Effect of WEB 2086 on Leukocyte Adherence in Response to Hemorrhagic Shock in Rats

The gastric damage associated with hemorrhagic shock appears to occur, at least in part, through neutrophil-dependent mechanisms. Nitric oxide (NO)-releasing derivatives of aspirin have been shown to spare the gastrointestinal tract of injury. As NO can inhibit neutrophil adherence, it is possible that such a derivative of aspirin (NCX-4016) would exert inhibitory effects on neutrophil adherence and therefore be capable of protecting the stomach against shock-induced gastric damage. This hypothesis was tested in this study. Oral administration of NCX-4016 or glyceryl trinitrate or depletion of circulating neutrophils with antineutrophil serum significantly reduced the extent of gastric damage induced by hemorrhagic shock, whereas aspirin had no effect. NCX-4016 and antineutrophil serum pretreatment resulted in significant preservation of gastric blood flow during the shock period. Moreover, NCX-4016, but not aspirin, was capable of inhibiting N-formyl-Met-Leu-Phe-induced leukocyte adherence to postcapillary mesenteric venules. These results suggest that an NO-releasing aspirin derivative reduces the susceptibility of the stomach to shock-induced damage through inhibitory effects on neutrophil adherence to the vascular endothelium.

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EFFECT OF LFA-1β ANTIBODY ON LEUKOCYTE ADHERENCE IN RESPONSE TO HEMORRHAGIC SHOCK IN RATS

Shock ◽

10.1097/00024382-200014010-00009 ◽

2000 ◽

Vol 14 (1) ◽

pp. 49-52 ◽

Cited By ~ 10

Author(s):

Ed W. Childs ◽

David M. Smalley ◽

Michael Moncure ◽

Jerrihlyn L. Miller ◽

Laurence Y. Cheung

Keyword(s):

Hemorrhagic Shock ◽

Leukocyte Adherence

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Role of platelet-activating factor in ischemia/reperfusion-induced leukocyte adherence

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1990.259.2.g300 ◽

1990 ◽

Vol 259 (2) ◽

pp. G300-G305 ◽

Cited By ~ 20

Author(s):

P. Kubes ◽

G. Ibbotson ◽

J. Russell ◽

J. L. Wallace ◽

D. N. Granger

Keyword(s):

Blood Flow ◽

Ischemia Reperfusion ◽

Platelet Activating Factor ◽

Vessel Diameter ◽

Control Group ◽

Leukocyte Adherence ◽

Adhesive Interaction ◽

Microvascular Endothelium ◽

Rolling Velocity ◽

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The objective of this study was to determine whether platelet-activating factor (PAF) mediates the leukocyte-endothelial cell interactions elicited by ischemia/reperfusion. The rates of adherence and extravasation of leukocytes 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. Leukocyte rolling velocity, red blood cell velocity, and vessel diameter were also measured. The experiments were performed in control (untreated) animals and in animals pretreated with one of two PAF receptor antagonists, i.e., BN 52021 or WEB 2086. The responses of venular blood flow, wall shear rate, and vessel diameter did not differ between the three groups. In the control group, 1 h of ischemia was associated with significant adherence and extravasation of leukocytes, with reperfusion greatly enhancing these responses. The rates of leukocyte adherence and extravasation during reperfusion were greatly attenuated by both PAF antagonists. Furthermore, the proportion of adherent leukocytes that ultimately extravasate during reperfusion was markedly reduced by WEB 2086. These results suggest that PAF plays an important role in mediating the adhesive interaction between circulating leukocytes and microvascular endothelium induced by ischemia/reperfusion and that the phospholipid promotes the leukocyte extravasation associated with ischemia/reperfusion.

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Pressure-related capillary leukostasis following ischemia-reperfusion and hemorrhagic shock

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.265.1.h381 ◽

1993 ◽

Vol 265 (1) ◽

pp. H381-H388

Author(s):

P. Hansell ◽

P. Borgstrom ◽

K. E. Arfors

Keyword(s):

Hemorrhagic Shock ◽

Intravital Microscopy ◽

Perfusion Pressure ◽

Ischemia Reperfusion ◽

Leukocyte Infiltration ◽

Leukocyte Adherence ◽

Arterial Perfusion ◽

Fixed Volume ◽

Total Ischemia ◽

Early Restoration

Although the receptor-dependent venular adhesion of leukocyte adherence has been relatively well characterized, less is known about capillary leukostasis. With the use of fluorescence intravital microscopy, leukocyte behavior in the capillaries of rabbit tenuissimus muscle was evaluated after ischemia-reperfusion or hemorrhage. After fixed volume hemorrhage or 4 h of total ischemia, inflammatory injury was manifest by broken fibrils, edema, leukocyte infiltration, and margination along the postcapillary venular walls. Nevertheless, as long as arterial perfusion pressure was between 27 and 72 mmHg, the frequency of capillary leukostasis was low (4-8 cells/mm2) and similar in all groups, including animals treated with the antiadhesion antibody IB4. In contrast, when perfusion pressure decreased to 20 mmHg, capillary leukostasis increased similarly (to 16–21 cells/mm2) in controls (with or without IB4) and in those subjected to ischemia. Furthermore, when perfusion pressure was increased to more than 27 mmHg, (27–72 mmHg) stationary leukocytes returned to the original low level (4–5 cells/mm2). These results are consistent with the conclusion that during some inflammatory injuries, capillary leukostasis is a pressure-related phenomena that is not receptor dependent and is freely reversible with the early restoration of perfusion pressure.

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Mesenteric microvascular inflammatory responses to systemic hypoxia are mediated by PAF and LTB4

Journal of Applied Physiology ◽

10.1152/japplphysiol.00047.2002 ◽

2003 ◽

Vol 94 (6) ◽

pp. 2313-2322 ◽

Cited By ~ 20

Author(s):

Alfred J. Casillan ◽

Norberto C. Gonzalez ◽

Jennifer S. Johnson ◽

Dawn R. S. Steiner ◽

John G. Wood

Keyword(s):

Inflammatory Response ◽

Vascular Permeability ◽

Inflammatory Responses ◽

Platelet Activating Factor ◽

Ros Generation ◽

Leukocyte Adherence ◽

Anesthetized Rats ◽

Systemic Hypoxia ◽

Paf Receptor ◽

Web 2086

Systemic hypoxia produces a rapid microvascular inflammatory response characterized by increased reactive oxygen species (ROS) levels, leukocyte-endothelial adherence and emigration, and increased vascular permeability. The lipid inflammatory mediator leukotriene B4 (LTB4) is involved in the early hypoxia-induced responses (ROS generation and leukocyte adherence). Whether other lipid inflammatory mediators participate in this phenomenon is not known. The objective of these experiments was to study the role of platelet-activating factor (PAF) in the microvascular inflammatory response to hypoxia and its potential interactions with LTB4 in this response. Intravital microscopy was used to examine mesenteric venules of anesthetized rats. We found that WEB-2086, a PAF receptor antagonist, completely prevented the increase in ROS levels and leukocyte adherence during a brief reduction in inspired Po 2 to anesthetized rats; administration of either WEB-2086 or the LTB4 antagonist LTB4-DMA attenuated leukocyte emigration and the increase in vascular permeability to the same extent during prolonged systemic hypoxia in conscious rats. Furthermore, no additive effect was observed in either response when both antagonists were administered simultaneously. This study demonstrates a role for PAF in the rapid microvascular inflammatory response to hypoxia, as well as contributions of PAF and LTB4 to the slowly developing responses observed during sustained hypoxia. The incomplete blockade of the hypoxia-induced increases in vascular permeability and leukocyte emigration by combined administration of both antagonists indicates that factors in addition to LTB4 and PAF participate in these phenomena.

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Heme-Oxygenase-1 mRNA Expression Affects Hemorrhagic Shock-Induced Leukocyte Adherence

Journal of Trauma and Acute Care Surgery ◽

10.1097/01.ta.0000075333.04091.4a ◽

2003 ◽

Vol 55 (1) ◽

pp. 118-125 ◽

Cited By ~ 12

Author(s):

Michael Moncure ◽

Lijun Chen ◽

Ed W. Childs ◽

David Smalley ◽

Kahdi F. Udobi ◽

...

Keyword(s):

Hemorrhagic Shock ◽

Mrna Expression ◽

Heme Oxygenase ◽

Heme Oxygenase 1 ◽

Leukocyte Adherence

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Platelet Mobilization Induced by PAF and Its Role in the Thrombocytosis Triggered by Adrenaline in Rats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647127 ◽

1989 ◽

Vol 62 (04) ◽

pp. 1107-1111 ◽

Cited By ~ 5

Author(s):

Hugo C Castro-Faria-Neto ◽

Patricia T Bozza ◽

Marco A Martins ◽

Paulo M F L Dias ◽

Patricia M R Silva ◽

...

Keyword(s):

Receptor Antagonists ◽

Blood Samples ◽

Platelet Counts ◽

Platelet Number ◽

Edta Solution ◽

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Dependent Mechanism

SummaryThe injection of PAP (6 μg/kg, i. v.) induced, in rats, haemoconcentration accompanied by an increase in the platelet number, as attested by the counts of platelets in blood samples diluted in formalin-free EDTA solution. This increase was significant at 15 min, peaked from 1 to 4 h and returned to basal levels 24 h after the lipid administration. The release of platelets induced by PAP was inhibited dose-dependently by specific PAP receptor antagonists such as WEB 2086 (0.5-2 mg/kg), BN 52021 and 48740 RP (5-25 mg/kg). Furthermore, platelet mobilization was clearly impaired in splenectomized animals stimulated by PAP, whereas thrombocytopenia and haemoconcentration by the same stimulus were intact. It was also noted that a second injection of PAP, 24 h after the initial stimulation with the lipid, failed to induce an increase in platelet counts, indicating autodesensitization. Desensitization to PAP or pretreatment with PAP antagonists clearly prevented the increase in the platelet counts after stimulation by adrenaline (15 μg/kg). These findings suggest that, in rats, PAP can induce release of platelets by a spleen-dependent mechanism and that this lipid may be relevant to the thrombocytosis triggered by adrenaline.

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