTA increased sixfold and water absorption was abolished after reperfusion. Both short-term and long-term administration of MAb IB4 prevented the net fluid loss into the lumen, but only long-term administration of MAb IB4 blunted the increased mucosal permeability induced by ischemia/reperfusion. These data suggest that interstitial granulocytes contribute significantly to the mucosal dysfunction associated with reperfusion of the ischemic intestine.

Animals↗

PubMed1992

Modulation of leukocyte adhesion in rat mesenteric venules by aspirin and salicylate.

Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and number of adherent and emigrated leukocytes were measured in postcapillary venules both before and during superfusion of rat mesentery with either aspirin or sodium salicylate. In some experiments, animals were treated with either a leukotriene (LT)-synthesis inhibitor (L-663,536), an LTD4 antagonist (MK-571), an LTB4 antagonist (SC-41930), misoprostol, or prostaglandin (PG) I2, then the aspirin protocol was repeated. Superfusion of aspirin but not sodium salicylate resulted in increased leukocyte adherence and a reduced leukocyte rolling velocity but did not affect leukocyte emigration. Aspirin-induced leukocyte adhesion was effectively prevented by the LT-synthesis inhibitor and LTB4 antagonist but not by the LTD4 antagonist. Misoprostol and PGI2 also prevented the aspirin-induced adhesion responses. Superfusion of the mesentery with either platelet-activating factor (PAF) or LTB4 enhanced leukocyte adherence and emigration while reducing leukocyte rolling velocity. Sodium salicylate prevented all of the adhesion responses elicited by LTB4. Although salicylate did not affect the PAF-induced leukocyte adherence and rolling responses, it completely prevented the increased leukocyte emigration. These results indicate that aspirin promotes, whereas sodium salicylate inhibits, leukocyte-endothelial cell adhesive interactions at therapeutically relevant concentrations.

Animals↗

PubMed1992

Reduction of leukocyte adherence and emigration by cyclosporine and L683,590 (FK506) in postcapillary venules.

Although the actions of immunosuppressive agents on lymphocytes are well characterized, their influence on leukocyte-endothelial cell adhesive interactions has not been defined. The objective of this study was to determine whether cyclosporine and L-683,590 (FK520) could modify the adhesion and emigration of leukocytes in postcapillary venules that are exposed to inflammatory mediators such as platelet activating factor (PAF) and leukotriene B4 (LTB4). The rat mesentery was prepared for in vivo microscopic observation. Venules with internal diameters ranging between 25 microns and 35 microns were selected for study. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for > 30 sec) and emigrated leukocytes were measured during superfusion of the mesentery with bicarbonate-buffered saline. Repeat measurements of adhesive and hemodynamic parameters were obtained between 50 and 60 min of superfusion with either 100 nM PAF or 20 nM LTB4 added to bicarbonate-buffered saline. In some experiments, animals were treated with either cyclosporine or L-683,590. Both PAF and LTB4 caused increases in leukocyte adherence and emigration, and reductions in leukocyte rolling velocity and venular shear rate. Cyclosporine prevented all of the adhesive and hemodynamic alterations induced by PAF, but not LTB4. L-683,590 was effective in preventing the responses elicited by both PAF and LTB4. These results indicate that modulation of leukocyte-endothelial cell adhesive interactions may represent a novel mechanism of action for cyclosporine and L-683,590.

Animals↗

PubMed1992

Immunopathology of NSAID-gastropathy: inhibitory effects of interleukin-I and cyclosporin A.

The present study demonstrates that CSA is capable of inhibiting indomethacin-induced leukocyte adherence to the vascular endothelium, and can reduce the severity of indomethacin-induced gastric mucosal injury. These results are therefore consistent with the hypothesis that leukocyte (particularly neutrophil) adherence is a critical event in the pathogenesis of NSAID-induced gastropathy. The mechanism through which CSA inhibits leukocyte adherence is not clear, and warrants further investigation. This study also confirmed the protective effects of IL-1 in experimental NSAID-gastropathy, and demonstrates that one of the ways the IL-1 may protect the mucosa is through its ability to inhibit the release of proinflammatory mediators (e.g., PAF) and promote the release of antiinflammatory mediators (e.g., nitric oxide). IL-1 modulated the release of these mediators from peritoneal mast cells at doses in the pg/ml to ng/ml range. IL-1 can inhibit the ability of neutrophils to respond to chemotactic stimuli and can prevent LTB4-induced neutropenia. Inhibition of neutrophil function by IL-1 may therefore account for its ability to reduce NSAID-induced gastric mucosal injury. Whether or not effects of IL-1 on the production of mediators such as nitric oxide and PAF is an underlying mechanism for the inhibitory effects on neutrophil function remains to be determined.

Animals↗

PubMed1992

Indomethacin-induced leukocyte adhesion in mesenteric venules: role of lipoxygenase products.

Although the pathogenetic mechanisms underlying indomethacin-induced mucosal injury remain undefined, the results from recent studies suggest that leukocyte adherence in gastric microvessels may be an important component of this injury process. The objective of this study was to determine whether clinically relevant plasma concentrations of indomethacin promote leukocyte-endothelial cell adhesive interactions in postcapillary venules. Erythrocyte velocity, vessel diameter, leukocyte rolling velocity, and the number of adherent (stationary for greater than or equal to 30 s) and emigrated leukocytes were measured in rat mesenteric venules. Repeat measurements of all parameters were obtained within 20 min after addition of either 2.5 or 25 micrograms/ml indomethacin to the mesenteric superfusate. In some experiments, rats were pretreated with either a leukotriene (LT) synthesis inhibitor (L 663,536), an LTD4 (MK-571) or LTB4 (SC 41930) receptor antagonist, misoprostol, or prostacyclin (PGI2). Indomethacin alone increased the number of adherent leukocytes, reduced both leukocyte rolling velocity and venular shear rate, but did not promote leukocyte emigration. L 663,536 and SC 41930 prevented all of the adhesive and hemodynamic alterations induced by indomethacin; misoprostol and PGI2, but not MK-571, exerted similar beneficial effects. These results indicate that indomethacin promotes leukocyte adherence in postcapillary venules through an LTB4-dependent mechanism.

Animals↗

PubMed1992

Nitric oxide modulates epithelial permeability in the feline small intestine.

The objective of this study was to assess whether inhibition of nitric oxide production leads to increased epithelial permeability in feline small intestine. Local intra-arterial infusion of the nitric oxide synthesis inhibitor NG-nitro-L-arginine-methyl ester (L-NAME; 0.025 mumol.ml-1.min-1) was performed in autoperfused segments of cat ileum for 90 min. An exogenous source of nitric oxide, sodium nitroprusside (SNP) was infused (0.025 mumol.ml-1.min-1) for the last 30 min of the 90-min L-NAME infusion. Epithelial permeability was quantitated by measuring blood-to-lumen clearance of 51Cr-labeled EDTA throughout the experiment. An increase of approximately sixfold in mucosal permeability was observed within 30 min of L-NAME infusion and this effect was completely reversed by infusion of either SNP or L-arginine (0.125 mumol.ml-1.min-1). NG-nitro-D-arginine-methyl ester (D-NAME) had no effect on mucosal permeability. The increase in epithelial permeability was sufficiently large that rhodamine-dextran (mol wt = 17,200) clearance from interstitium to lumen was increased. Pretreatment with IB4, a monoclonal antibody directed against the leukocyte adhesive glycoprotein complex (CD11/CD18) did not prevent the L-NAME-induced increase in epithelial permeability. These data suggest that inhibition of nitric oxide production leads to a reversible circulating leukocyte-independent increase in epithelial permeability.

Animals↗

PubMed1992

Nitric oxide modulates microvascular permeability.

We recently demonstrated that inhibitors of nitric oxide (NO) production cause a dramatic increase in leukocyte adherence and emigration in postcapillary venules. The objective of this study was to assess whether inhibition of NO production leads to vascular protein leakage and increased microvascular permeability in feline small intestine and to determine whether adherent leukocytes contribute to these responses. Whereas NG-nitro-L-arginine methyl ester (L-NAME) produced fivefold increases in microvascular fluid and protein fluxes, capillary pressure remained unchanged. In some experiments, venous pressure was elevated and the microvascular reflection coefficient for total proteins (sigma d) was estimated from lymph to plasma protein concentration ratio at high capillary filtration rates. L-NAME infusion increased 1 - sigma d (permeability index) from a control value of 0.21 +/- 0.02 to 0.41 +/- 0.07. All of the L-NAME-induced microvascular alterations were completely reversed by nitroprusside. Some animals were pretreated with a monoclonal antibody (MoAb IB4) directed against the leukocyte adhesion glycoprotein complex CD11/CD18. MoAb IB4 did not prevent the initial rise in vascular protein leakage but greatly attenuated the later (30-60 min) phase of enhanced vascular protein leakage. Local intra-arterial infusion of the NO synthesis inhibitor L-NAME (0.025 mumol.ml-1.min-1) produced a profound increase in leukocyte adhesion in postcapillary venules that was partly reversed by sodium nitroprusside administration (0.025 mumol.ml-1.min-1). These results suggest that inhibition of NO production by vascular endothelium leads to a reversible increase in microvascular protein efflux that is mediated by both leukocyte-dependent and -independent mechanisms.

Animals↗

PubMed1992

Participation of alpha 2-adrenergic receptors in neural vascular tone of canine skeletal muscle.

Studies were carried out in anesthetized, paralyzed, and ventilated dogs to determine whether postsynaptic alpha 2-adrenergic receptors participated in neurally mediated vascular tone in skeletal muscle. Hindlimb skeletal muscle resistance (RL) and blood flow (QL) were determined before, during, and after reversible cold block of the sciatic nerve. This sequence of observations was repeated 30 min after blockade of alpha 1-adrenergic receptors with prazosin. Then the alpha 2-adrenergic receptors were blocked with yohimbine, and the nerve cold block was repeated. When the sciatic nerve was cold blocked before alpha 1-adrenergic blockade, RL decreased approximately 50% and QL increased 75% (P less than 0.05) and then returned to control when the nerve was rewarmed. After alpha 1-block 76% of neural tone remained as assessed by nerve cooling (P less than 0.05). This phenomenon occurred despite effective alpha 1-adrenergic blockade as assessed by the alpha 1-receptor agonist methoxamine. With alpha 1- plus alpha 2-block no change in RL or QL was seen with nerve cold block. The same protocol was repeated in a second series of animals, but mean arterial pressure, which fell after alpha 1-block in the group above, was maintained by dextran infusion at normotensive levels. In these animals, 40% of neural tone remained after alpha 1-block. Both alpha 1- and alpha 2-adrenergic blockers were again needed to abolish the QL and RL response to nerve cold block. In another series of animals, yohimbine was administered before prazosin. In this series, alpha 2-adrenergic blockade greatly reduced neural tone as assessed by nerve cooling.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Involvement of neutrophils in ischemia-reperfusion injury in the small intestine.

Reperfusion of the ischemic intestine results in injury to the microvasculature and mucosal membrane. Inflammatory mediators released as a consequence of oxygen radical formation at the time of reperfusion promote neutrophil adhesion and emigration in postcapillary venules. Agents that interfere with leukocyte adherence afford significant protection against reperfusion injury.

Animals↗

PubMed1991

Nitric oxide: an endogenous modulator of leukocyte adhesion.

The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors of NO production, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME), and observing single (30-microns diameter) venules by intravital video microscopy. Thirty minutes into the superfusion period the number of adherent and emigrated leukocytes, the erythrocyte velocity, and the venular diameter were measured; venular blood flow and shear rate were calculated from the measured parameters. The contribution of the leukocyte adhesion glycoprotein CD11/CD18 was determined using the CD18-specific monoclonal antibody IB4. Both inhibitors of NO production increased leukocyte adherence more than 15-fold. Leukocyte emigration was also enhanced, whereas venular shear rate was reduced by nearly half. Antibody IB4 abolished the leukocyte adhesion induced by L-NMMA and L-NAME. Incubation of isolated cat neutrophils with L-NMMA, but not L-NAME, resulted in direct upregulation of CD11/CD18 as assessed by flow cytometry. Decrements in venular shear rate induced by partial occlusion of the superior mesenteric artery in untreated animals revealed that only a minor component of L-NAME-induced leukocyte adhesion was shear rate-dependent. The L-NAME-induced adhesion was inhibited by L-arginine but not D-arginine. These data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern of leukocyte adhesion and emigration that is characteristic of acute inflammation.

Animals↗

PubMed1991

Effects of cyclosporin A and FK506 on ischemia/reperfusion-induced neutrophil infiltration in the cat.

Isolated segments of cat small intestine were subjected to 3 hr of ischemia followed by 1 hr reperfusion (I/R). Mucosal biopsies were obtained for measurement of myeloperoxidase (MPO) activity, an index of tissue neutrophil count, and leukotriene B4 (LTB4) production. Animals were pretreated with either cyclosporin A (CsA) or FK506, which are potent immunosuppressants. Both agents significantly attenuated the neutrophil infiltration induced by I/R. FK506, but not CsA, reduced the elevated mucosal LTB4 production normally observed following reperfusion. The results of this study suggest that FK506 and CsA may be important agents in modulating neutrophil infiltration in acute inflammatory conditions.

Animals↗