Expression of activation antigen, CD69, on human local eosinophils

The activation antigen, CD69, has been shown to be expressed on activated lymphocytes. CD69 has also been shown to be associated with the signal transduction process. Recently, we demonstrated the expression of CD69 on lung eosinophils obtained from the bronchoalveolar lavage fluid of patients with eosinophilic pneumonia. In this study, we performed flowcytometric analysis of CD69 expression on eosinophils obtained from the bronchoalveolar lavage fluid, pleural effusion or peripheral blood of various patients. Whatever the disease, local eosinophils expressed significant levels of CD69, whereas most peripheral blood eosinophils did not express CD69. These findings suggest that CD69 is a marker for local eosinophils and that local eosinophils may differ functionally from peripheral blood eosinophils.     

Bronchoalveolar lavage cell findings in three types of eosinophilic pneumonia: acute, chronic and drug-induced eosinophilic pneumonia

There are clinically different types of eosinophilic pneumonia (EP) but no study to date has compared pulmonary inflammatory cells between different types of EP, such as acute eosinophilic pneumonia (AEP), chronic eosinophilic pneumonia (CEP) and drug-induced eosinophilic pneumonia (drug-EP). The present study compared bronchoalveolar lavage fluid (BALF) cell findings to elucidate whether the profiles of the pulmonary inflammatory cells were different among the three types of EP. Clinical records of 28 patients with EP, consisting of eight AEP patients, 10 CEP patients and 10 drug-EP patients, were examined retrospectively. The differential cell counts, the CD4+/CD8+ ratio of lymphocytes, the percentage of HLA-DR+ in CD4+ and CD8+ lymphocytes, and the mean number of nuclear segmentations in cosinophils in BALF were compared among the three types of EP. The numbers of total cells, lymphocytes, neutrophils and eosinophils in BALF from patients with AEP were increased compared with those from normal subjects, and patients with CEP and drug-EP. The CD4+/CD8+ ratio of the BALF lymphocytes in patients with AEP, which exceeded 1.0 in all patients, was significantly higher than that in normal subjects. The percentages of HLA-DR+ cells in CD8+ lymphocytes in BALF from patients with CEP were significantly higher than those from patients with AEP and drug-EP. There was no significant difference in the mean number of nuclear segmentations in eosinophils in BALF among the three types of EP. The BALF cell findings in patients with EP showed some characteristics in accordance with type of EP. It is suggested that pulmonary neutrophils and lymphocytes, rather than eosinophils, may be related to the pathogenesis of the different types of EP.     

The role of LDL in the origin and progression of atherosclerosis: pathobiological concepts on the origin and development of atherosclerotic lesions and the role of the endothelium

We investigated the effects of in vivo intraperitoneal treatment with the rat monoclonal antibody (mAb), YN1.7.4 (YN1) against intercellular adhesion molecule-1 (ICAM-1) on the ovalbumin (OA)-inhalation-induced infiltration of leukocytes into the airways of OA-sensitized mice. YN1 (100 to 400 microg) given over a period of 72 h dose-dependently reduced the influx of lymphocytes and eosinophils into the bronchial lumen by > 60% and > or = 70%, respectively, when compared with saline or purified rat IgG-treated controls. Alveolar macrophages (AM) in the bronchoalveolar lavage fluid (BALF) were also decreased by > 50%. Lung tissue inflammation as determined by histopathologic examination was reduced. The number of neutrophils in the blood of OA-sensitized mice 3 days after challenge was significantly increased by treatment with YN1. However, at 24 h and 72 h after OA-challenge, the numbers of eosinophils and mononuclear cells in the bone marrow were reduced by YN1 treatment. Additionally, at 72 h after OA-challenge, the numbers of bone-marrow neutrophils were depressed. BALF levels of interleukin-5 (IL-5) and of IgA were lower for YN1-treated mice than for controls. With increasing doses of YN1, the levels of anti-ICAM-1 mAb in the plasma were proportionally increased. To correlate these results with YN1 treatment, blood and BALF T cells and BALF eosinophils were examined with flow cytometry. Blood T cells from YN1-treated mice were unable to bind phycoerythrin (PE)-labeled anti-ICAM- mAb ex vivo. These results implied that ICAM-1 on these cells was bound (occupied) by YN1 administered in vivo. Dose-related decreases were observed in the percentage and mean channel fluorescence (MCF) values of ICAM-1+ BALF T cells and eosinophils. The percentages of CD11a+ or CD49d+ eosinophils were also suppressed. Our data suggest that ICAM-1 is an important molecule involved in the recruitment of leukocytes into the airways of sensitized mice after pulmonary challenge.     

Monocrotaline pyrrole induces apoptosis in pulmonary artery endothelial cells

Eosinophilic myocarditis followed by fibrosis of the cardiac muscle was observed in addition to peripheral blood eosinophilia in CBA/J mice infected with Toxocara canis. The infected mice were used as an experimental model of eosinophilic endomyocarditis associated with hypereosinophilic syndrome. Effects of in vivo treatment with MoAbs to adhesion molecules on eosinophilic myocarditis were examined using this experimental model. Expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells of capillaries in myocardium were increased 1 and 2 weeks after infection. Infiltration of very late antigen (VLA)-4+ and/or CD11a+ cells into the cardiac muscles was also observed 1 and 2 weeks after infection. Infiltration of eosinophils into the heart was significantly suppressed by anti-CD18 MoAb and anti-VLA-4 MoAb, and focal fibrosis of the cardiac muscle was also significantly suppressed by combined administration of anti-CD18 and anti-ICAM-1 MoAbs. These results indicate that adhesion molecules may play important roles in eosinophilic myocarditis, and that blockade of interaction between adhesion molecules and their ligands may help to control it.     

Organization of the human RH50A gene (RHAG) and evolution of base composition of the RH gene family

The alpha4 chain (CD49d), which constitutes one of the chains of alpha4beta1 (very late activating antigen-4 [VLA-4]) and alpha4beta7 integrins, mediates migration of T cells to extravascular spaces. The interaction between VLA-4 and vascular cell adhesion molecule-1 (VCAM-1) has been shown to be the critical pathway for the selective accumulation of eosinophils and basophils at sites of allergic inflammation. T lymphocytes are also specifically recruited into allergic sites, including the allergic asthmatic airway. Increased numbers of activated CD4+ cells expressing the DR antigen subset of the human leukocyte antigens (HLA-DR) appear in the allergic lung 48 h after allergen inhalation. The mechanisms by which these cells localize into the lung are still unknown. We report that stimulation of allergen-specific T cells with allergen in vitro resulted in enhanced expression of alpha4 chain (CD49d) as measured by receptor density on allergen-specific T-cell lines and T-cell clones. Kinetic studies showed that CD49d density was enhanced over a 24- to 48-h period in a time-dependent fashion, and was coordinately upregulated with HLA-DR expression. We also demonstrated that increased expression of CD49d on T-cell lines 24 h and 48 h after stimulation correlated with increased adhesion to the CS-1 fragment of fibronectin. In contrast, lymphocyte function-associated antigen-1b (LFA-1b) (CD11b), LFA-3 (CD58), and intercellular adhesion molecule-1 (ICAM-1) (CD54) expression did not change with allergen stimulation. We also showed that CD49d receptor density on T cells obtained by bronchoalveolar lavage (BAL) of allergic patients before and 48 h after allergen challenge was significantly higher than that on T cells taken from BAL of normal subjects and from controls with other inflammatory lung diseases. Taken together, these findings indicate that allergen stimulation activates allergen-specific T cells and coordinately induces increased CD49d receptor expression and binding to counterligands. We postulate that allergen-driven upregulation of CD49d, which together with the beta1 chain constitutes VLA-4 integrin, may be responsible for the selective accumulation of T cells in the allergic asthmatic lung.     

Evaluation of eosinophilic cationic protein levels in patients with eosinophilic pneumonia

We investigated the significance of eosinophilic cationic protein (ECP) as a biological indicator of disease activity in patients with eosinophilic pneumonia (EP). ECP levels were measured in serum and bronchoalveolar lavage fluid (BALF) samples from patients with EP or other diffuse interstitial lung diseases and from healthy subjects. Also we performed immunohistochemical staining of lung tissue sections from patients with EP using anti-EG 2 antibody, and computed the correlation between the number of EG 2-positive cells in lung tissues and ECP levels in serum and BALF from patients with EP. Levels of ECP in serum and BALF samples from patients with EP were significantly elevated compared to the levels in samples from other interstitial lung-disease patients and healthy subjects. Additionally, changes in serum ECP levels reflected the clinical courses for EP patients. Approximately 90 percent of the infiltrated eosinophils in tissue sections from patients with EP were EG 2-positive and activated. The number of EG 2-positive cells in lung tissues correlated significantly with levels of ECP in serum and BALF samples from patients with EP. These findings suggested that ECP levels in serum and BALF reflect the degree of eosinophil activation in lung tissues and the degree of disease activity in patients with EP. We concluded that ECP may serve as a useful biological indicator in EP.     

Sequence analysis of the coat protein and 3''-noncoding region for Korean and other strains of sweet potato feathery mottle virus

A murine model of asthma is described in which we examined the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of airway reactivity, pulmonary eosinophilia, and inflammation. We sensitized wild-type control [C57BL/6J, (+/+)] and ICAM-1 knockout [C57BL/6J-ICAM-1, (-/-)] mice to ovalbumin (OVA), and challenged them with OVA delivered by aerosol (OVA-OVA) to induce a phenotype consistent with an asthmatic response. Bronchial responsiveness to methacholine and counts of cell numbers and measurements of eosinophil content and cytokine levels in bronchoalveolar lavage fluid (BALF) were significantly attenuated in ICAM-1(-/-) mice as compared with (+/+) mice. We also showed that the absence of ICAM-1 had no significant affects on the production of serum IgE antibody, but did have an effect on ex vivo lymphocyte proliferation. Additionally, immunohistochemistry: (1) revealed increased staining for vascular cell adhesion molecule-1 (VCAM-1) after antigen challenge in the ICAM-1(-/-) mice but not in the ICAM-1(+/+) controls; and (2) confirmed the presence of alternatively spliced forms of ICAM-1 in the lungs of ICAM-1(-/-) mice. Thus, despite the availability of alternate adhesion pathways in ICAM-1(-/-) mice, the absence of ICAM-1 prevented eosinophils from entering the airways. In summary, we found that the ICAM-1 knockout mice exhibited a significantly inhibited response to aerosol antigen challenge for most of the parameters examined, and conclude that ICAM-1 is an important ligand mediating T-cell proliferation in response to antigen, eosinophil migration into the airways, and the development of airway hyperreactivity (AHR) in allergen-sensitized and -challenged mice.     

Cell adhesion molecules--update

Cell adhesion molecules are glycoproteins expressed on the cell surface and play an important role in inflammatory as well as neoplastic diseases. There are four main groups: the integrin family, the immunoglobulin superfamily, selectins, and cadherins. The integrin family has eight subfamilies, designated as beta 1 through beta 8. The most widely studied subfamilies are beta 1 (CD29, very late activation [VLA] members), beta 2 (leukocyte integrins such as CD11a/CD18, CD11b/CD18, CD11c/CD18, and alpha d beta 2), beta 3 (CD61, cytoadhesions), and beta 7 (alpha 4 beta 7 and alpha E beta 7). The immunoglobulin superfamily includes leukocyte function antigen-2 (LFA-2 or CD2), leukocyte function antigen-3 (LFA-3 or CD58), intercellular adhesion molecules (ICAMs), vascular adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PE-CAM-1), and mucosal addressin cell adhesion molecule-1 (MAdCAM-1). The selectin family includes E-selectin (CD62E), P-selectin (CD62P), and L-selectin (CD62L). Cadherins are major cell-cell adhesion molecules and include epithelial (E), placental (P), and neural (N) subclasses. The binding sites (ligands/receptors) are different for each of these cell adhesion molecules (e.g., ICAM binds to CD11/CD18; VCAM-1 binds to VLA-4). The specific cell adhesion molecules and their ligands that may be involved in pathologic conditions and potential therapeutic strategies by modulating the expression of these molecules will be discussed.     

High levels of elastolytic activity in bronchoalveolar lavage fluid from a patient with idiopathic interstitial pneumonia]

A 63-year-old female with acure exacerbution of idiopathic interstitial pneumonia (IIP) showed high levels of elastolytic activity in bronchoalveolar lavage fluid (BALF). She was admitted to our hospital with progressive dyspnea. Arterial blood gas analysis and pulmonary function tests were abnormal. Examination of the bronchoalveolar lavage fluid revealed an increased numbers of neutrophils. Despite the administration of corticosteroids, the patient died of respiratory failure. A high level of elastolytic activity was present in the BALF. Western immunoblot analysis, using an anti-alpha 1-protease inhibitor (PI) antibody, revealed a truncated alpha 1-PI in the BALF. These findings suggest that an imbalance between protease and PI in the lower respiratory tract contribute to lung tissue damage in patients with IIP.     

Eosinophil recruitment to the lung in a murine model of allergic inflammation. The role of T cells, chemokines, and adhesion receptors

Eosinophil accumulation is a distinctive feature of lung allergic inflammation. Here, we have used a mouse model of OVA (ovalbumin)-induced pulmonary eosinophilia to study the cellular and molecular mechanisms for this selective recruitment of eosinophils to the airways. In this model there was an early accumulation of infiltrating monocytes/macrophages in the lung during the OVA treatment, whereas the increase in infiltrating T-lymphocytes paralleled the accumulation of eosinophils. The kinetics of accumulation of these three leukocyte subtypes correlated with the levels of mRNA expression of the chemokines monocyte chemotactic peptide-1/JE, eotaxin, and RANTES (regulated upon activation in normal T cells expressed and secreted), suggesting their involvement in the recruitment of these leukocytes. Furthermore, blockade of eotaxin with specific antibodies in vivo reduced the accumulation of eosinophils in the lung in response to OVA by half. Mature CD4+ T-lymphocytes were absolutely required for OVA-induced eosinophil accumulation since lung eosinophilia was prevented in CD4+-deficient mice. However, these cells were neither the main producers of the major eosinophilic chemokines eotaxin, RANTES, or MIP-1alpha, nor did they regulate the expression of these chemokines. Rather, the presence of CD4+ T cells was necessary for enhancement of VCAM-1 (vascular cell adhesion molecule-1) expression in the lung during allergic inflammation induced by the OVA treatment. In support of this, mice genetically deficient for VCAM-1 and intercellular adhesion molecule-1 failed to develop pulmonary eosinophilia. Selective eosinophilic recruitment during lung allergic inflammation results from a sequential accumulation of certain leukocyte types, particularly T cells, and relies on the presence of both eosinophilic chemoattractants and adhesion receptors.     

Corticosteroid reversibility in COPD is related to features of asthma

Eosinophilic inflammation has been observed in the airways of patients with chronic obstructive pulmonary disease (COPD). A subset of patients clinically diagnosed as having COPD show a reversibility of airflow obstruction when treated with corticosteroids, and may consist of patients with features of asthma including reticular basement membrane thickening and eosinophilic inflammation. Twenty-five unselected patients clinically diagnosed as having COPD received a daily oral dose of 1.5 mg/kg body weight of prednisolone for 15 d to assess the relationships between the functional response to corticosteroids and the presence of features of asthma. Eosinophilic inflammation was characterized before the course of corticosteroid therapy by enumerating eosinophils in peripheral blood, bronchoalveolar lavage fluid (BALF), and bronchial biopsies, using EG2 monoclonal antibody, and by measurement of eosinophil cationic protein (ECP) in BALF. A response to treatment was defined by an increase in FEV1 of at least 12% from baseline values and an absolute value of 200 ml measured at the end of the treatment. Twelve of 25 patients responded to the treatment. By comparison with nonresponders, responders had a significantly larger number of eosinophils (p < 0.015), and higher levels of ECP (p = 0.013) in their BALF. The responders had a thicker reticular basement membrane than the nonresponders (p < 0.04). These results indicate that a response to prednisolone in patients diagnosed as having COPD might occur more readily in a subset of patients presenting with features of asthma.     

Kinetics and quantitation of eosinophil and neutrophil recruitment to allergic lung inflammation in a brown Norway rat model

We quantitated neutrophil and eosinophil migration into lung parenchyma using specific peroxidase enzyme assays, and into the bronchoalveolar compartment by bronchoalveolar lavage (BALF), in sensitized brown Norway (BN), Fischer, and Lewis rats and also assessed the lungs by histopathology. Fourteen days after sensitization with ovalbumin (OA in alum [given subcutaneously] and OA with Bordetella pertussis [given intraperitoneally]), rats were challenged with an OA aerosol for 1 h. In BN rats, there was marked perivascular and peribronchial edema, focal hemorrhages, and increase in lung wet weight and BALF protein content, accompanied by neutrophilic infiltration at 3-14 h postchallenge. Few eosinophils were seen at 14 h in lung tissue or in BALF. Neutrophils peaked at 24 h in parenchyma ([94 +/- 7] x 10[6]) and in BALF ([2.7 +/- 0.4] x 10[6]) and declined rapidly thereafter. Marked eosinophil infiltration into parenchyma was apparent by 24 h. Eosinophil accumulation peaked at 48 h in parenchyma ([127 +/- 18] x 10[6]) and at 72 h in BALF ([10 +/- 2.4] x 10[6]), comprising up to 85% of lavage cells at this time. Lung eosinophilia persisted for at least 6 d with only a slow decline or clearance, not approximating baseline until day 13 after challenge. Histopathology showed peribronchial and interstitial eosinophilic pneumonia, most severe on day 3. In contrast to the BN rats, essentially no pulmonary inflammation was observed in Lewis and Fischer rats. This model in the BN rat, and the specific peroxidase assays for quantitating tissue eosinophils and neutrophils, should be useful for investigating the regulation of allergen-induced eosinophil and neutrophil migration into and clearance from the lung.     

A case of Sairei-to-induced pneumonitis diagnosed by lymphocyte stimulation test of bronchoalveolar lavage fluid

A 51-year-old woman was admitted with fever, cough and dyspnea. She had been taking Sairei-to, a traditional Chinese medicine, for 2 months. On admission, chest X-ray revealed a ground-glass appearance in the lung fields bilaterally and serum LDH was elevated. A differential cell count of the bronchoalveolar lavage fluid (BALF) showed that lymphocytes were increased, with a decreased ratio of CD4/CD8 cells. A lymphocyte stimulation test (LST) for Sairei-to using the lymphocytes in BALF was a positive, although a test of peripheral blood was negative. Sairei-to-induced pneumonitis was diagnosed based on the clinical course, laboratory findings, BALF cell analysis and LST of BALF. Only 4 cases of pneumonitis due to Sairei-to have been reported. This case suggests that LST of BALF is useful for diagnosing drug-induced pneumonitis.     

Inhalation of platelet-activating factor induced guinea pig airway hyperresponsiveness: role of eosinophils activation

Exposure of guinea pigs to aerosols of 200 micrograms/ml platelet-activating factor 24 h later, airway hyperresponsiveness to histamine induced and number of eosinophils and hypodense eosinophils in bronchoalveolar lavage fluid (BALF) increased, comparing with the control group. The number of eosinophils in BALF was corelated with PC20 value in PAF-treated group (r = -0.62, P < 0.05). However, the percentage of hypodense eosinophil in BALF had closer relation to airway responsiveness (r = -0.84, P < 0.01). The content of peroxidase in hypodense eosinophils in BALF for guinea pigs treated by inhalation of PAF was lowered markedly than that in normodense eosinophil (P < 0.05). The result suggested that chemotaxis and activation of eosinophils by PAF might play an important role in airway hyperresponsiveness.     

Lungs of patients with idiopathic pulmonary alveolar proteinosis express a factor which neutralizes granulocyte-macrophage colony stimulating factor

Mice deficient in granulocyte-macrophage colony stimulating factor (GM-CSF) develop pulmonary alveolar proteinosis (PAP). We found that bronchoalveolar lavage fluid (BALF) from 11 patients with idiopathic pulmonary alveolar proteinosis (IPAP) suppressed the growth of peripheral blood monocytes and TF-1 cells, a cell line dependent on either GM-CSF or interleukin-3 (IL-3). The inhibitory effect of PAP-BALF occurred only when TF-1 cells were cultured with GM-CSF but not when cultured with IL-3, suggesting that PAP-BALF contains a factor that specifically interferes with GM-CSF function. 125I-GM-CSF binding to TF-1 cells was prevented in the presence of BALF from IPAP patients. Furthermore, cross-linking of 125I-GM-CSF to IPAP-BALF produced two major bands on SDS-PAGE; these bands were not observed in normal BALF. These data suggest that IPAP is caused by expression of binding factor(s) which inhibit GM-CSF function in the lung.     

Dynamic expression changes in vivo of adhesion and costimulatory molecules determine load and pattern of lymphoma liver metastasis

Although intradermal primary tumor growth and spontaneous liver metastasis of ESbL-lacZ lymphoma in syngeneic DBA/2 mice are progressive and malignant, they are characterized by a transient plateau period with a constant tumor diameter and a low number of metastasized cells in the liver. This period, which was shown to be immune dependent, was followed by a second expansion phase characterized by a preferential localization of tumor cells in the periportal areas of liver lobules (mosaic phenotype). To elucidate possible mechanisms leading to the plateau period as well as for the mosaic-like metastasis pattern, we investigated, using flow cytometry analysis, alterations in costimulatory and adhesion molecule expression in liver sinusoidal cells as well as in tumor cells isolated directly ex vivo throughout the kinetics of metastasis. In tumor and sinusoidal cells, we found up-regulation in the expression of MHC class II and B7 molecules during the plateau period. These molecules, which facilitate cell-mediated immune responses, were again down-regulated during the final exponential tumor growth and metastasis. In the final expansion phase, in which the mosaic phenotype of liver metastasis is seen, we detected a significant increase of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 expression in both tumor and sinusoidal cells, suggesting tumor cell-sinusoidal cell interactions. vascular cell adhesion molecule-1/very late activated antigen-4 did not show any modification during the whole metastatic process. In vivo application of monoclonal antibodies directed to leukocyte function-associated antigen-1 and intercellular adhesion molecule-1 appeared to block the spread of metastasis, while no effect was seen with monoclonal antibodies directed to vascular cell adhesion molecule-1 and very late activated antigen-4. This study reveals in situ expression changes of cell surface molecules in tumor and host cells during metastasis. The changes seen during the plateau phase and during the second expansion phase differ, suggesting associations with mechanisms of immune control and tumor immune evasion, respectively.     

Measurement of T cell subsets in bronchoalveolar lavage fluid for diagnosis of pulmonary sarcoidosis

Pulmonary sarcoidosis is characterized by the accumulation in the lower respiratory tract of large numbers of activated CD4 T cells and elevated ratio of CD4/CD8 in bronchoalveolar lavage fluid (BALF). To study the value of CD4/CD8 ratio in BALF in the diagnosis of pulmonary sarcoidosis, we measured T cell subsets in BALF of patients with pulmonary sarcoidosis. The CD4/CD8 ratio in the patients (7.5 +/- 4.3) was significantly higher than that of the controls (2.1 +/- 0.7). The sensitivity and specificity of CD4/CD8 ratio in BALF for the diagnosis of sarcoidosis were 86% and 100%, respectively. We found that the CD4/CD8 ratio in BALF plays an important role in the diagnosis of pulmonary sarcoidosis. The analysis of CD4 in BALF may be useful in assessing the activity of sarcoidosis. The measurement of the CD4/CD8 ratio may be used to determine prognosis of pulmonary sarcoidosis.     

alphadbeta2 integrin is expressed on human eosinophils and functions as an alternative ligand for vascular cell adhesion molecule 1 (VCAM-1)

The beta2 family of integrins, CD11a, CD11b, CD11c, and alphad, are expressed on most leukocytes. We show that the newest member of this family, alphad, is expressed on human eosinophils in peripheral blood, and surface expression can be upregulated within minutes by phorbol ester or calcium ionophore A23187. Culture of eosinophils with interleukin 5 (IL-5) leads to a two- to fourfold increase in alphad levels by 3-7 d without a change in alpha4 integrin expression. Eosinophils isolated from late phase bronchoalveolar lavage fluids express alphad at levels similar to that seen after 3 d of IL-5 culture. Regarding alphadbeta2 ligands, in both freshly isolated and IL-5-cultured eosinophils, as well as alphadbeta2-transfected Chinese hamster ovary cells, alphadbeta2 can function as a ligand for vascular cell adhesion molecule 1 (VCAM-1). This conclusion is based on the ability of monoclonal antibodies to alphad, beta2, or VCAM-1 to block cell attachment in static adhesion assays. In experiments with eosinophils, the relative contribution of alphadbeta2 integrin- mediated adhesion is enhanced after IL-5 culture. These experiments demonstrate that alphadbeta2 is an alternative ligand for VCAM-1, and this integrin may play a role in eosinophil adhesion to VCAM-1 in states of chronic inflammation.     

The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106

Tepoxalin, a dual enzyme inhibitor of cyclooxygenase and 5-lipoxygenase has been shown to inhibit T-cell activation. Its immunosuppressive property is distinct from cyclosporin because only tepoxalin, but not cyclosporin, suppresses NF-kappa B activation. Here we report that tepoxalin selectively inhibits intercellular adhesion molecule-1 (ICAM-1, CD54)/MAC-1 (CD11b/CD18) dependent adhesion of polymorphonuclear cells to IL-1 activated human umbilical vein endothelial cells. The mechanism of inhibition is related to the surface expression of several cell adhesion molecules. Flow cytometry analyses on cultured cells that were treated with tepoxalin or antisense oligonucleotides to the P65/p50 subunit of NF-kappa B, and then stimulated with PMA, revealed a reduced expression of CD11b/CD18 on monocytic HL60 cells, and endothelial adhesion molecule-1 (CD62E) and vascular adhesion molecule-1 (CD106) on human umbilical vein endothelial cells. Expression of other adhesion molecules such as lymphocyte function associated-antigen-1 (CD11a/CD18) and CD54 were unaffected. Tepoxalin also inhibited the secretion of a NF-kappa B regulated chemokine, IL-8, a known inducer of CD11b/CD18 expression. Thus the suppression of CD11b/CD18 expression by tepoxalin may involve IL-8. Our results suggest that by inhibiting NF-kappa B activation, surface expression of several adhesion molecules can be modulated and that tepoxalin may be useful in treating selected adhesion mediated events such as leukocyte migration or atherosclerotic plaque formation.     

Successful treatment of chronic eosinophilic pneumonia with suplatast tosilate

The patient was a 59-year-old woman who complained of coughing, sputum production, and dyspnea. Abnormal moving shadows were found by chest radiography. There was prolonged eosinophilia in blood. Eosinophilia was also found in bronchoalveolar lavage fluid, and examination of a specimen obtained by transbronchial lung biopsy revealed eosinophil infiltration in alveolar septal walls, which led to a diagnosis of chronic eosinophilic pneumonia. Because of an attack of bronchial asthma and a high level of IL-5 in serum on admission, the patient was given suplatast tosilate. Symptoms were relieved, eosinophil counts in blood and in bronchoalveolar lavage fluid decreased, and the radiographic abnormality disappeared. The patient was not treated with steroids, and there has been no reccurrence to date, one year after discharge.