RU 41740 (Biostim) stimulates the production of granulocyte macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro.

1. In this study, we observed the effects of RU 41740 (Biostim) on the production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-8 (IL-8) in human bronchial epithelial cells in vitro. 2. Cytokine production was assessed by enzyme-linked immunosorbent assay. 3. We report that epithelial cells spontaneously released both cytokines and that RU 41740 induced a significant increase in production of IL-8 and GM-CSF. 4. This is the first observation of a stimulatory effect of an immunostimulating compound used in humans on cytokine production by epithelial cells.

Uptake of 12-HETE by human bronchial epithelial cells (HBEC): effects on HBEC cytokine production.

12-HETE, the major lipoxygenase end-product of platelets and macrophages, may be released in contact of bronchial epithelium in inflammatory diseases of the lung. We have studied the outcome of 12-HETE in presence of human bronchial epithelial cells (HBEC). When HBEC were incubated with [3H]12-HETE for 30 minutes, 27.5% of total radioactivity was found in HBEC and 72.5% in supernatants. Unesterified 12-HETE accounted for 22.4% of total radioactivity, 4.5% being recovered in phospholipids, preferentially in phosphatidylcholine and phosphatidylethanolamine. No incorporation in neutral lipids was detected. 72.9% of the incubated radioactivity was recovered in un identified metabolites. As 12-HETE has been shown to modulate the expression and production of various proteins, the consequence of the 12-HETE uptake on the release of GM-CSF and IL8 by HBEC was assessed. HBEC from control subjects were cultured for 24 hours with 12-HETE (10(-9) to 10(-7)M) in the presence or absence of TNF alpha. Detectable amounts of both cytokines were released in the supernatant in basal conditions at 24hr, and TNF alpha increased significantly the release of GM-CSF. 12-HETE at 10(-7)M weakly but significantly decreased the TNF-induced release of GM-CSF from HBEC. Thus the uptake of 12-HETE could affect the epithelial cell function in some situations.

Antihistamines and production of granulocyte-macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro: evaluation of the effects of loratadine and cetirizine.

1. In this study, we compared the effects of two antihistamine drugs on the production of granulocyte-macrophage colony-stimulating factor and interleukin-8 by human bronchial epithelial cells in vitro. 2. Cytokine production was assessed by the use of an enzyme-linked immunosorbent assay. 3. Epithelial cells spontaneously released both cytokines and tumor necrosis factor alone induced a significant increase in this production but loratadine and cetirizine had no effect at the various concentrations studied. 4. The antihistamines have no effect and this suggests that histamine plays no role in cytokine production under these conditions.

Increased respiratory burst and phosphodiesterase activity in alveolar eosinophils in chronic eosinophilic pneumonia.

A 43 year old woman presented with chronic eosinophilic pneumonia characterised by a high alveolar eosinophilic count, which allowed biochemical study of these cells. Alveolar eosinophils spontaneously produced high amounts of oxygen free radicals and exhibited an increased level of cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) activity compared to blood eosinophils from control or allergic subjects. This activity was preferentially located in the plasma membrane, whilst the PDE activity of blood eosinophils from asthmatics or controls predominated in the cytosol. Because of the potential role of phosphodiesterase during eosinophil activation and recruitment, phosphodiesterase inhibitors may be useful in the treatment of eosinophilic pneumonia.

[Pulmonary cancer and recurrent arterial and venous thromboses]. / Cancer pulmonaire et thromboses artérielles et veineuses récidivantes.

Coagulation disorders frequently complicate cancer. We observed a patient with lung cancer who developed recurrent thromboembolism. Hypercoagulation was induced by tumor cells via different factors enhancing coagulation. Heparinotherapy, or in certain cases oral anticoagulants, are often ineffective.

Leukotriene B4 production by blood neutrophils in allergic rhinitis--effects of cetirizine.

BACKGROUND: Mucosal inflammatory processes in late phase of allergic diseases involve cytokine production, cell adhesion molecule overexpression and release of inflammatory mediators with chemotactic activity, such as leukotriene B4 (LTB4). We had previously observed increased production of LTB4 by neutrophils in patients with allergic rhinitis and discussed the role of granulocyte macrophage-colony stimulating factor (GM-CSF) priming. Some antihistaminic compounds were shown to diminish the production of leukotrienes by neutrophils. OBJECTIVES: In a first step, we evaluated in ex vivo and in vitro studies, the effects of cetirizine on LTB4 production by blood neutrophils from allergic and healthy subjects. In a second step, we studied the in vitro effect of cetirizine on LTB4 production by neutrophils from healthy subjects during GM-CSF priming of these cells. METHODS: Neutrophils from both populations were purified from venous blood and LTB4 production was measured using high performance liquid cromatography (HPLC) method. RESULTS: In ex vivo studies, cetirizine treatment induced a decreased LTB4 production by neutrophils in allergic rhinitis. This effect of decreased LTB4 production was reproduced in vitro with 10(-8)-10(-6)M cetirizine. Nevertheless, this anti-H1 compound had no effect on neutrophil priming with GM-CSF. CONCLUSION: As LTB4 is an important chemotactic factor, Cetirizine could act on inflammatory cell recruitment by inhibiting LTB4 production by neutrophils.

Granulocyte-macrophage colony stimulating factors (GM-CSF) and interleukin 8 (IL-8) production by human bronchial epithelial cells (HBEC) in asthmatics and controls. Lack of in vitro effect of salbutamol compared to sodium nedocromil.

The bronchial epithelium produces cytokines that could contribute to inflammatory events in airways. In this study we determined the basal and TNFalpha stimulated productions of GM-CSF and IL-8 by human bronchial epithelial cells (HBEC) collected from 12 control and six asthmatic patients. Spontaneous and TNFalpha-induced GM-CSF or IL-8 released levels increased significantly with time. Epithelial cells from asthmatic patients spontaneously released high levels of GM-CSF (24 h). TNFalpha potentiated GM-CSF and IL-8 release in control subjects and only the IL-8 production in asthmatics. Nedocromil sodium, an antiinflammatory drug, and salbutamol, a beta2-agonist, are commonly used in asthma. They were evaluated on the spontaneous and TNF-induced expression of GM-CSF and IL-8 in cultured bronchial epithelial cells. Nedocromil sodium, at the concentration of 10(-6) M, reduced the TNF-induced increase in GM-CSF but not the IL-8 release. Salbutamol, at the concentration of 10(-6) or 10(-5) M, did not affect the constitutive or stimulated production of both cytokines.

Antibiotics and production of granulocyte-macrophage colony-stimulating factor by human bronchial epithelial cells in vitro. A comparison of cefodizime and ceftriaxone.

Cultured human bronchial epithelial cells (HBEC) produce both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 8 (IL-8). The influence of cefodizime (CAS 69739-16-8), a new broad spectrum cephalosporin with immunostimulatory effects, and ceftriaxone on the production of GM-CSF and IL-8 in HBEC primary cultures was investigated. HBEC were isolated from biopsy specimens obtained during fibreoptic bronchoscopy in 12 patients (most frequent diagnosis: chronic bronchitis). Confluent monolayers of HBEC cultured on collagen were incubated for 24 h in a medium without study drugs (spontaneous production) or containing cefodizime or ceftriaxone at the clinically relevant concentrations of 1, 10 and 100 mg/l, with or without tumor necrosis factor alpha (TNF alpha, 100 U/ml). GM-CSF and IL-8 were measured in supernatant by ELISA technique. TNF alpha alone led to a significant (p < 0.005) increase in both GM-CSF and IL-8 production. Cefodizime induced a significant (p < 0.05), dose-dependent increase in GM-CSF release. No additive effect of cefodizime with TNF alpha was observed. Cefodizime did not affect IL-8 production and ceftriaxone had no influence on cytokine production. This is the first report of a stimulatory effect of a beta-lactam antibiotic on cytokine production by epithelial cells. GM-CSF production by epithelial cells is an important immunological step for neutrophil and monocyte recruitment and cell priming during lung defence. Previous studies with cefodizime in immunodepressed subjects have shown activation of phagocytosis and phagocytosis-related functions in non-lung phagocytes. An indirect mechanism of action, similar to that indicated by our results, may have been responsible for these stimulatory effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Concentrations of cefodizime in bronchial secretions after single intravenous administration.

UNLABELLED: The concentrations of cefodizime (HR 221, CAS 69739-16-8) in bronchial secretions were measured after administration of a single intravenous bolus of 2 g in 19 patients requiring fibreoptic bronchoscopy for diagnostic purposes or as therapeutic follow-up. These concentrations, which were obtained in absence of inflammation of the mucosa, were compared to serum concentrations obtained simultaneously. The penetration into bronchial secretions was rapid, maximum levels of between 1 and 5 mg/kg being already observed 1 h after injection. Most concentrations remained about 1 mg/kg throughout the whole observation period of about 5.5 h. The percent penetration amounted to about 1.5% of the corresponding serum concentrations. CONCLUSION: Concentrations well above the MIC90s of the relevant respiratory pathogens--S. pneumoniae, M. catarrhalis, H. influenzae, K. pneumoniae--and Enterobacteriaceae were reached in bronchial secretions after intravenous injection of a single 2 g dose of cefodizime. Even higher levels may be expected in the usual condition of inflamed bronchial mucosa as found in respiratory infections.

Impaired G-proteins and cyclic nucleotide phosphodiesterase activity in T-lymphocytes from patients with sarcoidosis.

Among the various immune abnormalities which characterize active sarcoidosis, a low proliferative response of peripheral blood lymphocytes to mitogenic lectins has long been observed. Since membrane-associated G-proteins are very likely to be crucial elements in lectin signal transduction, we investigated the binding of 5'-guanylylimidodiphosphate (GppNHp), a non hydrolyzable GTP analogue, to blood total lymphocyte membranes and to blood T-lymphocyte membranes from patients with active sarcoidosis, and from healthy control subjects. GppNHp binding was markedly decreased in peripheral cells from patients with sarcoidosis as compared to controls, suggesting the occurrence of a defect at the level of G-protein(s). A further characterization of G-proteins in these cells by means of ADP-ribose-labelling in the presence of bacterial toxins brought forward a significant decrease in the labelling of a 40 kDa protein, the major pertussis toxin substrate, in membranes from sarcoid patients, while the labelling of the major 44 kDa cholera toxin substrate proved to be unchanged with respect to control membranes. It is hypothesized that, in sarcoid lymphocytes, a defect in the negative control of adenylate cyclase mediated by the inhibitory G-protein Gi, prevents the lowering of cAMP necessary to normal mitogenic response of blood lymphocytes to stimulation. cAMP degradation by the specialized enzyme phosphodiesterase constitutes another critical step in the control of cAMP levels. Both cAMP and cGMP phosphodiesterase activities were found decreased in blood total lymphocyte preparations from sarcoid patients. With purified T-cells, although the mean cAMP and cGMP phosphodiesterase activities from sarcoid patients were found more markedly decreased with respect to healthy donors, only the decrease in cGMP phosphodiesterase was found statistically significant. The role these defects in cyclic nucleotide degradation potentially play in the disturbance of blood lymphocytes response associated with sarcoidosis is discussed.

Cyclic nucleotide phosphodiesterases and methyltransferases in purified lymphocytes, monocytes and polymorphonuclear leucocytes from healthy donors and asthmatic patients.

Cyclic nucleotide phosphodiesterase and phospholipid N-methyl-transferase activities were simultaneously measured in purified polymorphonuclear cell-, mononuclear cell-, lymphocyte- and monocyte-homogenates from control subjects, from patients with atopic asthma and from patients with non-atopic asthma. Whereas cyclic AMP and cyclic GMP phosphodiesterase activities were found to be about 10-fold lower in polymorphonuclear than in mononuclear cells, phospholipid N-methyltransferase proved to be rather similar in each cell type from control donors. Cyclic AMP phosphodiesterase and phospholipid N-methyltransferase were significantly decreased in polymorphonuclear cells and monocytes from asthmatic patients compared with the control group while cyclic GMP phosphodiesterase was significantly impaired only in the monocyte subpopulation.

[Penetration of antibiotics in alveolar macrophages compared by in vitro and in vivo data in man]. / Pénétration des antibiotiques dans les macrophages alvéolaires comparaison des données in vitro et in vivo chez l'homme.

Optimal therapy of infections caused by intracellular organisms requires an active antibiotic prone to intracellular penetration. This phenomenon has been studied on alveolar macrophages as well in vitro as in vivo for most groups of antibiotics. The comparison of data shows that the values obtained by incubation are not predictive of what happens in situ. These results must be taken in account for the choice of an antibiotic in pulmonary infections as well as its spectrum, pharmacokinetic, and possible side effects.

[Chiasmal radionecrosis after irradiation of the sella turcica using a conventional dosage. Contribution of magnetic resonance imaging]. / Radionécrose chiasmatique après irradiation de la selle turcique à doses conventionnelles. Apport de l'imagerie par résonance magnétique.

A 47 year-old man developed rapid visual loss, visual field defects and memory disturbances after radiotherapy with conventional doses for a pituitary metastasis from a renal carcinoma. CT and MRI did not show recurrent tumour, pituitary apoplexy or empty sella. Eventually, T2-weighted MRI images showed abnormal high signals in the optic chiasm, the left mesial temporal lobe and the right inferior frontal lobe, supporting the diagnosis of delayed radionecrosis. The role of chemotherapy associated with radiotherapy is discussed.

[T-lymphocytes disorders in pulmonary sarcoidosis]. / Perturbations lymphocytaires T au cours de la sarcoïdose pulmonaire.

Sarcoidosis is a granulomatous disorder of unknown aetiology accompanied by variable immunological changes which concern both the monocyte and lymphocyte cell line. During the course of this disease anomalies of distribution (with accumulation in the disease tissue contrasting with a peripheral lymphopenia) and also of T cell functions (a predominance of CD4 T lymphocytes within the lesions and spontaneous expression of activation criteria) have been described. Recent works show some disturbances of T cell function and evoke the possibility of the initial pathology being related to this cell. Some current hypotheses place the T cell receptor for the antigen and the interleukin 2 receptor whose dysfunction will lead to an anomaly of the transduction of the activating signal of the T lymphocyte. The intrinsic origin (genetically determined) or extrinsically (retroviral) of these disturbances remains however to be determined.

Long-term results of surgical treatment for gastroesophageal reflux in asthmatic patients.

We report the long-term results of surgical repair of gastroesophageal reflux in 44 asthmatic patients who underwent surgery more than five years earlier (mean = 7.9 +/- 1.5 years). The severe asthma was associated with clinically evident reflux, and repair was attempted by surgical technique Nissen transabdominal gastropexy, with the following results: total cure, 11 cases (25 percent); marked improvement, 7 (16 percent); moderate improvement, 11 (25 percent); no improvement, 15 (34 percent). Cure was attained in intrinsic asthma with a predominance of nocturnal crises, associated with nocturnal tracheitis and with significant reflux, objective signs of which had appeared before the beginning of the asthma. Other results concerned asthmas complicated secondarily by GER in which it was impossible to determine whether the reflux was only a complication, without effect on the respiratory illness, or exacerbating the asthma. The question of surgery in these patients should be considered with care, being reserved for cases of severe asthma, poorly controlled by antiasthmatic drugs, and complicated by a severe reflux that encompasses ulcerative esophagitis.

[Metachronous primary pulmonary cancers. Apropos of a new case report]. / Cancers pulmonaires primitifs métachrones. A propos d'une nouvelle observation.

The appearance of a second primary lung cancer more than four months after the initial cancer is called a metachronous cancer (as opposed to a synchronous cancer). We provide a case report of an epidermoid carcinoma coming more than three years after the initial diagnosis of an anaplastic small cell cancer of the lung. This second cancer developed in a different territory from the initial lesion. Amongst the hypotheses proposed chemotherapy may through an oncogenic action favour the appearance of a new type of cancer.