Expression of ICAM-1, VCAM-1, E-selectin and TNF-alpha on the endothelium of femoral and iliac arteries in thromboangiitis obliterans

Immunohistochemical light and electron microscopical analysis of surgical biopsies obtained from femoral and iliac arteries of patients with thromboangiitis obliterans (TAO) were performed to investigate the presence of tumour necrosis factor-alpha (TNF-alpha) and expression of the endothelial cell adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Expression of ICAM-1, VCAM-1 and E-selectin was increased on endothelium and some inflammatory cells in the thickened intima in all TAO patients. Ultrastructural immunohistochemistry revealed contacts between mononuclear blood cells and ICAM-1-, and E-selectin-positive endothelial cells. These endothelial cells showed morphological signs of activation. The present data indicate that endothelial cells are activated in TAO and that vascular lesions are associated with TNF-alpha secretion by tissue-infiltrating inflammatory cells, ICAM-1-, VCAM-1- and E-selectin expression on endothelial cells and leukocyte adhesion via their ligands. The preferential expression of inducible adhesion molecules in microvessels and mononuclear inflammatory cells suggests that angiogenesis contributes to the persistence of the inflammatory process in TAO.     

The distribution of adhesion molecules in human atherosclerosis

Chronic inflammatory cells are a recognized component of atherosclerotic plaques at all stages of development. As adhesion molecules play a fundamental role in inflammatory processes, we have carried out an immunohistochemical investigation of the distribution of endothelial leucocyte adhesion molecule-1 (ELAM-1)*, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human atherosclerotic lesions. Autopsy specimens from abdominal aorta and coronary arteries were obtained from 21 cases within 24 h of death. ELAM-1 and ICAM-1 were consistently expressed by the entire intimal endothelium of normal coronary arteries and also by the intimal endothelium overlying aortic fatty streaks. Both coronary artery and aortic lesions showed strong staining for ICAM-1 on and around macrophages. VCAM-1 was not detected on intimal endothelial cells, but strong staining of adventitial lymphoid aggregates for this molecule was seen. This work suggests a role for ELAM-1 and ICAM-1 in mononuclear cell recruitment during atherogenesis.     

Cutaneous expression of Thy-1 in mycosis fungoides.

Dermal dendritic cells from eleven cases of mycosis fungoides (MF) (six patch and five plaque stage), two cases of pre-MF, and five specimens of normal human skin, were characterized immunohistochemically using a panel of antibodies including anti-human Thy-1, intercellular adhesion molecule-1 (ICAM-1; CD54), endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD1a, CD2, CD14, CD18, CD34, MAC387, KP-1, EBM-11, factor XIIIa, factor XIIIs, and S100. Thy-1 expression in normal skin was limited to the microvascular endothelium and perivascular dendritic cells. An extensive interstitial network of Thy-1+ dendritic cells was seen in the papillary dermis of all cases of MF, whereas no epidermal cells were Thy-1+. The mean +/- standard deviation of interstitial Thy-1+ cells per high power field in the dermis was: normal skin, 2.86 +/- 0.34; pre-MF, 15; patch stage MF, 13.4 +/- 7.08; plaque stage MF, 49.96 +/- 21.29. Thy-1+ dendritic cells morphologically resembled the factor XIIIa+ "dermal dendrocyte" (DD) and shared their VCAM-1+, ICAM-1+, CD1a, CD2-, CD14+, CD18+, EMB11+, factor XIIIa+, factor XI-IIs-, S100-, MAC387- and KP-1-immunophenotype in MF. Double labeling studies revealed up to 50% of Thy-1+DD were also factor XIIIa+ in MF. Immediately beneath these cells was a similar network of CD34+, Thy-1-, factor XIIIa- dendritic cells limited to the reticular dermis. Strong microvascular endothelial cell expression of Thy-1 and VCAM-1, and focal vascular ELAM-1 expression were also seen in MF. Distinct cellular compartmentalization (papillary dermis versus reticular dermis versus epidermis) of dendritic cells is demonstrated by the differential expression of Thy-1, factor XIIIa, and CD34 antigens. The extensive number and prominent dermal dendritic network in the papillary dermis juxtaposed between epidermal keratinocytes (KC) and dermal/epidermal T cells, suggests an important pathophysiologic role for this newly recognized and immunophenotypically distinctive cell population in MF.     

IL-6 acts on endothelial cells to preferentially increase their adherence for lymphocytes

Using a quantitative monolayer adhesion assay, the current report shows that treatment of human umbilical vein endothelial cells (HUVEC) with IL-6 increases their adhesiveness for blood lymphocytes, particularly CD4⁺ cells, but not for polymorphonuclear cells and monocytes. This effect, which was most pronounced when using low concentrations of the cytokine (0.1–1.0 U/ml) and a short incubation period (4 h), was also apparent with microvascular endothelial cells and a hybrid endothelial cell line. Skin lesions from patients with mycosis fungoides contain high levels of IL-6, and blood lymphocytes from patients with this disorder also exhibited an enhanced adhesion to IL-6-treated HUVEC. The cytokine enhanced intercellular adhesion molecule-1 (ICAM-1) expression and induced the expression of vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on endothelial cells. Antibody blocking studies demonstrated that the vascular adhesion molecules ICAM-1, VCAM-1 and E-selectin and the leucocyte integrin LFA-1 all contributed to lymphocyte binding to endothelium activated by IL-6. It is proposed that IL-6 may be involved in the recruitment of lymphocytes into non-lymphoid tissue.     

Soluble ICAM-1 and VCAM-1 as markers of endothelial activation

Activated endothelium releases the soluble adhesion molecules vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1). Measurement of fluid-phase adhesion molecules is therefore used to quantify endothelial activation, but it is unclear which is the better marker. The aims of the study were to compare the relationships between mRNA, surface and total expression and released VCAM-1 and ICAM-1 in endothelial cell cultures during activation, and to compare human umbilical vein endothelial cells (HUVEC) with the microvascular cell line HMEC-1. sVCAM-1 better represented mRNA and surface expression changes in HUVEC undergoing endotoxin stimulation than did sICAM-1. Very little VCAM-1 was released from endotoxin-stimulated HMEC-1, and sICAM-1 seemed a better activation marker for these cells. During incubation of HUVEC in media with glucose concentrations of 5.6, 10.6 or 20.6 m m , VCAM-1 was released to the media in a dose-dependent way without changes in surface expression. ICAM-1 was not influenced by the glucose concentration. There are situations when VCAM-1 concentrations in the media do not mirror the surface expression on HUVEC in culture, indicating that measurements of soluble adhesion molecules may not necessarily be representative of the conditions on the cell surface. Endothelium from different locations showed varying responses with respect to VCAM-1 and ICAM-1 liberation upon endotoxin stimulation. Thus, both sVCAM-1 and sICAM-1 should be quantified in clinical studies of endothelial activation until their characteristics are better clarified.     

Expression of leukocyte adhesion molecules by endothelial cells seeded on various polymer surfaces

Although endothelial cell seeding in small-diameter vascular prostheses significantly improves graft survival, the detachment of adherent endothelial cells after the restoration of circulation remains one of the major obstacles. Because in vivo experiments indicate that leukocyte infiltration is involved in endothelial cell loss, we hypothesize that seeded endothelial cells become activated and express leukocyte adhesion molecules and cytokines because of an interaction with the underlying polymer surface. The aim of this study was to investigate the expression of the leukocyte adhesion molecules ICAM-1, VCAM-1, PECAM-1, and E-selectin by cultured human umbilical vein endothelial cells (HUVECs) and human adipose microvascular endothelial cells (HAMVECs). The cells were seeded on tissue culture poly(styrene) and the vascular graft materials Dacron and Teflon. The results of this study indicate that the expression of leukocyte adhesion molecules by cultured endothelial cells is mainly affected by the endothelial cell origin, that is, umbilical vein or adipose tissue. Expressions of both ICAM-1 and E-selectin by HUVECs and HAMVECs are characterized by the presence of two cell populations with distinct levels of expression. With respect to endothelial cell seeding in vascular prostheses, the increased expression of E-selectin by microvascular endothelial cells deserves further attention.     

Expression of cell adhesion molecules and their beta1 and beta2 integrin ligands in human liver peliosis

The expression of the following cell adhesion molecules and their beta1 and beta2 integrin ligands was investigated in the liver tissue from 3 patients with non-bacillar peliosis using light and electron microscope immunohistochemistry: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, platelet endothelial cell adhesion molecule-1 (PECAM-1), leukocyte function-associated antigen-1 (LFA-1), macrophage antigen-1 (Mac-1), and very late antigen-4 (VLA-4). We found a parallel enhancement of the adhesion molecules expression in the dilated sinusoids and cavities in all 3 cases with peliosis. Mononuclear blood cells were detected in the sinusoids and sometimes perisinusoidally. These cells were mainly ICAM-1-, LFA-1-, and VLA-4-positive. At the ultrastructural level, ICAM-1-positive immune deposits were observed on the membrane of sinusoidal endothelial cells, Kupffer cells, and hepatocytes. The expression of cell adhesion molecules on liver sinusoids in peliosis is probably triggered by factors released from damaged endothelial cells and hepatocytes. The prevalence of the ICAM-1/LFA-1 and VCAM-1/VLA-4 patterns of mononuclear blood cell/sinusoidal cell interactions could support the macrophage-induced or lymphocyte-induced type of liver injury. PECAM-1 was also included in the non-specific immune response in peliosis. The presence of erythrostasis or thrombosis in liver sinusoids could participate in the induction of adhesion molecule expression in peliosis.     

免疫球蛋白超家族黏附分子在淋巴管和不同血管内皮细胞的表达

目的比较免疫球蛋白超家族黏附分子在淋巴管、大血管和微血管内皮细胞的表达特点,探讨免疫球蛋白超家族黏附分子在淋巴管内皮细胞表达的意义。方法从狗的胸导管、颈总动脉、颈内静脉、肺微血管分离内皮细胞,利用免疫荧光标记法检测PECAM-1、ICAM-1、ICAM-3、VCAM-1和CD44在各种内皮细胞的表达,在荧光显微镜和激光共聚焦扫描显微镜下观察,并用图像分析仪分析表达强度。结果动脉、静脉和肺微血管内皮细胞表达PECAM—1、ICAM—1、ICAM-3、VCAM—1和CD44。其中,ICAM-1和ICAM-3的表达较弱。VCAM—1在动脉和肺微血管内皮细胞的表达比静脉强。淋巴管内皮细胞表达PECAM—1、ICAM—1、ICAM-3和CD44,未观察到VCAM—1的表达。ICAM-3和CD44的表达比血管内皮细胞强。结论与动脉、静脉和微血管内皮细胞比较,淋巴管内皮细胞不表达VCAM—1,而ICAM-3和CD44表达较强,这有助于解释淋巴细胞和肿瘤细胞与淋巴管内皮的黏附以及淋巴管新生的机制。     

Vascular cell adhesion molecule-1 expression and signaling during disease: regulation by reactive oxygen species and antioxidants

The endothelium is immunoregulatory in that inhibiting the function of vascular adhesion molecules blocks leukocyte recruitment and thus tissue inflammation. The function of endothelial cells during leukocyte recruitment is regulated by reactive oxygen species (ROS) and antioxidants. In inflammatory sites and lymph nodes, the endothelium is stimulated to express adhesion molecules that mediate leukocyte binding. Upon leukocyte binding, these adhesion molecules activate endothelial cell signal transduction that then alters endothelial cell shape for the opening of passageways through which leukocytes can migrate. If the stimulation of this opening is blocked, inflammation is blocked. In this review, we focus on the endothelial cell adhesion molecule, vascular cell adhesion molecule-1 (VCAM-1). Expression of VCAM-1 is induced on endothelial cells during inflammatory diseases by several mediators, including ROS. Then, VCAM-1 on the endothelium functions as both a scaffold for leukocyte migration and a trigger of endothelial signaling through NADPH oxidase-generated ROS. These ROS induce signals for the opening of intercellular passageways through which leukocytes migrate. In several inflammatory diseases, inflammation is blocked by inhibition of leukocyte binding to VCAM-1 or by inhibition of VCAM-1 signal transduction. VCAM-1 signal transduction and VCAM-1-dependent inflammation are blocked by antioxidants. Thus, VCAM-1 signaling is a target for intervention by pharmacological agents and by antioxidants during inflammatory diseases. This review discusses ROS and antioxidant functions during activation of VCAM-1 expression and VCAM-1 signaling in inflammatory diseases.     

Expression and cell distribution of the intercellular adhesion molecule, vascular cell adhesion molecule, endothelial leukocyte adhesion molecule, and endothelial cell adhesion molecule (CD31) in reactive human lymph nodes and in Hodgkin''s disease.

The immunocytochemical expression of intercellular adhesion molecule (ICAM-1), vascular cell adhesion molecule (VCAM-1), endothelial leukocyte adhesion molecule (ELAM-1), endothelial cell adhesion molecule (EndoCAM CD31), and HLA-DR antigens was investigated in sections of 24 reactive lymph nodes and in 15 cases of Hodgkin's disease. ICAM-1 was detected in sinus macrophages, follicular dendritic reticulum cells (FDRCs), interdigitating reticulum cells (IDRCs), epithelioid macrophages, Hodgkin's cells (HCs), and vascular endothelium. ICAM-1 expression was often associated with that of HLA-DR antigens. VCAM-1 was detected in FDRCs, in fibroblast reticulum cells (FRCs), in macrophages, and in rare blood vessels. EndoCAM (CD31) was constitutively expressed in all types of endothelial cells, sinus macrophages, and in epithelioid granulomas. ELAM-1 was selectively expressed by activated endothelial cells of high endothelium venules (HEVs). When expression of the inducible adhesion molecules ICAM-1, VCAM-1 and ELAM-1 was comparatively evaluated in HEVs, it was found that ICAM-1 + HEVs were present in all reactive and HD nodes, whereas ELAM-1 and/or VCAM-1 were expressed only in those pathologic conditions characterized by high levels of interleukin-1/tumor necrosis factor (IL-1/TNF) production, such as granulomatosis and Hodgkin's disease. In Hodgkin's disease, the expression of ELAM-1/VCAM-1 was more pronounced in cases of nodular sclerosis and was associated with a significantly higher content of perivascular neutrophils.     

终末糖基化产物对培养的人脐静脉内皮细胞粘附分子表达的影响

目的：探讨终末糖基化产物在糖尿病动脉粥样硬化（AS）形成中的作用机理。 方法： 分离正常人脐静脉内皮细胞（HUVECs），将终末糖基化终产物（AGE）修饰的人血清白蛋白（AGE-HSA）、人血清白蛋白（HSA）与HUVECs在体外共同培养，并用荧光单克隆抗体染色，流式细胞仪定量检测细胞间粘附分子-1（ICAM-1）、血管细胞粘附分子-1（VCAM-1）的表达。 结果： 正常人HUVEC表达ICAM-1和VCAM-1。AGE-HSA能以时间和剂量依赖的方式上调ICAM-1、VCAM-1的表达（P<0.05），而HSA对HUVECs上述粘附分子的表达均无影响。 结论： AGE能上调HUVECs粘附分子的表达，从而促进AS时单核/巨噬细胞的浸润。     

Human papillomavirus-16-E7 oncoprotein enhances the expression of adhesion molecules in cervical endothelial cells but not in human umbilical vein endothelial cells.

OBJECTIVES: E7 is one of the oncoproteins encoded by human papillomavirus-16 (HPV-16), the major etiologic factor responsible for cervical cancer. Human papillomavirus-16-E7 expressed by human uterine cervix carcinoma cells is also released in the extracellular compartment where it induces immune suppression. We investigated whether E7 was also responsible for the enhanced endothelial adhesiveness required in cancer progression. STUDY DESIGN/METHODS: We treated cervical microvascular endothelial cells (CrMVEn) and human umbilical vein endothelial cells (HUVEC) with E7, tumor necrosis factor-alpha (TNF-alpha), and hydrogen peroxide (H2O2) and measured the expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) by fluorescent-activated cell sorter analysis. RESULTS: E7 strongly induced the expression of E-selectin, ICAM-1, and VCAM-1 in CrMVEn, but not in HUVEC. Tumor necrosis factor-alpha further increased the endothelial expression of adhesion molecules in CrMVEn. Hydrogen peroxide pre-treatment resulted in an enhanced ICAM-1 and a decreased E-selectin and VCAM-1 expression. We also show indirect effects when endothelial cells were stimulated with the supernatant of E7-pretreated macrophages. CONCLUSIONS: These results show that HPV-16-E7 oncoprotein strongly induces adhesion molecules expression in organ-specific endothelial cells.     

Direct cell/cell contact with stimulated T lymphocytes induces the expression of cell adhesion molecules and cytokines by human brain microvascular endothelial cells

Upon inflammation, stimulated, but not resting T lymphocytes cross the blood-brain barrier and migrate into the central nervous system. This study shows that direct contact between stimulated T lymphocytes and human brain microvascular endothelial cells (HB-MVEC) induces phenotypic and functional changes on the latter cells. Plasma membranes isolated from stimulated T lymphocytes (S-PM) up-regulated the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin on isolated HB-MVEC. In addition, HB-MVEC activated by S-PM secreted interleukin (IL)-6 and IL-8. The levels of ICAM-1, E-selectin, IL-6, and IL-8 expressed in S-PM-activated HB-MVEC were similar to those observed with 1000 U/ml tumor necrosis factor (TNF). In contrast, VCAM-1 expression was 15% of that induced by TNF. Inhibitors of TNF diminished (≤ 45 %), but did not abolish the expression of cell adhesion molecules and IL-6 induced by S-PM, IL-8 production being insignificantly affected (≤ 10 %). This suggests that membrane-associated TNF was partially involved in HB-MVEC activation. The present study demonstrates that stimulated T lymphocytes are able to activate HB-MVEC upon direct cell contact. This novel mechanism of inducing the expression of cell adhesion molecules may prompt the initial adhesion of stimulated T lymphocytes to brain endothelium.     

Biological function of CD40 on human endothelial cells: costimulation with CD40 ligand and interleukin-4 selectively induces expression of vascular cell adhesion molecule-1 and P-selectin resulting in preferential adhesion of lymphocytes

The expression of adhesion molecules on vascular endothelial cells determines the pattern of migration and extravasation of leucocytes in inflammation and immunity. Here we show that costimulation with CD40 ligand (CD40L) and interleukin (IL)-4 (or IL-13) gives rise to a unique pattern of adhesion molecule expression by human umbilical vein endothelial cells (HUVEC). CD40 ligation alone enhanced expression of vascular cell adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and E-selectin whereas IL-4 and IL-13 increased expression of VCAM-1 and P-selectin but not ICAM-1 or E-selectin. When IL-4 and CD40L were combined there was an additional increase of both VCAM-1 and P-selectin, but ICAM-1 and E-selectin were both inhibited. The combined effects of IL-4 and CD40L signalling were not the result of altered response kinetics, enhanced sensitivity of the endothelium, or increased expression of CD40 or the IL-4 receptor. The rise in VCAM-1 expression induced by combined IL-4 and CD40L stimulation was slower and more sustained than with tumour necrosis factor-alpha (TNF-alpha) and occurred only on a subset (75-80%) of the endothelial cell population compared to 100% with TNF-alpha. Costimulation with IL-4 and CD40L increased adhesion of T cells and B cells above levels obtained with either signal alone, but decreased adhesion of neutrophils. Furthermore, CD40 and IL-4 synergistically increased IL-6 but decreased IL-8 production by HUVEC. These results show that interactions between IL-4 and CD40 on endothelial cells give rise to specific patterns of adhesion molecule expression and cytokine production that may have important implications for lymphocyte and neutrophil migration and function at sites of inflammation.     

Direct interaction with primed CD4+ CD45R0+ memory T lymphocytes induces expression of endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 on the surface of vascular endothelial cells.

The process of recruitment of leukocytes at sites of inflammation involves direct cell-to-cell interactions between leukocytes and vascular endothelial cells (EC) mediated by various adhesion receptors on leukocytes and their inducible endothelial ligands. In this study we have examined the induction on EC of endothelial leukocyte adhesion molecule-1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) upon their interaction with subpopulations of human T cells. When co-cultured with EC both resting CD4+ T and CD8+ T cells caused a modest increase in the expression of endothelial ICAM-1. Moreover, resting CD4+ but not CD8+ T cells induced expression of ELAM-1 and VCAM-1 on a small fraction of unstimulated EC. Prior activation with phorbol 12-myristate 13-acetate (PMA) significantly increased the ability of T cells to up-regulate endothelial ICAM-1 and also induced the expression of both ELAM-1 and VCAM-1. PMA-primed CD4+ T cells induced both VCAM-1 and ELAM-1 on EC more efficiently than CD8+ T cells. Furthermore, the ability to induce the expression of ELAM-1 and VCAM-1 was confined to the CD4+ CD45R0+ memory/primed subpopulation of T cells. This induction of various endothelial adhesion ligands could also be mediated by antigen-primed CD4+ T cell lines. The CD4+ T cell-mediated induction of adhesion ligands required direct intercellular contact with EC because neither cultures of EC and PMA-primed CD4+ T cells separated by a microporous membrane insert nor the conditioned medium of PMA-primed T cells induced expression of ELAM-1 and VCAM-1 on EC. Cyclosporin A significantly inhibited the activation of T cells with PMA but had no effect on the ability of PMA-primed T cells to up-regulate endothelial CAM. Thus, CD4+CD45R0+ T cells via as yet unknown mechanism can significantly enhance the expression of each of the three endothelial adhesion ligands and, thereby, may facilitate the process of recruitment of additional leukocytes to exacerbate inflammation.     

Effect of ultraviolet light on the expression of adhesion molecules and T lymphocyte adhesion to human dermal microvascular endothelial cells

In order to determine the effect of ultraviolet radiation (UVR) on the cell adhesion molecules expressed in human dermal microvascular endothelial cells (HDMEC), the cells were exposed to varying UVR doses and the cell surface was examined for expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM- 1), and E-selectin. The effect of UVB irradiation on the binding of T lymphocytes to HDMEC was also examined. UVA irradiation did not affect the surface expression of ICAM-1, VCAM-1, or E-selectin on the HDMEC. However, following UVB exposure, ELISA demonstrated a significant increase in the baseline ICAM-1 cell surface expression on the HDMEC. However, no induction of either E-selectin or VCAM-1 was noted. UVB also significantly augmented ICAM-1 induction by IL-1alpha and TNF-alpha. VCAM-1 was induced by stimulating HDMEC with IL-1alpha following a UVB irradiation dose of 100 mJ/cm2. Flow cytometric analysis of the HDMEC stimulated with IL-1alpha for 24h demonstrated that 12% of the cells expressed VCAM-1 but either IL-1alpha or UVB irradiation alone failed to induce VCAM-1 expression. Enhancement of T cell-HDMEC binding by IL-1alpha or TNF-alpha treatment was not significantly affected after UVB irradiation. This study demonstrated that UVB irradiation can alter ICAM-1 and VCAM-1 expression on the HDMEC surface and that augmentation of ICAM-1 expression and the IL-1alpha-dependent induction of VCAM-1 following UVB exposure might be important steps in the pathogenesis of sunburn.     

Disturbed homeostasis of lung intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 during sepsis

Cecal ligation and puncture (CLP)-induced sepsis in mice was associated with perturbations in vascular adhesion molecules. In CLP mice, lung vascular binding of (125)I-monoclonal antibodies to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 revealed sharp increases in binding of anti-ICAM-1 and significantly reduced binding of anti-VCAM-1. In whole lung homogenates, intense ICAM-1 up-regulation was found (both in mRNA and in protein levels) during sepsis, whereas very little increase in VCAM-1 could be measured although some increased mRNA was found. During CLP soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1) appeared in the serum. When mouse dermal microvascular endothelial cells (MDMECs) were incubated with serum from CLP mice, constitutive endothelial VCAM-1 fell in association with the appearance of sVCAM-1 in the supernatant fluids. Under the same conditions, ICAM-1 cell content increased in MDMECs. When MDMECs were evaluated for leukocyte adhesion, exposure to CLP serum caused increased adhesion of neutrophils and decreased adhesion of macrophages and T cells. The progressive build-up in lung myeloperoxidase after CLP was ICAM-1-dependent and independent of VLA-4 and VCAM-1. These data suggest that sepsis disturbs endothelial homeostasis, greatly favoring neutrophil adhesion in the lung microvasculature, thereby putting the lung at increased risk of injury.