Showing papers by "Sussan Nourshargh published in 1993"
TL;DR: A role for VLA-4 in eosinophil accumulation in vivo is suggested and a dissociation between the inflammatory events of eos inophils accumulation and edema formation is indicated.
Abstract: Using an in vivo test system, the role of the beta 1 integrin very late activation antigen-4 (VLA-4) in eosinophil accumulation in allergic and nonallergic inflammatory reactions was investigated. Eosinophil infiltration and edema formation were measured as the local accumulation of intravenously injected 111In-labeled eosinophils and 125I-human serum albumin. The inflammatory reactions investigated were a passive cutaneous anaphylaxis (PCA) reaction and responses elicited by intradermal soluble inflammatory mediators (platelet-activating factor, leukotriene B4, C5a des Arg), arachidonic acid, and zymosan particles. The in vitro pretreatment of 111In-eosinophils with the anti-VLA-4 monoclonal antibody (mAb) HP1/2, which crossreacts with guinea pig eosinophils, suppressed eosinophil accumulation in all the inflammatory reactions investigated. Eosinophil accumulation was inhibited to the same extent when mAb HP1/2 was administered intravenously. It is interesting that HP1/2 had no effect on stimulated edema formation. These results suggest a role for VLA-4 in eosinophil accumulation in vivo and indicate a dissociation between the inflammatory events of eosinophil accumulation and edema formation.
183 citations
TL;DR: Although the neutrophil and eosinophil have distinct roles in host defense, they have been implicated in the pathogenesis of a number of inflammatory disorders and a better understanding of the events mediating and regulating neutrophils and eOSinophils accumulation in vivo will be of considerable value in the development of therapeutic strategies for inflammatory disease states.
Abstract: The accumulation of leukocytes into tissues is a characteristic feature of inflammatory reactions. This process is triggered by chemical signals generated in a tissue in response to an inflammatory stimulus e.g., invading microbes, other foreign organisms, allergens, or damaged tissue cells. The mechanisms involved in neutrophil and eosinophil accumulation in vivo are complex and dependent on an initial interaction between the leukocytes and the microvascular endothelial cells. This response is regulated by the coordinated expression and/or activation of leukocyte and endothelial cell adhesion molecules. The precise mechanisms that control the selective accumulation of eosinophils, as opposed to neutrophils, in certain inflammatory reactions (e.g., in IgE-mediated allergic reactions) remain unclear. This may be explained partly by the generation of eosinophil-specific inflammatory mediators and activation of selective adhesion pathways such as the VLA-4/VCAM-1 interaction. Although the neutrophil and eosinophil have distinct roles in host defense, they have been implicated in the pathogenesis of a number of inflammatory disorders. Thus, a better understanding of the events mediating and regulating neutrophil and eosinophil accumulation in vivo will be of considerable value in the development of therapeutic strategies for inflammatory disease states.
40 citations
TL;DR: The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedema formation and indicate that at least part of the inhibitory effect is on the circulating neutrophil induced by dexamithasone or a dexamETHasone‐induced product.
Abstract: 1. The anti-inflammatory actions of dexamethasone on vascular and leukocyte responses in rabbit skin were investigated. 2. Neutrophil accumulation and oedema formation were simultaneously measured as the local accumulation of i.v. administered 111In-labelled neutrophils and 125I-labelled albumin. Systemically administered dexamethasone (3 mg kg-1) inhibited neutrophil accumulation induced by i.d. zymosan activated plasma (ZAP), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4) when co-injected with prostaglandin E2 (PGE2). Dexamethasone also inhibited oedema formation elicited by these stimuli and the responses induced by i.d. platelet activating factor (PAF)+PGE2 and bradykinin (BK)+PGE2. 3. Intradermal dexamethasone (2 x 10(-10) mol per site) but not indomethacin (10(-8) mol per site) inhibited oedema formation induced by i.d. ZAP+PGE2 and BK+PGE2. This inhibitory effect of dexamethasone was significant only with pretreatment periods of 4 h, shorter pretreatment periods resulting in greatly reduced effects. Intradermal dexamethasone had no effect on neutrophil accumulation induced by ZAP+PGE2. 4. Intradermal dexamethasone (2 x 10(-10) mol per site) had no effect on increase in blood flow induced by PGE2 as measured by 133Xenon clearance. 5. The accumulation of neutrophils isolated from donor rabbits pretreated with i.v. saline or dexamethasone (3 mg kg-1) was investigated in untreated recipient rabbits. The accumulation of neutrophils, induced by ZAP+PGE2, FMLP+PGE2 and LTB4+PGE2, from dexamethasone-pretreated donors was significantly smaller than the accumulation of neutrophils from saline-pretreated donors. 6. The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedema formation. 7. Neutrophil accumulation can be inhibited by an effect of dexamethasone on the neutrophil itself or on the vascular endothelium. These results indicate that at least part of the inhibitory effect is on the circulating neutrophil induced by dexamethasone or a dexamethasone-induced product.
27 citations
TL;DR: The results suggest that PAF is an important mediator of oedema formation and platelet accumulation in the RPA reaction in rabbit skin and question the role of PAF receptors on platelets in this model.
Abstract: 1. The contribution of platelet-activating factor (PAF) to platelet deposition and oedema formation induced by exogenous soluble mediators, zymosan particles and associated with a reversed passive Arthus (RPA) reaction in rabbit skin was investigated by use of a novel long-acting PAF receptor antagonist, UK-74,505. 2. Oedema formation and platelet accumulation were simultaneously measured by i.v. injection of [125I]-albumin and 111In-labelled rabbit platelets. UK-74,505 was either administered i.v. or used to pretreat radiolabelled platelets in vitro before their injection into recipient animals. Platelets pretreated with UK-74,505 were also labelled with the fluorescent calcium indicator, Fura-2, to assess their ex vivo reactivity to PAF at the end of the in vivo experiment. 3. UK-74,505 (0.5 mg kg-1), administered i.v., inhibited PAF-induced oedema formation, but did not affect oedema induced by zymosan particles, bradykinin (BK), histamine, formyl-methionyl-leucylphenylalanine (FMLP), zymosan-activated plasma (ZAP, as a source of C5a des Arg), leukotriene B4 (LTB4) or interleukin-8 (IL-8). 4. UK-74,505, administered i.v. also suppressed the small platelet accumulation induced by exogenous PAF, but had no effect on accumulation induced by IL-8 or ZAP. Although oedema induced by zymosan was not affected by i.v. UK-74,505, zymosan-induced platelet accumulation was significantly attenuated by the antagonist. 5. The RPA reaction in rabbit skin was associated with marked oedema formation and platelet accumulation which were both inhibited by i.v. UK-74,505. 6. In vitro, UK-74,505 inhibited aggregation and the increase in intracellular calcium concentration induced by PAF in rabbit washed platelets in a concentration-dependent manner (IC50 = 1.6 x 10-8 M and 1.1 x 10-8 M, respectively). Platelets pretreated with 10-6 M UK-74,505, and maintained at 37 degrees C,were unresponsive to PAF, whilst responding normally to thrombin, for up to 4 h.7. In a second series of in vivo experiments, platelets were labelled with 111In and loaded with Fura-2.The platelets were then pretreated with 10-6 M UK-74,505, washed, and injected into recipient rabbits.These platelets, prepared from blood samples taken at the end of the in vivo experiments, exhibited an 80% reduction in their response to PAF as measured ex vivo with Fura-2. However, in contrast to the effects of i.v. UK-74,505, platelets pretreated with the antagonist did accumulate effectively in the RPA reaction, a significant reduction only being observed in responses at the lowest antibody dose. In addition, pretreatment of platelets had no effect on the small platelet accumulation induced by PAF.8. These results suggest that PAF is an important mediator of oedema formation and platelet accumulation in the RPA reaction in rabbit skin. However, they question the role of PAF receptors on platelets in this model. The results also indicate that PAF may be involved in platelet accumulation induced by zymosan in rabbit skin.
19 citations
01 Jan 1993
TL;DR: The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedemaformation and that neutrophil accumulation can be inhibited by an effect ofdexameth asone on theneutrophil itself or on the vascular endothelium.
Abstract: (FMLP)andleukotriene B4(LTB4) whenco-injected withprostaglandin E2(PGE2). Dexamethasone alsoinhibited oedemaformation elicited bythese stimuli andtheresponsesinduced byi.d.platelet activating factor (PAF)+ PGE2and bradykinin (BK)+ PGE2. 3 Intradermal dexamethasone (2x 10-1 molper site) butnot indomethacin (10-s mol per site) inhibited oedemaformation induced byi.d. ZAP+ PGE2andBK + PGE2.Thisinhibitory effect of dexamethasone was significant onlywithpretreatment periods of4h,shorter pretreatmentperiods resulting ingreatly reduced effects. Intradermal dexamethasone hadno effect on neutrophil accumulationinduced byZAP+ PGE2. 4 Intradermal dexamethasone (2x 10 molpersite) hadno effect on increase inbloodflowinduced byPGE2as measured by'3Xenon clearance. 5 Theaccumulation ofneutrophils isolated fromdonorrabbits pretreated withi.v. saline or dexamethasone (3mg kg-') was investigated inuntreated recipient rabbits. Theaccumulation ofneutrophils, induced byZAP+ PGE2,FMLP + PGE2andLTB4+PGE2,fromdexamethasone-pretreated donors was significantly smaller thantheaccumulation ofneutrophils fromsaline-pretreated donors. 6 Theresults ofthis study suggest thatdexamethasone can havea direct effect on vascular endothelial cells resulting inan inhibition ofoedemaformation. 7 Neutrophil accumulation can beinhibited byan effect ofdexamethasone on theneutrophil itself or on thevascular endothelium. Theseresults indicate that atleast partoftheinhibitory effect ison the circulating neutrophil induced bydexamethasone or a dexamethasone-induced