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At least 649 records · Page 36Linked to original sources
PubMed1996

Increased expression of intercellular adhesion molecule 1, CD11/CD18 cell surface adhesion glycoproteins and alpha 4 beta 1 integrin in a rat model of chronic interstitial lung fibrosis.

The expression of the intercellular adhesion molecule 1 (ICAM-1), and the integrins CD49, CD11b/c, and CD11a (LFA-1 alpha chain) was analyzed in an experimental model of pulmonary fibrosis. Adult rats were exposed to 75% oxygen during 10 weeks, and to 2.0 mg/kg of paraquat twice weekly. Rats were sacrificed at 2 days, and at 2 and 10 weeks after the first injection of paraquat. Lungs were fixed in 4% paraformaldehyde and used for histology and immunohistochemistry. At 2 days the lungs showed a diffuse inflammation composed of a mixed polymorphonuclear and mononuclear cell infiltrate. Afterwards, the inflammatory process was predominantly mononuclear, and an increasing fibroblast proliferation was observed. Early inflammatory events (48 h) correlated with a moderate increased expression of ICAM-1, LFA, and CD11b/c in epithelial cells as well as a pronounced expression of ICAM-1 and CD11b/c in macrophages. At 2 and 10 weeks, there was a progressive increased expression of CD11b/c and ICAM-1 by macrophages, as well as of LFA in epithelial cells, and of ICAM-1 and CD49 by epithelial and interstitial cells. Lymphocytes showed a slight increased expression of LFA at 2 weeks, and of CD49 at 2 and 10 weeks. These results suggest that macrophages expressing ICAM-1, CD11b/c, and CD49 are involved in the earlier and late phases of the disease whereas fibroblast and epithelial cells expressing ICAM-1 and CD49 might play a role in the cell interactions involved in the fibrotic phase.

Animals↗
PubMed1996

Adhesion molecules and wound healing in spinal cord injury.

The purpose of this study was to design and test a model that could identify and define which cellular adhesion molecules (CAMs) present on peripheral blood leukocytes were depressed in spinal cord injury (SCI) patients. CAMs on peripheral blood cells of SCI patients with pressure ulcers were measured by flow cytometry and compared with those of age-matched healthy controls and SCI patients on physical rehabilitation therapy (PRT) protocols without pressure ulcers. The latter patients had normal levels (97%) of lymphocyte function-associated antigen 1 (LFA-1; CD11a/CD18) and a low incidence of infection. By contrast, prior to undergoing rehabilitation therapy, SCI patients with pressure ulcers had significantly diminished LFA-1 levels (62%). Very late antigen 4 (VLA-4; alpha 4 beta 1; 34%) levels (i.e., alpha 4 = 34% and beta 1 = 44%) were approximately half those in controls (72%). Expression of alpha 2 and alpha 3 was also diminished in patients. Patients receiving PRT after debridement developed increased levels of LFA-1 and VLA-4 by the 6th week but alpha 2 and alpha 3 remained relatively low. These results combined with data from previous studies suggest that patients not receiving PRT developed severe pressure ulcers which required debridement surgery and healed more slowly due, in part, to reduced levels of CAMs.

Adult↗
PubMed1997

Expression and function of integrins on hematopoietic progenitor cells.

The growth and differentiation of hematopoietic stem cells are highly dependent on regulatory molecules produced by stromal cells of the marrow environment. Evidence has accumulated over the past years which shows that adhesive receptors on hematopoietic cells and their ligands on stromal cells and extracellular matrix play a crucial role in these interactions. Integrins of the beta 1 family, mostly VLA-4 and VLA-5, are the best characterized and have been identified on committed progenitor cells of the hematopoietic hierarchy as well as on more primitive stem cells defined by their long-term repopulating capacity assayed in vitro as well as in vivo. Functional assays demonstrate that most progenitor cells efficiently bind to ECM components through beta 1 integrins and lineage- and maturation stage-specific differences have been described. Evidence exists on the direct control of late erythroid differentiation by VLA-4, but whether or not the triggering of beta 1 integrins is critically required for hematopoietic stem cell functioning at more immature steps is unclear. Many other integrin and non-integrin receptors involved in adhesive interactions are expressed on hematopoietic progenitor cells and tightly regulated during differentiation but their function is still controversial. Our main purpose in this review is to describe recent advances in the knowledge of integrin expression on hematopoietic progenitor cells in both mouse and man. The emerging importance of the synergy between integrins and cytokine signalling pathways in the regulation of hematopoietic differentiation will also be discussed.

Animals↗
PubMed1997

Beta-1-integrin expression in adult acute lymphoblastic leukemia: possible relationship with the stem cell antigen CD34.

In the hemopoietic system, interactions between stem cells and components of the bone marrow microenvironment play a pivotal role in blood cell proliferation and differentiation. Among the adhesion molecules, the integrins of the beta 1-subfamily are known to direct cell-cell and cell-matrix interactions and evidence has been provided that CD34-positive stem cells bind either to the bone marrow stroma or to the extracellular matrix proteins through the beta 1-integrins. It seems that changes in their expression pattern or signalling function are likely to reflect disturbances at the hemopoietic bone marrow microenvironmental level. Any alteration of their biological functions makes them attractive candidates for playing decisive roles in the leukemic processes. In this view, beta 1-integrins have been recognized to mediate those cellular interactions and migrations that are important in the biology of leukemia. In this paper we review some aspects of the role played by beta 1-integrins, especially VLA-4 and VLA-5, in adult acute lymphoblastic leukemia in relation with the expression rate of the stem cell antigen CD34.

Adult↗
PubMed1997

Regulation and function of adhesion molecules in B-cell chronic lymphocytic leukaemia.

Cell surface expression of adhesion molecules in B-cell chronic lymphocytic leukemia (B-CLL) may determine the patterns of dissemination and infiltration. B-CLL cells express high levels of CD44, but expression of the leucocyte integrins was low or absent, while expression of VLA-4 is high. Most cases examined expressed no detectable ICAM-1, but some cases demonstrated levels of up to 30%. Levels of L-selectin were also variable, and expression could be induced/enhanced in vitro by incubation with cytokines such as IL-4, interferon-alpha and interferon-gamma. B-CLL cells bound normally to vascular endothelium, but binding to IL-1-activated endothelium was significantly lower than that of normal peripheral blood lymphocytes. Cytokine enhancement of L-selectin expression was not accomplished by changes in binding to vascular endothelium. Patterns of adhesion molecule expression and their regulation by cytokines may underly some of the clinical features of this disease.

Apoptosis↗
PubMed1997

Homing and trafficking of hemopoietic progenitor cells.

Investigations of the homing of transplanted hemopoietic cells into preconditioned recipients have in most studies been referable to parameters that determine engraftment. The principles, however, that govern their early traffic into the host's blood and tissues have remained much less explored. Early studies and experiments from our own laboratory suggest that intravenously administered hemopoietic cells, including progenitors, are not selectively taken up by bone marrow, as they are distributed widely in several tissues (liver, lung, kidney, spleen, bone marrow). As the hemopoietic cells are later on found almost exclusively in the bone marrow (and spleen in the mouse), the data argue for either preferential retention in these tissues or just only preferential survival and proliferation. Our recent studies showing modulation of cells lodged to the bone marrow, before proliferation ensues (i.e. 3 h after infusion), would favor preferential retainment and/or survival of these cells within the bone marrow. Furthermore we established that the VLA4/VCAM-1 adhesion pathway plays a significant role in this process, thus defining VCAM-1 as the dominant bone marrow endothelial addressin in hemopoietic cell homing. Since homing likely represents a cascade of adhesive interactions between hemopoietic cells and bone marrow stroma and/or its extracellular matrix, other adhesion pathways are likely to be involved and remain to be defined. Finally, our data on mobilization of hemopoietic progenitors from normal individuals, induced by blocking the VLA4/VCAM-1 adhesion pathway, suggest that the molecular pathways involved in homing are also of importance in governing hemopoietic progenitor cell trafficking in and out of the bone marrow.

Animals↗
PubMed1995

Influence of cytokine stimulation (granulocyte macrophage-colony stimulating factor, interleukin-3 and transforming growth factor-beta-1) on adhesion molecule expression in normal human bone marrow fibroblasts.

Interactions between stromal cells or extracellular matrix and hematopoietic cells are important factors for the very complex processes associated with differentiation and maturation in the bone marrow. To elucidate these multifold processes, the expression pattern of various adhesion molecules was studied on enriched fibroblastic populations derived from healthy volunteers. CD44 (homing cell adhesion molecule) and very late activation antigen beta 1 (VLA beta 1; CD29) could be demonstrated on almost all fibroblasts without an alteration following cytokine stimulation. On the other hand, VLA-2 (CDw49b), VLA-3 (CDw49c), VLA-4 (CDw49d), VLA-5 (CDw49e), intercellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106) were only represented by certain cell fractions. In our studies recombinant human granulocyte macrophage-colony stimulating factor failed to alter the expression pattern of these adhesion molecules, whereas recombinant human interleukin-3 (rhIL-3 showed a tendency for downregulation of the VLA antigens except for VLA beta 1. However, recombinant human transforming growth factor-beta 1 (rhTGF beta 1) exerted a reducing effect on the expression of VLA-3 and induced an increase in the VLA-5-positive fraction. In the immunoglobin class VCAM-1 revealed a decrease staining capacity after stimulation with rhTGF beta 1 and rhIL-3. Contrary to this finding, the presentation of ICAM-1 increased after administration of these mediators.

Bone Marrow↗
PubMed1997

Characterization of a liver metastatic variant of murine colon 26 carcinoma cells.

Intraportal vein injection of highly metastatic L5 cells consistently resulted in liver metastases (increases in the number of tumor colonies in the liver), whereas inoculation of P cells rarely did. L5 cells invaded the basement membrane Matrigel in greater numbers than did P cells, suggesting that the metastatic potential of L5 cells is partly related to enhanced invasive properties. The enhanced adhesion of L5 cells to fibronectin-, laminin- and Matrigel-coated substrates, as well as their haptotactic migration to fribronectin, may be associated with the preferential expression of VLA-2 and VLA-4 integrins on the surface of these cells detected by flow cytometry. Gelatin zymograms showed that the degradative activity of 72-kD gelatinases was greater in L5 cells than P cells. These results indicate that, in addition to adhesiveness and motility, the invasive ability of L5 cells may also be attributed to enhanced gelatinolytic activity. L5 cells grew more rapidly than P cells in vitro. Thus, an experimental model using highly metastatic colon 26 L5 cells would be useful for analyzing the molecular mechanism of liver metastasis and for evaluating the efficacy of treatment of occult micrometastases which may already have been disseminated at the time of surgery.

Adenocarcinoma↗
PubMed1996

Heterogeneity of eosinophils in chronic eosinophilic pneumonia.

It has previously been shown that patients with chronic eosinophilic pneumonia can be divided into 2 groups according to the chemotactic response of their eosinophils to 5 different eosinophil chemotactic factors (ECFs) and laboratory findings. In contrast, eosinophils obtained by bronchoalveolar lavage from both groups responded to all 5 ECFs. The correlation between the two groups and the expression of several antigens (VLA-4, CD69, ICAM-1 and CD11b) on eosinophils. The VLA-4 expression of group 1 eosinophils was higher than that of group 2 eosinophils. More interestingly, eosinophils that migrated towards ECF-PI9 expressed less CD69 than those that migrated towards other STO-2-derived ECF. The heterogeneous response of eosinophils to STO-2-derived ECFs suggests that the population of eosinophils is heterogeneous.

Antigens, CD↗
PubMed1996

Comparison of adhesion molecule expression on light and normal-density eosinophils from patients with eosinophilia.

Increased numbers of light-density eosinophils (LDEs) are observed in the blood of patients with eosinophilia and are associated with disease activity. LDEs are thought to be metabolically more activate than normal-density eosinophils (NDEs). Recent studies suggest that cytokine-induced eosinophil activation is associated with adhesion molecule expression. The activated state of LDEs may result from increased expression of adhesion molecules. This study compared the expression of eosinophil adhesion molecules on LDEs and NDEs from various diseases characterized by eosinophilia. Expression of very late antigen-4 (VLA-4), lymphocyte function-associated antigen-I (LFA-1) and macrophage antigen-1 (Mac-1) on eosinophils from patients with eosinophilia was increased compared with those from healthy subjects. Mac-1 expression on LDEs was higher than on NDEs. These results suggest that VLA-4 plays a role in selective migration of eosinophils into the inflammatory tissue, and that Mac-1 is associated with activation of eosinophils in eosinophilic diseases.

Cell Adhesion Molecules↗
PubMed1996

Regulation of eosinophil cell death by adhesion to fibronectin.

Fibronectin is an extracellular matrix (ECM) that binds to very late antigen-4 (a beta 1 integrin molecule) expressed by eosinophils. To investigate the effect of adherence to fibronectin on regulation of eosinophil cell death, survival of eosinophils was examined by trypan blue exclusion and Fas antigen expression on the cell surface using an eosinophilic cell line (EoL-1). Adhesion to fibronectin resulted in prolongation of eosinophil survival (fibronectin vs. bovine serum albumin (BSA), 62.9 +/- 5.10 vs. 53.9 +/- 4.30% viability at 72 h) and the decreasement of Fas antigen expression on EoL-1 (fibronectin vs. BSA, 24.3 +/- 2.15 vs. 74.5 +/- 8.25% positive). These findings suggest that eosinophil adhesion to ECM via adhesion molecules plays an important role in the pathogenesis of allergic inflammation, which involves eosinophil accumulation at the inflammatory site, through regulation of eosinophil cell death.

Apoptosis↗
PubMed1997

A monoclonal antibody against very late activation antigen-4 inhibits eosinophil accumulation and late asthmatic response in a guinea pig model of asthma.

Preferential eosinophil accumulation is a characteristic of airway inflammation in asthma. Although little is known about its mechanism, recent in vitro observations suggest that the very late activation antigen-4 (VLA-4, CD49d/CD29) and vascular cell adhesion molecule-1 (VCAM-1) adhesion pathway may be involved in specific eosinophil migration. To test this hypothesis, we studied the effect of an anti-VLA-4 monoclonal antibody (mAb) on the airway eosinophilia in a guinea pig model of asthma. Guinea pigs were sensitized by repeated inhalation of ovalbumin. After a single inhalation challenge, the animals showed a striking airway eosinophilia and late asthmatic response (LAR). In contrast, when guinea pigs were pretreated intravenously at 2 h before antigen challenge with a rat antimouse VLA-4 mAb, PS2/3, cross-reacting with guinea pig eosinophils and lymphocytes, eosinophil, basophil and lymphocyte infiltration in the tracheal wall was significantly inhibited as well as LAR in a dose-dependent manner. These results suggest that VLA-4 plays a critical role in antigen-induced airway eosinophilia and LAR.

Animals↗
PubMed2002

Monocyte and neutrophil adhesion molecule expression during acute hyperglycemia and after antioxidant treatment in type 2 diabetes and control patients.

OBJECTIVE: We hypothesized that acute hyperglycemia (an independent cardiovascular risk factor) increases the expression of proatherogenic leukocyte adhesion molecule in type 2 diabetes and controls and that the expression of these adhesion molecules would be antioxidant sensitive. METHODS AND RESULTS: Twenty-three type 2 diabetes patients and 13 control patients underwent two oral glucose tolerance tests 14 days apart and took placebo or 800 IU daily of oral alpha tocopherol between tests. Monocyte and neutrophil expression of adhesion molecules Mac-1, LFA-1 and 3, ICAM-1, and VLA-4 were measured at 0, 120, and 240 minutes by using laser flow cytometry. Baseline adhesion molecule expression did not differ between groups, but there was a rapid, highly significant increase (P<0.0001) in the intensity of monocyte Mac-1 expression after a glucose load in both groups. Alpha-tocopherol supplementation reduced only Mac-1 expression in the diabetes group (P=0.03). CONCLUSIONS: Acute glycemic excursions of any degree cause highly significant, rapid increases in monocyte Mac-1 expression in type 2 diabetes patients and controls. Mac-1 mediates leukocyte vascular infiltration and is prothrombotic. These data suggest a mechanism for the link between glycemic excursions and increased vascular event rates.

Acute Disease↗
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↗
PubMed2002

Role of alpha4 integrin and VCAM-1 in CD18-independent neutrophil migration across mouse cardiac endothelium.

Myocardial damage due to reperfusion of ischemic tissue is caused primarily by infiltrating neutrophils. Although leukocyte beta2 integrins (CD18) play a critical role, significant neutrophil emigration persists when CD18 is neutralized or absent. This study examined the role of leukocyte beta1 integrin (alpha4) and its endothelial ligand VCAM-1 in CD18-independent neutrophil migration across cardiac endothelium. In a mouse model of myocardial ischemia and reperfusion, we show that compared with wild-type mice, neutrophil infiltration efficiency was reduced by 50% in CD18-null mice; in both types of mice, myocardial VCAM-1 staining increased after reperfusion. In wild-type mice, antibodies against CD18, ICAM-1 (an endothelial ligand for CD18), or VCAM-1 given 30 minutes before ischemia did not block neutrophil emigration at 3 hours reperfusion. Although anti-VCAM-1 attenuated neutrophil emigration by 90% in CD18-null mice, it did not diminish myocardial injury. To determine if CD18-independent neutrophil emigration was a tissue-specific response, we used isolated peripheral blood neutrophils from wild-type or CD18-null mice and showed neutrophil migration across lipopolysaccharide-activated cultured cardiac endothelium is CD18-independent, whereas migration across endothelium obtained from inferior vena cava is CD18-dependent. Consistent with our in vivo findings, migration of CD18-deficient neutrophils on cardiac endothelial monolayers is blocked by antibodies against alpha4 integrin or VCAM-1. We conclude tissue-specific differences in endothelial cells account, at least partially, for CD18-independent neutrophil infiltration in the heart.

Animals↗
PubMed1995

Mononuclear leukocytes invade rabbit arterial intima during thickening formation via CD18-and VLA-4-dependent mechanisms and stimulate smooth muscle migration.

The role of mononuclear leukocytes for the migration of smooth muscle cells (SMCs) during intimal thickening was investigated in the rabbit model of electrically stimulated carotid artery. The approach was to inhibit leukocyte entry into the arterial intima with antibodies against the adhesion molecules very late activation antigen-4 (VLA-4) and CD11/CD18. In electrically stimulated control rabbits treated either with saline or a nonspecific antibody, all types of granulocytes, monocytes, and lymphocytes migrated across an intact endothelium into the acellular subendothelial space, followed by the movement of SMCs from the media into the intima within 36 hours of applying electrical current. Treatment of the rabbits with monoclonal antibody (mAb) HP1/2 directed toward the alpha 4 subunit (CD49d) of VLA-4 inhibited mononuclear leukocyte invasion (consisting of monocytes and lymphocytes) by approximately 70% compared with the IgG-treated control rabbits and completely abolished the minimal influx of basophils and eosinophils after 36 hours. Neutrophil infiltration, however, remained unaffected by anti-VLA-alpha 4 treatment. Under these conditions, SMC migration across the internal elastic lamina was reduced by 50%. The use of mAb HP1/2 together with mAb 60.3 (directed to the beta 2 chain of CD11/CD18) completely abolished the influx of monocytes, lymphocytes, and all types of granulocytes into the arterial intima. This complete blockade of leukocyte infiltration resulted in a 70% reduction of intimal SMC accumulation. Together with our previous findings excluding neutrophils as stimulators of SMC migration, the present results indicate that mononuclear leukocyte promote lesion development by stimulating SMC migration.

Analysis of Variance↗
PubMed1997

The integrin very late antigen-4 is expressed in human smooth muscle cell. Involvement of alpha 4 and vascular cell adhesion molecule-1 during smooth muscle cell differentiation.

Vascular cell adhesion molecule-1 (VCAM-1) and its counterreceptor, the integrin very late antigen-4 (VLA-4), have recently been identified in smooth muscle cells during intimal thickening in humans and in newly forming vessels during ontogeny in mice, respectively. We examined the coexpression of VCAM-1 and the alpha 4 integrin subunit in human smooth muscle cells. The expression of VCAM-1 and alpha 4 subunit were studied during development of the aorta. In the 10-week-old human fetal aorta, VCAM-1 and alpha 4 were strongly expressed in smooth muscle cells. Their expression was dramatically reduced within the 24th week of gestation and disappeared in the adult aortic media. However, smooth muscle cells from intimal atherosclerotic thickening of adult aorta reexpressed both VCAM-1 and alpha 4. In a culture model mimicking smooth muscle differentiation, VCAM-1 mRNA and protein and alpha 4 integrin protein were coexpressed with smooth muscle-specific variants of cytoskeletal and contractile proteins, smooth muscle myosin heavy chain, caldesmon heavy chain, and desmin. Treatment with antibodies against VCAM-1 or alpha 4 integrin subunit interfered with the mRNA induction of smooth muscle-specific markers of differentiation. These results in vitro, associated with the transitory expression of VCAM-1 and VLA-4 during vascular ontogeny and the atherosclerosis process, point to a possible role of VCAM-1 and VLA-4 in the induction of smooth muscle differentiation.

Adult↗
PubMed1999

Blocking very late antigen-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet.

Atherosclerotic lesion development is characterized by the recruitment of leukocytes, principally monocytes, to the vessel wall. Considerable interest has been focused on the adhesion molecule(s) involved in leukocyte/endothelial interactions. The goal of the present study was to determine the role of the very late antigen-4 (VLA-4) integrin/ligand interaction in fatty streak development using murine models. Because alpha4 null mice are not viable, a peptidomimetic was used to block VLA-4-mediated leukocyte binding. The ability of a synthetic peptidomimetic of connecting segment-1 (CS-1 peptide) to block the recruitment of leukocytes and the accumulation of lipid in the aortic sinus of either wild-type mice (strain C57BL/6J) or mice with a low-density lipoprotein null mutation (LDLR-/-) maintained on an atherogenic diet was assessed. The active (Ac) CS-1 peptide or scrambled (Sc) CS-1 peptide was delivered subcutaneously into mice using a mini osmotic pump. Mice were exposed to the peptide for 24 to 36 hours before the onset of the atherogenic diet. In C57BL/6J mice, leukocyte entry into the aortic sinus, as assessed by en face preparations, was inhibited by the active peptide (Ac=28+/-4, Sc=54+/-6 monocytes/valve; P=0.004). Additionally, frozen sections stained with Oil Red O were analyzed to assess lipid accumulation in the aortic sinus. C57BL/6J mice that received the (Ac) compound demonstrated significantly reduced lesion areas as compared with mice that received the (Sc) peptide (Ac=4887+/-4438 microm2, Sc=15 009 +/-5619 microm2; P<0.0001). In a separate study, LDLR-/- mice were implanted with pumps containing either the (Ac) or (Sc) peptide before initiation of the atherogenic diet. Because LDLR-/- mice fed a chow diet displayed small lesions at 14 weeks, the effects of the peptide seen in these animals represented a change in early lipid accumulation rather than initiation. By using whole-mount preparations, the (Ac) but not the (Sc) peptide significantly reduced the area of lipid accumulation in the aortic sinus, resulting in an approximate 66% decrease. Plasma analysis from all studies revealed concentrations of peptide to be present at levels previously determined by in vitro analysis to block adhesion. (Ac) CS-1 peptide, which blocks VLA-4 on the leukocyte surface, is effective in reducing leukocyte recruitment and lipid accumulation in the aortic sinus. The present study provides in vivo evidence that the VLA-4 integrin plays an important role in the initiation of the atherosclerotic lesion and lipid accumulation, and it suggests a potential therapeutic strategy for this disease.

Animals↗