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Biomedical subjects

R Rothlein

Publications and source records attributed to R Rothlein.

At least 73 records · Page 4Linked to original sources
PubMed1991

Chemotactic factors regulate lectin adhesion molecule 1 (LECAM-1)-dependent neutrophil adhesion to cytokine-stimulated endothelial cells in vitro.

Monoclonal antibodies recognizing CD18, CD11a, CD11b, and neutrophil lectin adhesion molecule 1 (LECAM-1), i.e., the human homologue of the murine MEL-14 antigen, were used to assess the relative contribution of these glycoproteins to neutrophil-endothelial adhesion. Under static conditions, the adhesion of neutrophils to IL-1-stimulated human umbilical vein endothelial cell (HUVEC) monolayers was inhibited by antibodies to CD18, CD11a, and the neutrophil LECAM-1, and the effect of combining anti-LECAM-1 and anti-CD11a was almost additive. Under flow at a wall shear stress 1.85 dyn/cm2, a condition where CD18-dependent adhesion is minimal, anti-LECAM-1 inhibited adhesion by greater than 50%. Chemotactic stimulation of neutrophils induced a rapid loss of LECAM-1 from the neutrophil surface, and the level of neutrophil surface LECAM-1 was closely correlated with adhesion under flow. Neutrophils contacting the activated endothelial cells for 30 min lost much of their surface LECAM-1, a phenomenon induced by a soluble factor or factors released into the medium by the stimulated monolayers, and a high percentage migrated through the HUVEC monolayer. This migration was almost completely inhibited by anti-CD18, but was unaffected by antibodies to neutrophil LECAM-1. These results support the concept that LECAM-1 is a neutrophil adhesion molecule that participates in the adherence of unstimulated neutrophils to cytokine-stimulated endothelial cells under conditions of flow, and is then lost from the neutrophil surface coincident with the engagement of CD18-dependent mechanisms leading to transendothelial migration.

Adult↗
PubMed1991

Endothelial leukocyte adhesion molecule-1 mediates antigen-induced acute airway inflammation and late-phase airway obstruction in monkeys.

This study examines the role of endothelial leukocyte adhesion molecule-1 (ELAM-1) in the development of the acute airway inflammation (cell influx) and late-phase airway obstruction in a primate model of extrinsic asthma. In animals sensitive to antigen, a single inhalation exposure induced the rapid expression of ELAM-1 (6 h) exclusively on vascular endothelium that correlated with the influx of neutrophils into the lungs and the onset of late-phase airway obstruction. In contrast, basal levels of ICAM-1 was constitutively expressed on vascular endothelium and airway epithelium before antigen challenge. After the single antigen exposure, changes in ICAM-1 expression did not correlate with neutrophil influx or the change in airway caliber. This was confirmed by showing that pretreatment with a monoclonal antibody to ICAM-1 did not inhibit the acute influx of neutrophils associated with late-phase airway obstruction, whereas a monoclonal antibody to ELAM-1 blocked both the influx of neutrophils and the late-phase airway obstruction. This study demonstrates a functional role for ELAM-1 in the development of acute airway inflammation in vivo. We conclude that, in primates, the late-phase response is the result of an ELAM-1 dependent influx of neutrophils. Therefore, the regulation of ELAM-1 expression may provide a novel approach to controlling the acute inflammatory response, and thereby, affecting airway function associated with inflammatory disorders, including asthma.

Acute Disease↗
PubMed1991

Reduction of central nervous system ischemic injury by monoclonal antibody to intercellular adhesion molecule.

Activated leukocytes appear to be directly involved in potentiating ischemic central nervous system (CNS) injury. Adhesion of leukocytes to endothelium is essential for their migration and requires the binding of adhesion receptors of the leukocyte (CD 18) to an intercellular adhesion molecule (ICAM) on endothelium. Monoclonal antibodies to an ICAM can block leukocyte adhesion and transendothelial migration. To determine the efficacy of anti-ICAM antibody treatment in preserving neurological function after CNS ischemia, two animal models were used. A 1-mg/kg dose of anti-ICAM was given to rabbits 30 minutes before induction of ischemia either in the spinal cord using temporary aortic occlusion or in the brain using intra-arterial microspheres. In this study, treatment with anti-ICAM produced a significant reduction in neurological deficits in the reversible spinal cord ischemia model but not in the irreversible brain ischemia model. This protective effect supports the active role of leukocytes in CNS reperfusion ischemic injury and offers potential for future therapy.

Animals↗
PubMed1991

Expression of intercellular adhesion molecule-1 (ICAM-1) in benign naevi and malignant melanomas.

Intercellular adhesion molecule-1 (ICAM-1) is a membrane-bound glycoprotein that is a ligand for lymphocyte function-associated antigen-1 (LFA-1) and is important for a number of cell adhesions in immune reactions. The molecule is expressed by several cell types (e.g. macrophages, endothelial cells, keratinocytes, melanoma cells and cell lines) and there are some indications that expression of this molecule in melanocytic lesions is confined to malignant tumours and is more pronounced in metastatic and advanced tumours than in earlier lesions. In an attempt to elucidate this issue, we have studied biopsy samples from benign naevi (n = 7) and malignant melanomas (n = 33) regarding reactivity with monoclonal anti-ICAM-1 (CD54). The results indicate that the great majority of malignant melanomas are ICAM-1-positive. The most abundant staining is seen in metastatic melanomas. In primary melanomas, staining is more variable and generally weaker. However, no correlation was found between the degree of ICAM-1 labelling and the degree of tumour invasion. Furthermore, ICAM-1 expression was not confined to malignant lesions, but was also seen in benign naevi. These data contrast with earlier reports and indicate that ICAM-1 expression is unlikely to be of major prognostic or diagnostic value in melanocytic tumours.

Antigens, CD↗
PubMed1991

Increased expression of intercellular adhesion molecule 1 on bile ducts in primary biliary cirrhosis and primary sclerosing cholangitis.

It has been suggested that immunological mechanisms involving lymphocyte-mediated damage are important in the characteristic bile-duct damage that occurs in primary biliary cirrhosis and primary sclerosing cholangitis. Because adhesion is necessary for the interaction of lymphocytes with their target structures, we have studied the expression of intercellular adhesion molecule 1, a ligand for the leukocyte adhesion receptor lymphocyte function-associated antigen 1 in the liver of patients with primary biliary cirrhosis and primary sclerosing cholangitis. Strong expression of intercellular adhesion molecule 1 was seen on interlobular bile ducts and proliferating bile ductules in both conditions. In primary biliary cirrhosis, medium-sized ducts, which are spared by the disease, were negative. Minimal bile-duct staining was seen in conditions in which bile-duct damage is not a major feature, such as nonbiliary cirrhosis and acute liver diseases. In patients with cirrhosis from any cause, strong expression of intercellular adhesion molecule 1 was detected on the periseptal hepatocytes adjacent to new connective tissue. The intensity of immunohistochemical staining was recorded using a semiquantitative visual scoring system that was subsequently validated quantitatively by confocal laser scanning microscopy. The expression/induction of intercellular adhesion molecule 1 on bile ducts may be important in the pathogenesis of bile-duct damage in primary biliary cirrhosis and primary sclerosing cholangitis and is further evidence to support an immune pathogenesis in these two conditions. Furthermore, the induction of intercellular adhesion molecule 1 on hepatocytes may be an important factor in the liver-cell damage and fibrosis that occur during the development of cirrhosis.

Bile Ducts↗
PubMed1991

Adhesion molecules in the pathogenesis of asthma.

Using a primate antigen inhalation model the mechanisms involved in the induction of airway hyperresponsiveness were studied. Antigen inhalation induced a prolonged airway eosinophilia. Chronic airway eosinophilia, intratracheal instillation of eosinophil major basic protein, repeated antigen inhalation, and airway epithelial desquamation induced, or were associated with, an increase in airway responsiveness. Using monoclonal antibodies to intercellular adhesion molecule-1 (ICAM-1) and endothelial-leukocyte adhesion molecule-1 (ELAM-1), the contributions of these cell adhesion molecules to antigen-induced airway hyperresponsiveness were studied. ICAM-1 partially mediated eosinophil adhesion to endothelium in vitro, was upregulated on inflamed endothelium and epithelium in vitro and in vivo, and contributed to repeated antigen-induced airway eosinophilia and hyperresponsiveness. ELAM-1 was upregulated on inflamed endothelium (but not epithelium) in vitro and in vivo, but did not contribute to the repeated antigen-induced airway eosinophilia and hyperresponsiveness. These results indicate that antagonism of ICAM-1, but not ELAM-1, may provide a novel therapeutic approach to reducing the airway inflammation and hyperresponsiveness commonly found in asthmatics.

Administration, Inhalation↗
PubMed1990

Impaired transendothelial migration by neonatal neutrophils: abnormalities of Mac-1 (CD11b/CD18)-dependent adherence reactions.

In order to evaluate the functions of lymphocyte function antigen-1 (LFA-1) (CD11a/CD18) and Mac-1 (CD11b/CD18) on neonatal neutrophils, we examined neutrophil adhesion to and migration through human umbilical vein endothelial cell (HUVEC) monolayers in vitro. Transendothelial migration of adult neutrophils was greatly enhanced by preincubation of HUVEC with interleukin-1 (IL-1). This migration was significantly inhibited by monoclonal antibodies (MoAbs) against LFA-1 (CD11a) and Mac-1 (CD11b) subunits. Migration of neonatal neutrophils was markedly diminished compared to adult neutrophils, and MoAbs against LFA-1 further reduced migration. In contrast, anti-Mac-1 MoAb was not inhibitory. Adhesion of adult neutrophils was significantly enhanced by prestimulation of HUVEC with IL-1, and was significantly inhibited by MoAbs against LFA-1. Adhesion of neonatal neutrophils was near adult levels and comparably inhibited by anti-LFA-1 MoAb. In addition, adhesion of neonatal and adult neutrophils to purified ICAM-1 in artificial planar membranes was comparable and almost completely inhibited by anti-LFA-1 MoAb. Chemotactic stimulation induced Mac-1-dependent adhesion of adult neutrophils to endothelial cells, purified intercellular adherence molecule-1 (ICAM-1) and protein-coated glass. In marked contrast, adhesion of neonatal neutrophils to these substrates was not significantly increased by chemotactic stimulation. These findings indicate that diminished transendothelial migration by neonatal neutrophils is related to abnormal interactions of Mac-1 with ICAM-1 and possibly other endothelial ligands. These functional deficits may contribute to impaired inflammation and infectious susceptibility in human neonates.

Aging↗
PubMed1990

In vivo effects of monoclonal antibody to ICAM-1 (CD54) in nonhuman primates with renal allografts.

These studies test whether allograft rejection can be blocked by interference with leukocyte adhesion, using a murine IgG2a mAb (R6.5) reactive with monkey ICAM-1 (CD54). In 16 Cynomolgus renal allograft recipients, R6.5 was administered prophylactically as the sole immunosuppressive agent for 12 days (0.01 to 2 mg/kg/day). Survival in 14 recipients with technically successful grafts was significantly prolonged (24.2 +/- 2.4 vs 9.2 +/- 0.6 days for controls; p less than 0.001). Intercellular adhesion molecule-1 (CD54) (ICAM-1) was expressed on vascular endothelium in the kidney and other organs in the monkey in a pattern similar to that in humans. During cellular rejection in controls, ICAM-1 expression increased on endothelial cells, infiltrating mononuclear leukocytes and tubular cells. Biopsies during R6.5 administration showed decreased T cell infiltration (CD2, CD8, CD4) compared with controls and decreased arterial endothelial inflammation. No changes occurred in circulating T cells, aside from variable coating with mIgG. In six of eight other recipients R6.5 administration (0.5 to 2 mg/kg/day for 10 days) reversed preexisting rejection that resulted from taper of Cyclosporine to subtherapeutic levels. Responding grafts showed decreased edema and hemorrhage but no consistent change in the infiltrate. At 1 h after the first dose, mouse IgG deposited primarily on the graft vascular endothelium without any change in the inflammatory infiltrate. Mouse IgG also deposited on the endothelium of normal organs without eliciting an inflammatory response and was cleared from the endothelium within 4 days. Inasmuch as the principal site of binding was the vascular endothelium, we hypothesize that the antibody blocks adhesion to graft ICAM-1 molecules on the vessels. Anti-ICAM-1 also binds to recipient cells and may interfere with Ag presentation and/or T cell interactions. Whatever the mechanism(s), these studies indicate that an anti-ICAM-1 antibody inhibits T cell mediated injury in vivo, and that ICAM-1 is a critical molecule in the pathogenesis of allograft rejection.

Animals↗
PubMed1990

Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma.

Airway eosinophilia, epithelial desquamation, and hyperresponsiveness are characteristics of the airway inflammation underlying bronchial asthma. The contribution of intercellular adhesion molecule-1 (ICAM-1) to eosinophil migration and airway responsiveness was studied. ICAM-1 partially mediated eosinophil adhesion to to endothelium in vitro and was upregulated on inflamed bronchial endothelium in vivo. ICAM-1 expression was also upregulated on inflamed airway epithelium in vitro and in vivo. In a primate model of asthma, a monoclonal antibody to ICAM-1 attenuated airway eosinophilia and hyperresponsiveness. Thus, antagonism of ICAM-1 may provide a therapeutic approach to reducing airway inflammation, hyperresponsiveness, and asthma symptoms.

Animals↗
PubMed1990

Role of adherence vs. spreading in the induction of membrane-associated interleukin-1 on mouse peritoneal macrophages.

Adherence of peritoneal exudate cells (PEC) to plastic has been shown to activate several PEC functions, such as tumor cell lysis and membrane-associated interleukin-1 (mIL-1) expression. Several studies have demonstrated that leukocyte adherence is dependent on divalent cations. In this study, ethylenediaminetetraacetic acid (EDTA), a known chelator of divalent cations, was used to evaluate the role of cell attachment vs. spreading in adherence-induced mIL-1 activity on resident C57BL/6 mouse PEC. Significant inhibition of PEC spreading on plastic and mIL-1 expression was noted when PEC were cultured in the presence of 10 mM EDTA. However, PEC remained adherent in the presence of EDTA and were able to express mIL-1 activity in response to a soluble stimulus lipopolysaccharide (LPS) 1 microgram/ml. These results suggest that the divalent cation-dependent spreading of PEC on plastic initiates or enhances the expression of mIL-1 activity. Additionally, adhesion and LPS stimulate mIL-1 expression by independent mechanisms.

Animals↗
PubMed1990

Endothelial cell expression of the intercellular adhesion molecule-1 (ICAM-1) in the central nervous system of guinea pigs during acute and chronic relapsing experimental allergic encephalomyelitis.

This study investigated the expression of intercellular adhesion molecule-1 (ICAM-1; CD54) by cells of the central nervous system (CNS) during acute experimental allergic encephalomyelitis (EAE) and chronic relapsing EAE (CREAE). In the CNS of normal guinea pigs, only a few endothelial cells expressed detectable levels of ICAM-1, whereas during the active phases of the disease ICAM-1 was present on cells of the perivascular infiltrate and the endothelia of both lesion- and non-lesion-associated blood vessels. In addition, cultured cerebrovascular endothelia maintained in 'standard' culture medium did not express ICAM-1, but they could be induced to express this antigen on incubation in a lymphocyte-conditioned medium. These findings suggest that the induction of ICAM-1 on CNS endothelia may be important in antigen presentation or in promoting lymphocyte extravasation across the blood-brain barrier in inflammatory disorders of the CNS.

Animals↗
PubMed1990

Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism.

Cardiac myocytes were isolated from adult dogs and incubated with isolated canine neutrophils (PMN). Intercellular adhesion was low and unchanged by stimulation of the PMN with zymosan activated serum or platelet activating factor (PAF) at concentrations that significantly enhance PMN adhesion to protein-coated glass and canine endothelial cell monolayers. Intercellular adhesion was significantly increased only when both myocytes and PMN were stimulated (e.g., myocytes incubated with IL-1, tumor necrosis factor, or phorbol myristate acetate, and PMN were chemotactically stimulated). Inhibitors of protein synthesis diminished the IL-1 beta-induced effect by greater than 80%. The IL-1 beta, PAF-stimulated PMN-myocyte adhesion was associated with substantial H2O2 production. Under conditions with low PMN-myocyte adhesion (i.e., IL-1 beta alone, PAF alone, or no stimulus) H2O2 production was generally less than 5% of that occurring with high adhesion. An anti-CD18 monoclonal antibody (R15.7) inhibited stimulated PMN-myocyte adhesion by greater than 95% and reduced H2O2 production by greater than 90%. Control isotype-matched, binding, and nonbinding antibodies were without effect on adherence or H2O2 production. The results indicate that cytokine stimulation of adult myocytes induces expression of a ligand involved in CD18-dependent adherence of canine neutrophils.

Animals↗
PubMed1989

Intercellular adhesion molecule 1 on liver allografts during rejection.

The expression of intercellular adhesion molecule 1 (ICAM-1), a ligand for the leucocyte adhesion receptor lymphocyte-function-associated antigen 1 (LFA-1), was studied on liver tissue after transplantation. There was greater ICAM-1 expression on bile ducts, endothelium, and perivenular hepatocytes (structures affected by the rejection process) in patients with acute rejection than in donor livers, patients with stable transplants, or patients with non-rejection complications. The expression on bile ducts and hepatocytes was greater in patients in whom there was progression to chronic, irreversible rejection. In patients with resolving rejection ICAM-1 expression was greatly reduced after high-dose corticosteroid treatment. The expression in patients with non-rejection complications and in those with long-term stable grafts was similar to that seen in the donor controls. The induction of ICAM-1 on tissues may be an important step in the development of the inflammatory response of rejection and in determining which cells are the targets of immune damage. The reduction of ICAM-1 expression seen after successful treatment with high-dose corticosteroids suggests that this might be an important mode of action of these drugs.

Acute Disease↗
PubMed1989

The effect of anti-intercellular adhesion molecule-1 on phorbol-ester-induced rabbit lung inflammation.

The role of the CD18 complex of leukocyte glycoproteins in adhesion-dependent functions of human leukocytes in vitro has been well documented. A ligand, intercellular adhesion molecule-1 (ICAM-1), for at least one member of the CD18 complex has been identified. This molecule is inducible on many cell types including vascular endothelium and keratinocytes by inflammatory mediators such as IL-1, TNF, and IFN-gamma. ICAM-1 has been shown to mediate, in part, the in vitro adhesion of lymphocytes and neutrophils to endothelial cells expressing ICAM-1. In the present study we have shown that mAb's to the human CD18 complex and to human ICAM-1 cross react with rabbit cells and that both anti-CD18 and anti-CD11b but neither anti-CD11a nor anti-ICAM-1 mAb's inhibit neutrophil migration, an adhesion-dependent function, in vitro. Pretreatment of rabbits with anti-CD18 and anti-ICAM-1 but not anti-CD11a mAb inhibited by greater than 60% neutrophil migration into PMA-induced inflamed rabbit lungs. This effect of anti-ICAM-1 mAb on pulmonary neutrophil influx after PMA injection has important implications. Specifically, that ICAM-1 can function as a ligand for CD18 and can mediate, at least in part, the migration of neutrophils to inflammatory sites.

Animals↗