Natural killer cells accumulate in lung-draining lymph nodes and regulate airway eosinophilia in a murine model of asthma.

Increasing evidence suggests a key role for the innate immune system in asthma development. Although the role of Natural Killer (NK) cells in allergic asthma is poorly known, modifications of the blood NK cell populations have been found in asthmatic and/or allergic patients. Their repartition and activation status in the inflammatory (lungs) and the regulatory (draining lymph nodes) sites of the allergic reaction is unknown. The aim of our study was to monitor NK cell migration pattern and activation status and to investigate the consequences of NK cell depletion during allergic airway reaction in a mouse model. Ovalbumin sensitization and challenges of BALB/cByJ mice had no effect on the total number of lung NK cells but significantly decreased the number of most mature NK cells and increased the level of the activation marker CD86. In the lung-draining mediastinal lymph nodes, ovalbumin sensitization and challenges led to increased number of NK cells, and more precisely, immature NK cells and increased expression of CD86. Ovalbumin-sensitized mice also exhibited increased percentage of proliferating NK cells in lung-draining mediastinal lymph nodes. Anti-ASGM1 antibody treatment depleted most NK cells and decreased bronchoalveolar lavage eosinophilia but did not modify airway responsiveness. Altogether, our study shows that pulmonary allergic sensitization induces modification in the NK cell compartment at the inflammatory and regulatory sites and suggests that NK cells may participate in the regulation of the asthmatic response and, more particularly, to the allergic airway eosinophilia.

[Mechanisms of deregulated response to hypoxia in sporadic amyotrophic lateral sclerosis: a clinical study]. / Mécanismes de dérégulation de la réponse à l'hypoxie dans la sclérose latérale amyotrophique.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of upper and lower motorneurons, leading to death in 3 to 5 years. Respiratory insufficiency and hypoxemia are closely linked during the clinical course of ALS. Chronic respiratory insufficiency and hypoxemia generally occur late in the disease course but rapid episodes of intermittent hypoxemia followed by reoxygenation can occur early and insidiously. Two pathways are involved in the response to hypoxemia: (i) hypoxia inducible factor-1 (HIF-1) and VEGF/HIF-2 and an erythropoietin (EPO) mediated pathway, in response to prolonged hypoxemia; and (ii) nuclear factor kappa-B (NFkappa-B) during acute hypoxemia followed by reoxygenation episodes, inducing inflammatory mediators: interleukin-6 (IL-6), TNF-alpha, cyclo oxygenase-2 (COX-2) and prostaglandin E-2 (PGE-2). Our aim was to specify the role of the different functional pathways of response to hypoxemia in sporadic ALS patients, compared with neurological controls and according to the level of hypoxemia. We report the results of several studies of hypoxemic and/or inflammatory mediators in the cerebrospinal fluid (CSF) from ALS patients, according to their respiratory status, showing a selective defect of HIF-1 mediated angiogenic factors (VEGF and angiogenin [ANG]) during chronic hypoxia in sporadic ALS patients, compared to hypoxemic neurological controls; contrasting with an early activation of the NFkappa-B pathway since the isolated desaturation stage (IL-6, TNF-alpha, PGE-2, angiopoietin-2) in the same cohort of sporadic ALS patients. All these results are consistent with a selective impairment of the HIF-1 pathway during chronic hypoxemia in ALS patients. Inflammatory mediators were strongly elevated, since the early stage of the disease until chronic hypoxemia, suggesting a compensatory mechanism.

Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy.

Endocan, previously called endothelial cell specific molecule-1, is a soluble proteoglycan of 50 kDa, constituted of a mature polypeptide of 165 amino acids and a single dermatan sulphate chain covalently linked to the serine residue at position 137. This dermatan sulphate proteoglycan, which is expressed by the vascular endothelium, has been found freely circulating in the bloodstream of healthy subjects. Experimental evidence is accumulating that implicates endocan as a key player in the regulation of major processes such as cell adhesion, in inflammatory disorders and tumor progression. Inflammatory cytokines such as TNF-alpha, and pro-angiogenic growth factors such as VEGF, FGF-2 and HGF/SF, strongly increased the expression, synthesis or the secretion of endocan by human endothelial cells. Endocan is clearly overexpressed in human tumors, with elevated serum levels being observed in late-stage lung cancer patients, as measured by enzyme-linked immunoassay, and with its overexpression in experimental tumors being evident by immunohistochemistry. Recently, the mRNA levels of endocan have also been recognized as being one of the most significant molecular signatures of a bad prognosis in several types of cancer including lung cancer. Overexpression of this dermatan sulphate proteoglycan has also been shown to be directly involved in tumor progression as observed in mouse models of human tumor xenografts. Collectively, these results suggest that endocan could be a biomarker for both inflammatory disorders and tumor progression as well as a validated therapeutic target in cancer. On the basis of the recent successes of immunotherapeutic approaches in cancer, the preclinical data on endocan suggests that an antibody raised against the protein core of endocan could be a promising cancer therapy.

High erythropoietin and low vascular endothelial growth factor levels in cerebrospinal fluid from hypoxemic ALS patients suggest an abnormal response to hypoxia.

Animal studies have highlighted the potentially neuroprotective role of vascular endothelial growth factor (VEGF). Low levels of this growth factor have been found in the cerebrospinal fluid (CSF) of patients with amyotrophic lateral sclerosis (ALS). VEGF (and other proteins, such as erythropoietin (EPO)) are produced in response to hypoxia via a common pathway involving a specific transcription factor (hypoxia-inducible factor, HIF) and a hypoxia responsive element (HRE) in the respective genes' promoter regions. In this study, we report finding the expected, high levels of VEGF and EPO in CSF from hypoxemic neurological controls, whereas EPO (but not VEGF) levels are high in the CSF from hypoxemic ALS patients. Hence, the VEGF levels in CSF from patients with ALS were significantly lower than those seen in hypoxemic controls. There was a trend towards higher CSF levels of EPO in hypoxemic ALS patients than in hypoxemic controls. Our results suggest that VEGF may not be produced in sufficient amounts in chronically hypoxic ALS patients and that this dysfunction may participate in the pathogenesis of the disease. The high EPO levels in hypoxemic ALS patients nevertheless suggest an intact common oxygen-sensor pathway.

Cell-surface estrogen receptors mediate calcium-dependent nitric oxide release in human endothelia.

BACKGROUND: Although estrogen replacement therapy has been associated with reduction of cardiovascular events in postmenopausal women, the mechanism for this benefit remains unclear. Because nitric oxide (NO) is considered an important endothelium-derived relaxing factor and may function to protect blood vessels against atherosclerotic development, we investigated the acute effects of physiological levels of estrogen on NO release from human internal thoracic artery endothelia and human arterial endothelia in culture. METHODS AND RESULTS: We tested the hypothesis that estrogen acutely stimulates constitutive NO synthase activity in human endothelial cells by acting on a cell-surface receptor. NO release was measured in real time with an amperometric probe. 17beta-Estradiol exposure to internal thoracic artery endothelia and human arterial endothelia in culture stimulated NO release within seconds in a concentration-dependent manner. 17beta-Estradiol conjugated to bovine serum albumin also stimulated NO release, suggesting action through a cell-surface receptor. Tamoxifen, an estrogen receptor inhibitor, antagonized this action. We further showed with the use of dual emission microfluorometry that 17beta-estradiol-stimulated release of endothelial NO was dependent on the initial stimulation of intracellular calcium transients. CONCLUSIONS: Physiological doses of estrogen immediately stimulate NO release from human endothelial cells through activation of a cell-surface estrogen receptor that is coupled to increases in intracellular calcium.

Anti-endothelial cell antibodies in sera from patients with inflammatory bowel disease.

IgG anti-endothelial cell antibodies (AECA) have been described in sera from patients with vasculitis and other immune disorders such as systemic lupus erythematosus. Presence of AECA may be relevant to the hypothesis that Crohn's disease (CD) is a form of intestinal vasculitis. The aim of this study was to search for IgG AECA among 141 patients with CD, 94 patients with ulcerative colitis (UC) and 71 healthy blood donors and to assess the relationship between AECA and demographic or disease data. The cut-off point was defined from the mean OD values + 2 SD obtained from healthy blood donors. Seventeen percent of sera from patients with CD were positive for IgG AECA, whereas 24.5% of sera from patients with UC were positive. Among disease data, only a significant relationship between presence of IgG AECA and CD activity was noticed. These results might reinforce the hypothesis that intestinal vascular injury may be an important event in CD. However, detection of AECA in an almost similar percentage of patients with UC is more suggestive of an immune response to hidden endothelial self-antigen exposed after endothelial cell damage or a further marker of disturbed immunoregulation in inflammatory bowel disease.

[The correlation between salivary endothelial expression of E-selectin and clinical and biological parameters in systemic scleroderma]. / Corrélations entre expression endothéliale salivaire de la E-sélectine et paramètres cliniques et biologiques au cours de la sclérodermie systémique.

OBJECTIVES: A body of evidence suggests the pivotal role of endothelial cells in the pathophysiology of systemic sclerosis. E-selectin is an adhesion molecule specifically expressed by activated endothelial cells. In previous studies we noticed that E-selectin was frequently expressed in the salivary gland tissue of patients with systemic sclerosis. Moreover, E-selectin expression was detectable very early in the course of the disease. To better define the role of E-selectin in the pathogenesis of systemic sclerosis, we conducted a study aimed at determining whether E-selectin expression was correlated to clinical and biological features in patients with systemic sclerosis. METHODS: Thirty-one patients presenting with systemic sclerosis were included in the study. The following parameters were systematically assessed: duration and cutaneous extent of the disease, presence of secondary Sjögren's syndrome, antinuclear antibodies, and pulmonary and esophagus involvement. E-selectin expression was assessed by immunocytochemistry on minor labial salivary glands. RESULTS: E-selectin expression was detected in 21 out of 31 patients (67%). The disease duration was significantly shorter in patients with E-selectin expression (mean 9.1 +/- 8.5 years versus 4.2 +/- 3.3 years, P < 0.05). No significant difference was found for other features. CONCLUSIONS: This study shows that endothelial E-selectin expression is mainly detectable early in the course of systemic sclerosis, when active and non-cicatrical sclerosis may be evidenced. No correlation was found between E-selectin expression and immunological disorders (antinuclear antibodies, secondary Sjögren's syndrome).

[Methotrexate in the treatment of asthma. Open trial in 10 corticoid-dependent patients with severe asthma]. / Le méthotrexate dans le traitement de l'asthme. Essai ouvert chez 10 asthmatiques sévères corticodépendants.

Methotrexate was suggested as a treatment in 1976 by Mullarkey for severe steroid-dependent asthma, in order to reduce the use of systemic steroids responsible for numerous undesired side-effects. The aim of this open trial was to study the efficacy and tolerance of Methotrexate in the short, medium and long term and after its cessation, in ten patients aged 49.2 (+/- 3.0) who were suffering from severe steroid-dependent asthma (18.5 +/- 4.8 mg of prednisone daily for at least one year). Methotrexate was given in a dose of 15-30 mg for 14.3 months (+/- 1.8) with a post-treatment follow-up for eight patients lasting 7.9 months (+/- 1.7). The efficacy was assessed on the daily dosage of prednisone and was also evaluated using the FEV1 (VEMS) (the variations expressed were a percentage of the variation from the predicted value). In the short term (six weeks) there was no significant change in the FEV1 nor in the dose of prednisone. In the medium term (12 weeks) there was evidence of a reduction in the average daily dosage of prednisone of 39.5% with an increase in the FEV1 of 14.1%. In the long term MTX was not found as effective in reducing the dose of prednisone (15.2 mg) as on the FEV1 (an increase of 5.1% on the theoretical values). There was a favourable outcome for two patients who maintained the benefit after stopping the MTX. Seven out of ten patients presented with side effects of MTX, in three of whom the drug has to be stopped.(ABSTRACT TRUNCATED AT 250 WORDS)

[Churg-Strauss syndrome]. / Le syndrome de Churg et Strauss.

The Churg-Strauss syndrome is part of the necrotizing vasculitis group of diseases. Its clinical diagnosis rests on the occurrence of a severe asthma followed, more or less closely, by systemic manifestations that are predominantly neurological, cutaneous, gastrointestinal and cardiovascular. To these must be added pulmonary infiltrates, eosinophilia and increase in serum IgE's. Three histological criteria (necrotizing vasculitis of the small vessels, perivascular infiltration with numerous eosinophils and extravascular granulomas) enable this anatomico-clinical syndrome to be identified, but the granuloma component is frequently missing and the existence of borderline states, notably with periarteritis nodosa, is unquestionable. Corticosteroids and immunodepressants have transformed the prognosis of the Churg-Strauss syndrome, while its physiopathological mechanism remains mysterious.

Deregulation of the hypoxia inducible factor-1α pathway in monocytes from sporadic amyotrophic lateral sclerosis patients.

The clinical course of the degenerative motor neuron disorder amyotrophic lateral sclerosis (ALS) is closely related to hypoxia. The normal response to hypoxia involves two pathways in particular: the hypoxia inducible factor 1α (HIF-1α) pathway (which notably controls the synthesis of vascular endothelial growth factor (VEGF)) and the nuclear factor kappa B (NF-κb) pathway (responsible for the production of inflammatory mediators, including prostaglandin E2 (PGE2)). Defects in VEGF gene expression are known to cause motor neuron degeneration in animal models. Circulating monocytes are precursors of the microglia, which are involved in the pathogenesis of ALS. To establish whether the HIF-1 and/or NF-κB pathways are deregulated during hypoxia in early-stage, sporadic ALS, we analyzed the response to acute (1 h) and prolonged (24 h) hypoxia in monocytes from ALS and healthy controls. We measured protein expression and mRNA transcription for VEGF, HIF-1, HIF-2, prolyl hydroxylases 1 and 2 (PHD-1 and -2, part of the HIF proteasome-dependent degradation pathway) and their modulation by PGE2. Our results showed that (i) the HIF-1 (but not HIF-2) and VEGF production induced by acute and prolonged hypoxia was selectively and markedly altered in ALS patients and (ii) this defect was not compensated for by PGE2 addition. Moreover, altered HIF-1α activation was associated with low levels of proteolysis by PHD-2 in cells from sporadic ALS patients (relative to controls). For the first time, we have demonstrated clinical and functional abnormalities in the HIF-1 pathway during hypoxia in monocytes from sporadic ALS patients.

Adipose tissue and circulating endothelial cell specific molecule-1 in human obesity.

Adipocytes produce the endothelial-cell specific molecule-1 (ESM-1), which inhibits leukocyte adhesion and migration through the endothelium. This study investigates ESM-1 expression and regulation in human adipose tissue. Subcutaneous abdominal adipose tissue was obtained from seventy postmenopausal women. Fourteen women subsequently underwent non-pharmacological weight reduction. In vitro experiments were performed on adipocytes isolated from human mammary adipose tissue. We determined gene expression by TaqMan RT-PCR and measured ESM-1 levels in serum and cell culture medium by ELISA. Mature adipocytes produced ESM-1. ESM-1 gene expression was higher in adipocytes than in preadipocytes. Cortisol inhibited ESM-1 gene expression in preadipocytes. Insulin and cortisol inhibited adipocyte ESM-1 production in adipocytes. This inhibitory effect of insulin was attenuated by insulin resistance, as ESM-1 gene expression in subcutaneous adipose tissue was increased in obese, hyperinsulinemic women. In contrast, ESM-1 serum levels were reduced in obese women and inversely correlated to C-reactive protein levels. Five percent weight loss did not markedly change gene expression. Circulating ESM-1 levels increased significantly, albeit modestly. ESM-1 is actively produced by adipocytes. However, since ESM-1 adipocyte gene expression and circulating plasma levels are not correlated, other sources of ESM-1 may be more important. Circulating ESM-1 levels are reduced in the overweight and obese, consistent with the notion that ESM-1 may play some role in obesity-associated vascular disease.

Elevated IL-6 and TNF-alpha levels in patients with ALS: inflammation or hypoxia?

Abnormal levels of interleukin (IL)-6 were described in patients with ALS, related to an inflammatory process. The authors compared IL-6 and tumor necrosis factor alpha (TNF-alpha) levels in CSF and sera from 10 hypoxemics and 10 normoxemics patients with ALS to those of 10 hypoxemics and 10 normoxemics neurologic controls. The same pattern exists in patients with ALS and controls: the highest levels are found in hypoxic conditions and undetectable levels are found in normoxemic conditions. Elevated IL-6 levels in ALS could correspond to a normal response to hypoxemia.

Role of endothelial cells in the pathogenesis of bronchial asthma.

Endothelial cells appear to play a dual role in the pathogenesis of bronchial asthma. These cells participate in recruitment of leukocytes to the site of the allergic response by releasing neutrophil chemotactic factors and modulating leukocyte-adhesion molecules. Enhanced expression of adhesion molecules has been detected in endothelial cell cultures subjected to various types of stimuli, including such cytokines as tumor necrosis factor alpha and interleukin-1 beta. In addition, there is evidence to suggest that antibodies directed against an endothelial cell component may also contribute to the inflammatory processes associated with severe asthma.

Potential implication of endothelial cells in bronchial asthma.

Inflammatory cells like eosinophils, neutrophils or mononuclear phagocytes have long been recognized as essential components in the pathophysiology of asthma. After recruitment in situ and subsequent activation, they are considered as responsible for epithelial and submucosal bronchial alterations. However, to access to the inflammatory site, these cells have to cross the endothelial wall, suggesting so a potential implication of endothelial cells (EC) in bronchial asthma. To test this hypothesis, we studied in a first step the modulation of vascular adhesions like intercellular adhesion molecule-1 (ICAM-1) on EC: supernatants of alveolar macrophages (AM) recovered by bronchoalveolar lavage in patients exhibiting a late asthmatic reaction, induced an enhanced expression of ICAM-1 on EC preparations; increase of ICAM-1 was clearly correlated to amounts of tumor necrosis factor-alpha (TNF alpha) present in AM supernatants, as shown by inhibition experiments with anti-TNF alpha antiserum. The second way to explore the possible role of EC in asthma was the detection of autoantibodies to EC in various allergic disorders: antibodies against a 120-kD EC antigen in patients with allergic granulomatosis and angiitis, antibodies towards a 55-kD component, common to human EC and platelets in patients with severe asthma, namely characterized by their corticosteroid dependence or by aspirin-induced intolerance. So our data suggest that bronchial asthma might result from either EC activation, through the induction of surface adhesion molecules or from an autoimmune process involving EC antigens.

Superoxide anion generation by alveolar inflammatory cells in simple pneumoconiosis and in progressive massive fibrosis of nonsmoking coal workers.

We have examined superoxide anion (O2-) release by alveolar inflammatory cells recovered by bronchoalveolar lavage from the lower respiratory tract of 10 healthy nonsmokers and 25 nonsmoking pneumoconiotic patients, 11 with radiographic changes of simple pneumoconiosis (SP) and 14 with changes of progressive massive fibrosis (PMF). Significant increased number of cells was recovered from the lower respiratory tract from both patients with SP or with PMF. Alveolitis was made up predominantly of alveolar macrophages (AM) and an increased percentage of neutrophils in patients with PMF (3.3 +/- 0.7%). O2- release was evaluated using a superoxide dismutase (SOD)-inhibitable lucigenin-dependent chemiluminescence method. Spontaneous O2- generation by alveolar inflammatory cells from pneumoconiotic patients with SP was three to four times greater than that from 10 age-matched, healthy control subjects. O2- release by alveolar inflammatory cells from patients with PMF was dramatically increased when compared with that in patients with SP and with that in control subjects and was observed before and after stimulation by phorbol myristate acetate (PMA) (p less than 0.001). The increased O2- release was not due to a lack of enzyme antioxidant system within AM since intracellular superoxide dismutase was not lower in AM from patients than in AM from control subjects (p less than 0.05). Alteration of DLCO correlated with PMA-induced superoxide release by alveolar inflammatory cells in patients with PMF (p less than 0.05). Our data demonstrate that alveolar inflammatory cells from pneumoconiotic patients with PMF are in the activated state and release more oxygen-reactive species that do those from patients with SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Alveolar macrophage and its participation in the inflammatory processes of allergic asthma.

Purified alveolar macrophages (AM) obtained by bronchoalveolar lavage of allergic asthmatic patients are stimulated by incubation with anti IgE or the exposure to the related allergen. Confirming the demonstration of a receptor for the Fc fragment of IgE on the surface of macrophages, IgE was characterised on AMs by a rosette-assay, showing an increased percentage of cells forming rosettes with red blood cells coated with anti-IgE or the specific allergen. The IgE-dependent secretion of arachidonic acid metabolites, PAF-acether and chemotactic factors for neutrophils and eosinophils demonstrated in vitro, together with the in vivo demonstration of the activation of AMs by a local provocation test, suggest that besides mast cell, AM do participate in the inflammatory processes of allergic asthma.

Comparative analysis of biological activities of Der p I-derived peptides on Fc epsilon receptor-bearing cells from Dermatophagoides pteronyssinus-sensitive patients.

The ability of four uncoupled synthetic peptides (p52-71, p117-133, p176-187, p188-199) derived from Der p I, a major allergen from the house dust mite Dermatophagoides pteronyssinus (Dpt) to stimulate Fc epsilon R+ cells from Dpt-sensitive patients was comparatively analysed. Each free peptide may specifically stimulate basophils (Fc epsilon RI+ cells) and platelets (Fc epsilon RII+ cells) from patients with significant levels of anti-Der p I IgE antibodies; p52-71 and p117-133 appear the best cell stimulation inducers. Both concentration-dependent biological activities of Der p I-peptide on Fc epsilon R+ cells are enhanced by coupling peptide to a carrier (as human serum albumin). Interestingly each Der p I-sensitive patient tested presents an individual pattern of response to peptide. Thus, from our results it appears that different Der p I sequences could be involved in the immune response to Der p I.

Plasmapheresis in a patient with severe asthma associated with auto-antibodies to platelets.

Although the pathogenesis of aspirin-sensitive asthma remains to be specified, it is known that in the presence of acetylsalicylic acid or non-steroidal anti-inflammatory drugs, platelets from aspirin-sensitive asthmatics have been described as generating cytocidal mediators that killed parasite targets such as Schistosoma mansoni larvae. Here we report, in a patient with corticosteroid-dependent asthma associated with aspirin sensitivity, the presence of circulating IgE antibodies against 55 kD and 68 kD platelet antigens. In addition, the serum from this patient was shown to contain a factor able to trigger the release of cytocidal mediators from his platelets as well as from normal individual platelets. This platelet stimulatory activity was presumably supported by IgE antibodies or immune complexes. After informed consent the patient was submitted to plasma exchanges. Plasma removal induced clinical improvement, anti-platelet antibody decrease, and the reduction of the platelet stimulatory activity. All clinical symptoms disappeared within 2 weeks. The disease remained quiescent for 2 months, and daily requirements for prednisone (20-5 mg), and beta-agonist (10-16 to 0-1 inhalations) could be kept at a low level follow-up. The plasma exchanges were delayed by 3 mg kg-1 azathioprine with the maintenance of clinical improvement. A relapse occurred after the arrest of immunosuppressive therapy with the reappearance of both asthma attacks and anti-platelet antibodies, as well as the increase of the platelet stimulatory activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine induces IL-6 production by human endothelial cells.

Histamine is one of the major mediators implicated in the physiopathology of allergy. On vascular endothelium, histamine mainly induces early effects: an increase in vasopermeability leading to oedema, a release of lipid mediators and a transient expression of P-selectin. The aim of this study was to evaluate the effects of histamine on adhesion molecule expression and IL-6 production by human endothelial cells. Histamine did not modulate the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, but induced a transient expression of P-selectin as previously reported. In addition, histamine increased in a dose- (from 10(-5) to 10(-3) M) and time- (from 4 h to 24 h) dependent fashion the IL-6 synthesis by endothelial cells. Tumour necrosis factor-alpha (TNF-alpha)-induced IL-6 production was also potentiated in a dose-dependent manner by histamine, without modification of the time course of IL-6 secretion. Moreover, this increase of IL-6 production induced by histamine was inhibited in a dose-dependent manner by H1 and H2 histamine receptor antagonists (50% inhibition of IL-6 production at 5 x 10(-4) M and 4 x 10(-5) M, respectively). So, histamine induces, besides already well known effects, a late stimulation of endothelial cells, i.e. the production of IL-6.

Modulation of endothelial cell adhesion molecule expression in a situation of chronic inflammatory stimulation.

Different disorders affecting the respiratory tract are characterized by the development of a chronic inflammatory reaction with an accumulation of immune and inflammatory cells into the bronchial walls and in interstitial and alveolar spaces. By its ability to secrete a large panel of cytokines, in particular TNF-alpha, the alveolar macrophage (AM) is undoubtedly playing a key role in the complex interactions between inflammatory and structural cells potentially implicated in the inflammatory reaction of the lung. One aspect of these interactions is the capacity of AM-derived TNF-alpha to induce the expression of cellular adhesion molecules (CAM) on the surface of endothelial cells. The main information concerning the induction of CAM have been obtained under experimental conditions mimicking an acute inflammatory reaction. In the present study, we propose an in vitro model allowing the reproduction of the conditions of a chronic inflammation, namely, the endothelial cell behavior submitted to a chronic TNF-alpha stimulation. The endothelial cell activation parameters were the modulation of expression of adhesion molecules: endothelial-leukocyte adhesion molecule-1 (E-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). Their functional abilities was evaluated using U937 cell adhesion analysis. Results demonstrated an overexpression of ICAM-1 after chronic stimulation performed with low but repeated doses of TNF-alpha. The level of ICAM-1 expression persisted throughout the culture to reach a high stable level despite the absence of detectable TNF-alpha activity in culture supernatants. If the stimulation was stopped after 6 days, the expression of ICAM-1 was still observed at least until Day 15. E-selectin and VCAM-1 expression remained absent or not significantly increased. The expression of ICAM-1 on endothelial cells was directly related to an enhanced adhesion capacity as demonstrated by the adhesion of U937 cells to endothelial cells by an ICAM-1/LFA-1 adhesion pathway. Taken together, these elements could bring new approaches in the investigation of mechanisms by which inflammatory cells are recruited and participate in chronic inflammatory processes.