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PubMed1999

Topical budesonide treatment reduces endothelial expression of intercellular adhesion molecules (vascular cell adhesion molecule-1 and P-selectin) and eosinophil infiltration in nasal polyps.

Infiltration of eosinophil granulocytes and endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and P-selectin was investigated in biopsies of polyps and inferior turbinates from 16 patients with nasal polyps, by the use of immunohistochemical staining and stereological quantification before, during and after topical treatment with budesonide (Rhinocort Turbuhaler). Before glucocorticoid treatment a higher density of eosinophil profiles (p < 0.005), making up a larger proportion of the total cellular infiltrate (p < 0.0005), was found in the polyps compared with the inferior turbinates. Endothelial VCAM-1 expression was higher in polyps than in inferior turbinates (p < 0.005), in contrast with the expression of P-selectin, which was more frequently expressed in the inferior turbinates (p < 0.05). Topical glucocorticoid treatment reduced the density of eosinophil profiles (p < 0.05) and the endothelial expression of VCAM-1 (p < 0.007) and P-selectin (p < 0.02) in polyps. Eosinophil counts and VCAM-1 expression returned to pre-treatment levels 8 weeks after discontinuation of budesonide treatment. The observed reduction in endothelial expression of cellular adhesion molecules may interfere with cellular recruitment in nasal polyps and thus contribute to the known anti-inflammatory effect of glucocorticoid in nasal polyposis.

Administration, Topical↗
PubMed2003

Adhesion of anaerobic microorganisms to solid surfaces and the effect of sequential attachment on adhesion characteristics.

The attachment of three anaerobic microorganisms, Desulfomonile tiedjei, Syntrophomonas wolfei, and Desulfovibrio sp. strain G11, was investigated to determine if the presence of one species could influence the adhesion of another species to glass surfaces. The results indicated that the numbers and distribution of attached cells of one species could be influenced considerably by the presence of another species and the order in which the test species were exposed to the surface. D. tiedjei was found to detach readily from surfaces when it was not the primary colonizer. The attachment of Desulfovibrio G11 as the primary colonizer appeared to be stabilized by exposure to another test species. Under certain experimental conditions the test organisms formed close associations with each other on the surfaces. These findings demonstrate that the characteristics of anaerobic community biofilms can be determined by both the adhesion characteristics of the individual species and the interactions among those microorganisms.

Bacteria, Anaerobic↗
PubMed2005

Serum levels of soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble endothelial leukocyte adhesion molecule-1(s-ELAM-1) in amyotrophic lateral sclerosis.

Immunological disturbances have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Adhesion molecules are markers of activated endothelial cells up-regulated by action of cytokines. To investigate the activation or inactivation of the vascular cells in ALS, serum soluble intercellular adhesion molecule-1 (s-ICAM-1) and soluble E-selectin (s-ELAM-1) were evaluated (ELISA) in 16 patients with ALS, 30 patients with non-inflammatory neurological diseases (NINDS) and 15 healthy control subjects. Patients with ALS had no higher s-ICAM-1 levels compared with the NINDS patients and the control subjects (p<0.31 and p<0.21, respectively). s-ELAM levels were not statistically significant compared with the NINDS patients and healthy subjects (p<0.21 and p<0.24, respectively). We conclude that the low values of s-ICAM-1 and s-ELAM-1 in the serum of ALS patients do not exclude the presence of immunological abnormality in this disorder. Soluble E-selectin is a glycoprotein which is considered an exclusive marker of endothelial activation. Its low level in our study may suggest a neural rather than an endothelial s-ICAM origin in patients with ALS.

Adult↗
PubMed2002

Adhesion and virulence properties of epidemic Canadian methicillin-resistant Staphylococcus aureus strain 1: identification of novel adhesion functions associated with plasmin-sensitive surface protein.

Epidemic Canadian methicillin-resistant Staphylococcus aureus strain 1 (CMRSA-1) comprises related subtypes that differ in phenotype and prevalence, with subtypes 1A, 1B, and 1D representing 1%, 71%, and 18%, respectively, of total CMRSA-1 isolates. The predominant CMRSA-1B subtype possesses a variant of the staphylococcal cassette chromosome mec, harboring pls, which encodes plasmin-sensitive surface protein (Pls). CMRSA-1B cells that express Pls exhibited poor adhesion to keratinocyte extracellular matrix. However, CMRSA-1B and purified Pls adhered to cellular lipids and glycolipids, and Pls promoted bacterial cell-cell interactions. Although exoprotein expression was restricted to a precursor form of lipase in CMRSA-1B, it was not attenuated in virulence relative to CMRSA-1A, which exhibits normal exoprotein expression. In contrast, CMRSA-1D exhibited a pleiotropic defect in exoprotein expression and attenuated virulence relative to CMRSA-1A. These data indicate that the high transmissibility of CMRSA-1B was not achieved at the expense of attenuated virulence and that Pls confers a novel adhesion mechanism.

Abscess↗
PubMedDate not supplied

Postoperative adhesion formation and the use of adhesion preventing techniques in cardiac and general surgery.

The formation of postoperative adhesions is an inevitable sequel to surgical intervention, and, as part of the healing process, they are often beneficial. Nevertheless, the presence of adhesions may impose postoperative and reoperative surgical problems. An overview of some of the attempts to overcome such problems is presented, and the research surrounding them is discussed.

Animals↗
PubMed1997

Immunosuppression by inhibition of cellular adhesion mediated by leukocyte function-associated antigen-1/intercellular adhesion molecule-1 in murine cardiac transplantation.

BACKGROUND: Donor alloantigen-specific tolerance to vascularized allografts can be induced by several treatments, but the immunological mechanism(s) of these effects remain unclear. One hypothesis is that allograft unresponsiveness is correlated with a shift in the pattern of expression of the T helper 1 versus T helper 2 T-cell cytokines. We report here an extensive analysis of murine cardiac allografts, during normal first set rejection and in mice treated with anti-adhesion molecule monoclonal antibodies (mAbs), a regimen that results in prolonged unresponsiveness. METHODS: A combination of immunohistochemical staining with a panel of mAbs, and in situ hybridization with a panel of digoxigenin-labeled riboprobes, was performed on frozen-tissue sections of cardiac allografts. RESULTS: In several strain combinations, injection of anti-leukocyte function-associated antigen-1 and anti-intercellular adhesion molecule-1, from day 0 to day 6 after transplantation, results in significant long-term survival. Examination of tolerated cardiac allografts by in situ hybridization and immunohistochemical staining shows an altered cytokine expression pattern, although the frequency of CD3 and CD4 cells is not dramatically reduced. These allografts show a decreased frequency of interferon-gamma and interleukin (IL)-2-expressing cells and a slightly increased frequency of cells expressing IL-4 and IL-10, compared with unmodified acute rejection. A direct role of these changes in T-cell cytokine expression is demonstrated by reversal of tolerance induction and rejection of the allograft by in vivo injection of either anti-IL-10 or anti-IL-4 mAb. CONCLUSIONS: Although there are significant differences in the frequency of different cellular subsets and patterns of cytokine gene expression, these differences are quantitatively subtle, suggesting a delicately balanced immune response that can develop a pattern of specific unresponsiveness, with relatively minor alterations in the specific T-cell response.

Animals↗
PubMed1995

Involvement of granulocytes and the adhesion receptors intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 in tissue inflammation induced by Th2-type helper cells.

We reported recently that subcutaneously injected, anti-CD3 epsilon-pulsed polyclonal Th2 cells mediate interleukin-4-dependent local tissue inflammation. Because a prominent polymorphonuclear infiltrate was observed in the lesions at the time of maximal tissue swelling, we investigated the involvement of polymorphonuclear leukocytes and their adhesion molecules lymphocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) in Th2-cell-mediated inflammation. Pretreatment of recipient mice with a depleting monoclonal antibody to neutrophils or with blocking antibodies to LFA-1 or to ICAM-1 completely abrogated tissue swelling in Th2-cell-mediated inflammation. Granulocyte infiltration at 6 h was also inhibited by the antibodies to neutrophils and to ICAM-1, but not by that to LFA-1. Tissue swelling mediated by Th1 cells had different kinetics and was not prevented by administration of anti-neutrophil antibody: maximal edema formation occurred at 24-48 h, when the predominant cellular infiltrate was mononuclear. Because the Th1-cell-induced infiltrate at 6 h also consisted of granulocytes but was not associated with pronounced edema, the mere presence of infiltrating polymorphonuclear leukocytes seems not to be sufficient to induce edema. Because edema but not granulocyte infiltration was inhibited by anti-LFA-1 and because anti-LFA-1 antibodies are known to inhibit several functions of neutrophils, our results suggest that, in inflammation mediated by Th2 cells, granulocytes induce edema through their activation and/or degranulation.

Animals↗
PubMed2005

Lactobacillus acidophilus expressing recombinant K99 adhesive fimbriae has an inhibitory effect on adhesion of enterotoxigenic Escherichia coli.

The most common enteric colibacillosis in neonatal and newborns is caused by enterotoxigenic Escherichia coli(ETEC). Colonization of ETEC in the small intestine is associated with adhesions using fimbriae, which is known as a specific adhesion factor and provides highly specific means for anchoring and prerequisite for an infectious agent. In the present study we have engineered Lactobacillus acidophilus to produce recombinant K99 fimbriae, which is used for the colonization to the intestine of pigs. The expression of K99 fimbrial protein was confirmed using SDS-PAGE, immunoblot and agglutination analyses. To evaluate a function of the K99 fimbrial protein, inhibition and competition tests were performed on pre-screened intestinal brush border from pigs. The tests showed that recombinant L. acidophilus, not control L. acidophilus, had a significant inhibitory effect to and competition against K99+ E. coli in a dose dependent manner. In conclusion, we demonstrated that recombinant K99 fimbriae producing L. acidophilus was able to prevent E. coli binding to intestinal brush border.

Animals↗
PubMed2005

Regulation of immune cell adhesion and migration by regulator of adhesion and cell polarization enriched in lymphoid tissues.

Rap1 has emerged as an important regulator of adhesion in multicellular organisms. In the immune system, Rap1 functions as an inside-out signalling molecule for leucocyte integrins following stimulation with chemokines or antigens. Regulator of adhesion and cell polarization enriched in lymphoid tissues (RAPL) is a novel Rap1 effector molecule that mediates Rap1 signalling to integrins. The Rap1-RAPL complex regulates the spatial distribution of the integrin lymphocyte function-associated antigen-1 as well as cell polarization. The linking of inside-out signalling with polarization synergistically promotes highly efficient lymphocyte trafficking. Targeted deletion of RAPL in mice has demonstrated multiple indispensable roles for this protein in lymphocyte and dendritic cell trafficking critical for immunosurveillance.

Animals↗
PubMed1986

Differences in adhesiveness among type 1 fimbriate strains of Enterobacteriaceae revealed by an in vitro HEp2 cell adhesion model.

Ten type 1 fimbriate strains of Enterobacteriaceae were examined in an in vitro adhesion assay with HEp2 epithelial cells. The range of HEp2 cell adhesiveness, which was characteristic for each strain, was affected by motility, type 1 fimbriation and production of mannose sensitive haemagglutinin. Nevertheless, not all type 1 fimbriate strains adhered well in this model. The findings are discussed with regard to the possibility that different type 1 fimbriate enterobacteria, though all are mannose sensitive, recognize different mannose-containing receptors present or available on the surfaces of the HEp2 cells.

Bacterial Adhesion↗
PubMed2004

ShcA regulates neurite outgrowth stimulated by neural cell adhesion molecule but not by fibroblast growth factor 2: evidence for a distinct fibroblast growth factor receptor response to neural cell adhesion molecule activation.

Homophilic binding in trans of the neural cell adhesion molecule (NCAM) mediates adhesion between cells and leads, via activation of intracellular signaling cascades, to neurite outgrowth in primary neurons as well as in the neuronal cell line PC12. NCAM mediates neurite extension in PC12 cells by two principal routes of signaling: NCAM/Fyn and NCAM/fibroblast growth factor receptor (FGFR), respectively. Previous studies have shown that activation of mitogen-activated protein kinases is a pivotal point of convergence in NCAM signaling, but the mechanisms behind this activation are not clear. Here, we investigated the involvement of adaptor proteins in NCAM and fibroblast growth factor 2 (FGF2)-mediated neurite outgrowth in the PC12-E2 cell line. We found that both FGFR substrate-2 and Grb2 play important roles in NCAM as well as in FGF2-stimulated events. In contrast, the docking protein ShcA was pivotal to neurite outgrowth induced by NCAM, but not by FGF2, in PC12 cells. Moreover, in rat cerebellar granule neurons, phosphorylation of ShcA was stimulated by an NCAM mimicking peptide, but not by FGF2. This activation was blocked by inhibitors of both FGFR and Fyn, indicating that NCAM activates FGFR signaling in a manner distinct from FGF2 stimulation, and regulates ShcA phosphorylation by the concerted efforts of the NCAM/FGFR as well as the NCAM/Fyn signaling pathway.

Adaptor Proteins, Signal Transducing↗
PubMed1986

Negative staining and immunoelectron microscopy of adhesion-deficient mutants of Streptococcus salivarius reveal that the adhesive protein antigens are separate classes of cell surface fibril.

The subcellular distribution of the cell wall-associated protein antigens of Streptococcus salivarius HB, which are involved in specific adhesive properties of the cells, was studied. Mutants which had lost the adhesive properties and lacked the antigens at the cell surface were compared with the parent strain. Immunoelectron microscopy of cryosections of cells labeled with affinity-purified, specific antisera and colloidal gold-protein A complexes was used to locate the antigens. Antigen C (AgC), a glycoprotein involved in attachment to host surfaces, was mainly located in the fibrillar layer outside the cell wall. A smaller amount of label was also found throughout the cytoplasmic area in the form of small clusters of gold particles, which suggests a macromolecular association. Mutant HB-7, which lacks the wall-associated AgC, accumulated AgC reactivity intracellularly. Intracellular AgC was often found associated with isolated areas of increased electron density, but sometimes seemed to fill the entire interior of the cell. Antigen B (AgB), a protein responsible for interbacterial coaggregation, was also located in the fibrillar layer, although its distribution differed from that of the wall-associated AgC since AgB was found predominantly in the peripheral areas. A very small amount of label was also found in the cytoplasmic area as discrete gold particles. Mutant HB-V5, which lacks wall-associated AgB, was not labeled in the fibrillar coat, but showed the same weak intracellular label as the parent strain. Immunolabeling with serum against AgD, another wall-associated protein but of unknown function, demonstrated its presence in the fibrillar layer of strain HB. Negatively stained preparations of whole cells of wild-type S. salivarius and mutants that had lost wall-associated AgB or AgC revealed that two classes of short fibrils are carried on the cell surface at the same time. AgB and AgC are probably located on separate classes of short, protease-sensitive fibrils 91 and 72 nm in length, respectively. A third class of only very sparsely distributed short fibrils (63 nm) was observed on mutant HB-V51, which lacks both wall-associated AgB and AgC antigens. The identity of these fibrils and whether they are present on the wild type are not clear. The function of long, protease-resistant fibrils of 178 nm, which are also present on the wild-type strain, remains unknown.

Adhesiveness↗
PubMed1997

Human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation mediated by vascular cell adhesion molecule-1: evidence for involvement of cell adhesion molecules in HTLV-1 biology.

While studying the potential role of vascular cell adhesion molecule-1 (VCAM-1) in infection of endothelial cells by human immunodeficiency virus (HIV), we found that VCAM-1 can mediate human T-cell lymphotropic virus type 1 (HTLV-1)-induced syncytium formation. Both expression-vector-encoded and endogenously expressed VCAM-1 supported fusion of uninfected cells with HTLV-1-infected cells. Fusion was obtained with cell lines carrying the HTLV-1 genome and expressing viral proteins but not with an HTLV-1-transformed cell line that does not express viral proteins. In clones of VCAM-1-transfected cells, the degree of syncytium formation observed directly reflected the level of VCAM-1 expression. Syncytium formation between HTLV-1-expressing cells and VCAM-1+ cells could be blocked with antiserum against HTLV-1 gp46 and with a monoclonal antibody (MAb) against VCAM-1. Fusion was not blocked by antiserum against HIV or a MAb against VLA-4, the physiological counter-receptor for VCAM-1. The results indicate that VCAM-1 can serve as an accessory molecule or potential coreceptor for HTLV-1-induced cell fusion and provide direct evidence of a role for cell adhesion molecules in the biology of HTLV-1.

Cell Line↗
PubMed1997

Cell adhesion and migration. III. Leukocyte adhesion and transmigration in the liver vasculature.

Leukocytes, i.e., neutrophils, monocytes, and lymphocytes, can accumulate in the hepatic vasculature and contribute to the pathophysiology of various liver diseases. Recently, significant progress has been made in the understanding of the basic mechanisms of neutrophil infiltration and cytotoxicity in the liver. However, there are a substantial number of unresolved issues. This article describes the current knowledge and the gaps in our understanding of mechanisms of neutrophil sequestration in sinusoids and venules, adhesion to endothelial cells, and transmigration and adherence to parenchymal cells. From these data, it is clear that assumptions regarding the roles of adhesion molecules in the liver may be misleading if drawn from studies of peripheral vascular beds. Greater insight into these mechanisms is critical for the development of selective therapeutic strategies that attenuate excessive inflammatory responses without compromising the vital host defense.

Animals↗
PubMedDate not supplied

Effects of intra-abdominal drainages on adhesion formation and prevention by phospholipids in a rat model. Drainages and adhesion formation.

BACKGROUND AND AIMS: The study was designed to asses the adhesiogenic capacity of silicone drainages and the protective effect of phospholipids (PL). MATERIALS AND METHODS: A total of 75 Wistar rats were randomly assigned to the different groups. In a preliminary trial (pt; n = 15), all rats underwent midline laparotomy. The control group (C(pt); n = 5) received no further treatment. In the other animals, either an 'easy flow' drainage (EF(pt); n = 5) or an 'Aachen' drainage (AC(pt); n = 5) was placed into the abdominal cavity. In the final study (fs; n = 60), rats underwent laparotomy and colonic anastomosis. The control groups (C(fs)) received no drainages. In the other groups either one of the two types of drainages (EF(fs), AC(fs)) were introduced. In 50% of the rats, 75 mg/kg of PL were administered intraperitoneally (C(fs)+PL, EF(fs)+PL, AC(fs)+PL). The other rats received no additional treatment (C(fs)ØPL, EF(fs)ØPL, AC(fs)ØPL). All animals were sacrificed 10 days after surgery. Areas of adhesions and anastomotic bursting pressures were measured (mean +/- SD). RESULTS: In the preliminary trial, analysis of variance (ANOVA) revealed no differences between the groups after application of drainages (values are given in mean +/- SD): C(pt) mean 23.3 +/- 29.4 mm(2), EF(pt) 829.7 +/- 679.3 mm(2), AC(pt) 609.9 +/- 219.4 mm(2). In the final study, 2-factorial ANOVA showed a significant effect (p < 0.001) for the use of drainages but not for the application of PL (C(fs)ØPL 140.6 +/- 124.2 mm(2), C(fs)+PL 67.7 +/- 60.4 mm(2), EF(fs)ØPL 1,217.0 +/- 458.3 mm(2), EF(fs)+PL 1,266.8 +/- 368.3 mm(2), AC(fs)ØPL 861.7 +/- 274.8 mm(2), AC(fs)+PL 544.2 +/- 193.8 mm(2)). Post hoc test for pairwise comparisons adjusted to Bonferroni showed significant differences (p < 0.001) between all of the three pairs (C(fs) 104.1 +/- 92.3 mm(2) vs. EF(fs) 1,241.9 mm(2) +/- 413.3 mm(2); C(fs) vs. AC(fs) 702.9 mm +/- 234.3 mm(2); EF(fs) vs. AC(fs)). DISCUSSION: The final study demonstrates the adhesiogenic capacity of silicone drainage tubes in combination with anastomoses. Any protective effect of PL alone or in combination with drainages could not be shown. CONCLUSIONS: Indication for the use of drainages in standard surgical procedures should be reconsidered within the scope of their potential to cause adhesions and subsequent complications.

Abdomen↗
PubMed2004

Precedence of cell-zona adhesion over cell-cell adhesion during marsupial blastocyst formation prohibits morula formation and ensures that both the pluriblast and trophoblast are superficial.

This study, based on 38 samples taken between the 16-cell stage on day 2.5 of gestation and the expanded 1.0-mm-diameter unilaminar blastocyst on day 6, describes the ultrastructural changes that occur in the conceptus of the marsupial Sminthopsis macroura in relation to cell-zonal adhesion initiated at the zygote stage and cell-cell adhesion initiated at the 16-cell stage, lineage allocation, extracellular matrix (ECM) secretion and embryo coat changes. In S. macroura, rather flattened pluriblast and rounded trophoblast cells appear as different cell types during the fourth division when nucleolar reticulation suggests activation of the zygotic genome in both cell types. The differences disappear nearly completely in blastocysts of 0.6-0.8 mm in diameter, but the two cell types then reappear as two distinct populations. The ECM varies depending on its location within the conceptus up to the stage of the expanding blastocyst. It is of rather granular appearance between the cell lining and zona pellucida and consists of patches of homogeneous material embedded in an electron-lucent substance in the cleavage cavity. Homogeneous ECM coats trophoblast but not pluriblast cells on blastocoelic surfaces. Transient structures such as 'myosin-like' fibrillar arrays, probably associated with exocytosis of ECM, and pearl string-like whorls are still present, but both disappear during further expansion of the 0.6- to 0.8-mm blastocyst. During blastocyst expansion, the patchy homogeneous ECM in the blastocoel changes structure and appears flocculent, while the continuous ECM coating trophoblast cells disappears. Pluriblast cells and yolk mass identify the embryonic pole and hemisphere, and the opposite hemisphere becomes abembryonic and is eventually fully lined by trophoblast cells. An increase in endocytotic, mainly coated vesicles at the apical, zona-orientated surface of both cell types is noticed and is probably responsible for uptake of the mucoid coat. In 1-mm blastocysts, numerous vesicles contain rod-shaped crystalline inclusions.

Animals↗
PubMed2000

Adhesion of monocyte very late antigen-4 to endothelial vascular cell adhesion molecule-1 induces interleukin-1beta-dependent expression of interleukin-6 in endothelial cells.

In atheroma, T cell-derived interferon-gamma (INF-gamma) stimulates endothelial cells and facilitates recruitment of monocytes. We investigated potential mechanisms by which these interactions could contribute to local and systemic inflammatory responses. Specifically, we analyzed the expression of interleukin (IL)-1beta and IL-6 in both cell types after coculture, the relevant adhesion molecules in this interaction, and transcriptional control by NF-kappaB. We studied coculture of purified peripheral blood monocytes with human umbilical vein endothelial cells (HUVECs), which were stimulated with INF-gamma (10(6) U/L) to model the activated endothelium of atherosclerotic lesions. Coculture of monocytes with activated HUVECs resulted in release of IL-1beta (40. 6+/-3 pg/24 h, P=0.002) and IL-6 (46.6+/-7 ng/24 h, P=0.0015). Electrophoretic mobility gel shift assay and Northern blotting in each cell type separately revealed NF-kappaB activation in both cell types, IL-1beta mRNA expression predominantly in monocytes, and IL-6 mRNA expression predominantly in HUVECs. The endothelial IL-6 release was IL-1-dependent, because it was suppressed by IL-1 receptor antagonist. Experiments with blocking antibodies demonstrated that binding of monocyte very late antigen-4 (VLA-4) to endothelial vascular cell adhesion molecule-1 (VCAM-1) was necessary for the induction of IL-1beta in monocytes. Binding of monocyte VLA-4 to endothelial VCAM-1 induces NF-kappaB activation in both cell types with expression and release of IL-1beta by monocytes, which in turn stimulates endothelial release of IL-6. The beta(1)-integrin-mediated expression of IL-1beta and IL-6 could contribute to local and systemic inflammatory reactions in atherosclerosis.

Cell Membrane↗
PubMed1997

Adhesion molecule P-selectin and vascular cell adhesion molecule-1 in enhanced heart allograft arteriosclerosis in the rat.

BACKGROUND: The increase of P-selectin on endothelial cells (EC) overlying human atherosclerotic plaques in classic atherosclerosis was recently established. We have previously shown that vascular cell adhesion molecule-1 (VCAM-1) is extensively expressed on EC of occluded arteries during accelerated transplant arteriosclerosis. In the present study, with the use of rat heart allografts under different doses of cyclosporine A (CsA), we investigated whether the expression of P-selectin is increased during chronic rejection and possibly coexpressed with VCAM-1 on EC. METHODS AND RESULTS: Rat cardiac allografts from DA donors to WF recipients were used. Without immunosuppression, these allografts show an irreversible rejection 7 days after transplantation. In the acute rejection model, syngeneic and allogeneic grafts were harvested 5 days after transplantation. In the chronic rejection model, allograft recipients received triple-drug immunosuppression, including azathioprine, methylprednisolone, and CsA in different doses. The grafts were removed 3 months after transplantation. During acute rejection, a significant expression of P-selectin (P < .01) and VCAM-1 (P < .05) on microvascular endothelia, but not on arteries, was noticed. During intense chronic rejection (5 mg/kg CsA), arterial EC expressed P-selectin (P < .01) and VCAM-1 (P < .05) extensively. The expression of tumor necrosis factor-alpha, a cytokine inducing both P-selectin and VCAM-1 expression, was upregulated in vascular medial cells (P < .05), in intimal cells (P < .01), and in interstitial mononuclear cells (P < .05). Linear regression analysis revealed a significant correlation between arterial P-selectin (P < .01) and VCAM-1 (P < .01) expression and the intensity of intimal thickening. Also, a significant correlation and coexpression of P-selectin and VCAM-1 in epicardial arteries was demonstrated (P < .05). CONCLUSIONS: The early expression of P-selectin on microvascular EC during acute rejection may be the basis of cell adhesion and infiltration into the site of inflammation. During chronic rejection, the intensity of arterial intimal thickening was significantly correlated with the intensity of P-selectin expression on EC, in addition to that of previously reported VCAM-1 expression. Thus, P-selectin may have a crucial role in the pathogenesis of chronic rejection in the vascular wall, augmenting the immune-mediated injury against the allograft.

Acute Disease↗