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Biomedical subjects

P Soler

Publications and source records attributed to P Soler.

At least 19 recordsLinked to original sources
PubMed2005

Pulmonary sarcoidosis.

Sarcoidosis is a multisystemic disease of unknown aetiology characterized by the formation of immune granulomas in involved organs. It is a worldwide disease that mainly affects 25-40 years old people with a lifetime incidence rate of 0.85-2.4%. Multiple clinical phenotypes are observed according to presentation, involved organs, disease duration and severity. Sarcoidosis primarily affects the lungs and the lymphatic system. The prevailing pathogenic hypothesis is that various antigens could promote sarcoidosis in genetically susceptible hosts, both these factors modulating the incidence and the clinical phenotype of sarcoidosis. So far, environmental agents have been suspected, including possible mycobacteria and propionibacteria. Interferon-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-12 and IL-18 play a critical role in driving the Th1 commitment in the course of granulomatous process. Evolution of sarcoidosis is often marked by spontaneous resolution within 12-36 months, but can be severe because of chronic cases with pulmonary fibrosis or involving other organs, including heart, central nervous system and eyes. Mortality, ranging between 0.5 and 5%, is most often related to pulmonary fibrosis. Corticosteroids can reverse the granulomatous process, but are only suspensive, and their long-term benefit remains under question. Corticosteroids are recommended when sarcoidosis shows unfavourable clinical tolerance and evolution. Alternative and corticosteroid-sparing therapies are of increased interest in difficult cases, while targeted new drugs such as anti-TNF-alpha are still under investigation.

Humans↗
PubMed2005

An outbreak of Campylobacter jejuni enteritis in a school of Madrid, Spain.

An outbreak of gastroenteritis caused by Campylobacter infection was identified in May 2003 in a school in Madrid, Spain. Eighty one cases were identified in a total of 253 people studied. A retrospective cohort study showed that a custard made with ultra high temperature (UHT) milk was associated with illness (RR: 3.15; 95% CI: 1.25-7.93). The custard was probably contaminated with Campylobacter jejuni from a raw chicken prepared a day previously in the same kitchen. Our recommendations were to periodically remind the school s authorities how to act if an outbreak should be suspected, to include the monitoring of a food handler s working day in each environmental investigation in order to detect any risk behaviour; to implement microbiological analysis from the surfaces and utensils of the collective kitchens and improve the sanitary education of food handlers.

Adult↗
PubMed2004

Upregulation of bronchioloalveolar carcinoma-derived C-X-C chemokines by tumor infiltrating inflammatory cells.

OBJECTIVE AND DESIGN: The presence of increased numbers of tumor-infiltrating neutrophils is associated with poorer outcome in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We evaluated the role of inflammatory environment on C-X-C chemokine tumor production. MATERIALS: Bronchoalveolar lavage from 31 consecutive patients with adenocarcinoma of the BAC subtype as well as tumor and normal pulmonary tissue samples. A549 BAC cell line. Peripheral blood mononuclear cells (PBMC), polymorphonuclear neutrophils (PMN) and alveolar macrophages (AM). METHODS: Elisa measurements and immunohistochemical studies of ENA-78, IL-8, IL-1beta and TNF-alpha. RNA isolation, reverse transcription, and PCR amplification of ENA-78 and IL-8. RESULTS: C-X-C peptides were expressed by tumor cells of all the tumor specimens tested. ENA-78 and IL-8 were also expressed by AM. To better understand the regulation of the C-X-C production, BAC cell line was cultured alone or with inflammatory cells. PBMC upregulated both tumor ENA-78 and IL-8 mRNA expression and protein release whereas AM only upregulated ENA-78 mRNA expression and protein release; PMN had no effect. Anti-human IL-1beta antibodies (ab) inhibited the A549 ENA-78 and IL-8 production stimulated by PBMC-CM. Anti-human TNF-alpha ab inhibited A549 ENA-78 production stimulated by AM-CM. IL-1beta and TNF-alpha were expressed in vivo by inflammatory cells, although TNF-alpha was also expressed by tumor cells. CONCLUSIONS: This work emphasizes the role of the host inflammatory response in promoting tumor growth in vivo.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2004

Expression of apoptosis-regulatory proteins in lesions of pulmonary Langerhans cell histiocytosis.

AIMS: Pulmonary Langerhans cell histiocytosis (PLCH) is characterized by the presence of lesions containing numerous activated Langerhans cells (LCs). An uncontrolled immune response sustained by activated LCs seems to be involved in the pathogenesis of the disease. The aim of this study was to establish whether disruption of LC apoptosis related to the expression of the Bcl-2 family proteins is implicated in the maintenance of PLCH lesions. METHODS: Six patients with PLCH were evaluated by morphological and immunohistochemical techniques to explore the incidence of apoptosis in pathological LCs and to characterize the expression of Bcl-2-related proteins by these cells. RESULTS: Very few LCs present in PLCH lesions exhibited nuclear apoptotic changes or expressed cleaved caspase-3, whereas they all strongly expressed the anti-apoptotic molecule Bcl-x(L). Interestingly, pulmonary LCs present in intervening lung tissue not involved by the pathological process and known to be immature dendritic cells did not express Bcl-2 family proteins. CONCLUSIONS: These findings suggest that activated LCs present within PLCH lesions are poorly susceptible to apoptosis and, thus, are able to sustain the pathological process by causing continuous local stimulation of T cells. Functional studies are needed, however, to demonstrate that they are actually resistant to programmed cell death.

Adult↗
PubMed2003

[Adult pulmonary Langerhans' cell histiocytosis].

INTRODUCTION: Adult pulmonary Langerhans'cell histiocytosis, also referred to as histiocytosis X, is a disorder of unknown etiology which affects preferentially young smokers. The disease is characterized by granulomatous lesions which progressively invade and destroy distal airways, leading to the formation of characteristic cicatricial kystic lesions. Florid granulomas contain numerous Langerhans'cells, antigen-presenting cells of the dendritic cell lineage, associated with T lymphocytes and eosinophils. The diagnosis rests on the combination of clinical and radiologic data, and particularly on high-resolution CT scan findings showing a typical association of nodular and cystic changes, predominantly in the upper and middle lobes. Further evaluation with surgical lung biopsy is indicated in less typical situations. CURRENT KNOWLEDGE AND KEY POINTS: The pathogenesis of Langerhans'cell histiocytosis is not fully understood, but several arguments suggest that the disease results from an abnormal immune reaction initiated by Langerhans'cells and directed against the bronchial epithelium. Other arguments suggest the presence of genetic abnormalities susceptible, for example, to increase the sensitivity of these cells to cytokines (GM-CSF, or others) known to influence their survival and maturation. FUTURE PROSPECTS AND PROJECTS: These recent advances in the pathogenesis of Langerhans'cell histiocytosis could promote the development of new therapeutic strategies designed to regulate the number and activated state of Langerhans'cells in specific lesions.

Adult↗
PubMed2003

Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF-beta and IL-10.

Modulation of cytokine expression represents a potentially useful approach for the treatment of idiopathic pulmonary fibrosis (IPF). To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids (mRNAs) coding for 17 cytokines in lung tissue obtained from patients with IPF at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques. mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor (TGF)-beta and interleukin (IL)-10 mRNAs were quantitatively increased in lung biopsies from patients with IPF compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor (PDGF)-BB and keratinocyte growth factor (KGF) were expressed in similar amounts in lungs from patients with IPF and controls, localised accumulation of both factors was also observed in IPF. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where IL-10, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed (PDGF-BB, TGF-beta). These results offer new insights into the cytokines produced in the lung in idiopathic pulmonary fibrosis and suggest that modulation of the production of transforming growth factor-beta and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.

Female↗
PubMed2001

Tumor-derived granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor prolong the survival of neutrophils infiltrating bronchoalveolar subtype pulmonary adenocarcinoma.

We evaluated the role of the tumor environment in the regulation of apoptosis of tumor-infiltrating neutrophils, the number of which correlates negatively with outcome, in patients with adenocarcinoma of the bronchioloalveolar (BAC) subtype. We examined three different parameters of apoptosis, namely morphological aspect, annexin-V expression, and DNA fragmentation. Bronchoalveolar lavage fluid (BALF) supernatants from patients with BAC significantly inhibited the 24-hour spontaneous apoptosis of normal peripheral blood neutrophils in vitro compared to BALF supernatants from control patients (64 +/- 4% versus 90 +/- 2% measured by annexin-V flow cytometry, P = 0.04). The alveolar neutrophil count correlated positively with the granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) concentrations in the patient's BALF. Furthermore, neutralizing antibodies (Abs) against GM-CSF and G-CSF significantly inhibited BALF anti-apoptotic activity (15 to 40% and 34 to 63% inhibition, respectively), whereas neutralizing Abs against interleukin (IL)-8, IL-6, IL-1beta and tumor necrosis factor-alpha had no significant effect. In an attempt to identify the cell origin of anti-apoptotic cytokines, we tested in vitro the effect of BAC cells (A549 cell line and primary culture derived from a patient's BAC tumor) on the apoptosis of peripheral blood neutrophils. Cell-free supernatants from tumor cells did not inhibit neutrophil apoptosis. In contrast, cell-free supernatants from tumor cells previously exposed to conditioned media from peripheral blood mononuclear cells and alveolar macrophages significantly inhibited spontaneous neutrophil apoptosis. This inhibition was partially lifted when conditioned media from mononuclear cells were previously treated with Abs against IL-1beta and tumor necrosis factor-alpha. As in vivo, neutralizing Abs against GM-CSF significantly inhibited the anti-apoptotic activity of cell culture supernatants, and combination with Abs against G-CSF had an additive effect. In vivo, GM-CSF and G-CSF were strongly expressed by tumor cells and moderately or not expressed by the normal epithelium, as assessed by immunohistochemical studies. These findings demonstrate that the tumor environment generates local conditions that prolong alveolar neutrophil survival through the production of soluble factors, thereby contributing to the persistence of the neutrophil alveolitis observed in BAC.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed2001

Bronchopulmonary disposition of the ketolide telithromycin (HMR 3647).

Telithromycin (HMR 3647) is the first member of a new family of antimicrobials, the ketolides, developed specifically for the treatment of community-acquired respiratory tract infections. Telithromycin has proven in vitro activity against both common and atypical respiratory tract pathogens. The penetration of telithromycin into bronchopulmonary tissues and subsequent elimination from these sites were evaluated in four groups (groups A, B, C, and D) of six healthy male subjects who received telithromycin at 800 mg once daily for 5 days. Subjects in groups A, B, C, and D underwent fiberoptic bronchoscopy and bronchoalveolar lavage 2, 8, 24, and 48 h after receipt of the last dose, respectively. The concentration of telithromycin in the alveolar macrophages, epithelial lining fluid (ELF), and plasma was determined by the agar diffusion method with Bacillus subtilis ATCC 6633 as the test organism. The concentration of telithromycin in alveolar macrophages markedly exceeded that in plasma, reaching up to 146 times the concentration in plasma 8 h after dosing (median concentration, 81 mg/liter). Telithromycin was retained in alveolar macrophages 24 h after dosing (median concentration, 23 mg/liter), and it was still quantifiable 48 h after dosing (median concentration, 2.15 mg/liter). Telithromycin median concentrations in ELF also markedly exceeded concentrations in plasma (median concentration in ELF, 3.7 mg/liter 8 h after dosing). Telithromycin achieves high and sustained concentrations in ELF and in alveolar macrophages, while it maintains adequate levels in plasma, providing an ideal pharmacokinetic profile for effective treatment of community-acquired respiratory tract infections caused by either common or atypical, including intracellular, respiratory tract pathogens.

Administration, Oral↗
PubMed2001

[Pathogeny-etiology of sarcoidosis].

It is now well established that sarcoidosis is a granulomatous disorder resulting from an uncontrolled cell-mediated immune reaction in response to unknown antigens. This reaction is characterized by the presence of typical granulomas at the sites of the disease, made of activated macrophages (epithelioid cells) and T lymphocytes. The interactions between both cell types lead to the production of numerous inflammatory mediators which are essential for the development of granulomas. Recently, sarcoid granulomas have been shown to express a Th1 pattern of cytokines. The modulation of the expression of some of them could be useful for the development of new therapies. The etiology of sarcoidosis remains unknown, but recent advances concerning this disorder suggest that it results from various causes involving a particular genetic background and exposure to specific environmental factors. Recent data have emphasized in some patients the expression of particular HLA haplotypes, the polymorphism of various genes, and the presence of oligoclonal T lymphocytes. The characterization of the antigenic specificity of these T cells could be helpful in identifying agents responsible for the disease. The role of mycobacterial agents is still controversial.

Environmental Exposure↗
PubMed2000

Is high-resolution computed tomography a reliable tool to predict the histopathological activity of pulmonary Langerhans cell histiocytosis?

High-resolution computed tomography (HRCT) has proved to be very useful in the diagnosis and follow-up of pulmonary Langerhans cell histiocytosis (PLCH), but the precise relationships between nodules and thin-wall cysts observed by HRCT, and granulomatous or cystic lesions present in lung tissue, remain to be established. The aim of this study was to compare quantitative data obtained by HRCT and those obtained by histopathological examination of corresponding lung tissue specimens in patients with biopsy-proven PLCH. The results demonstrated that the extent of nodular abnormalities was strongly correlated with the density of florid granulomatous lesions in lung tissue. A strong correlation was also found between the extent of cystic abnormalities and the density of cavitary lesions, but the latter included both still inflammatory cavitary granulomas and cicatricial fibrous cysts. Interestingly, small isolated florid granulomas were found in lung tissue from most patients with a predominant cystic CT scan pattern. Taken together, these results demonstrate that HRCT has to be considered with caution to evaluate the histopathological activity of PLCH. Patients presenting with predominant HRCT cystic abnormalities should benefit from a long-term follow-up. Because these patients are susceptible to developing severe respiratory insufficiency, they should also be considered for treatment as soon as an effective therapy for LCH is available.

Adult↗
PubMed2000

[Diesel particles and allergy: cellular mechanisms].

Urbain air pollutants, particularly diesel exhaust particles are now known to contribute to the increased prevalence of asthma and allergic rhinitis. Diesel exhaust particles act as adjuvants in the immune response and may lead to the enhancement of allergic inflammation. This was first suggested by epidemiological studies and now largely confirmed by numerous experimental studies in animals and humans. We review the different mechanisms involved, including effects on cytokine and chemokine production, as well as activation of different immune cells. We also discuss the metabolic and cellular activation pathways used by polycyclic aromatic hydrocarbons, allergens and their interaction with diesel particles which act in synergy in this immune response toward IgE production and induction of allergic inflammation.

Allergens↗
PubMed1999

Evidence that Langerhans cells in adult pulmonary Langerhans cell histiocytosis are mature dendritic cells: importance of the cytokine microenvironment.

Because Langerhans cells (LC) in peripheral tissues are generally "immature" cells with poor lymphostimulatory activity, the contribution of immune responses initiated by LC to the pathogenesis of pulmonary LC histiocytosis (LCH) has been uncertain. In this study we demonstrate that LC accumulating in LCH granulomas are phenotypically similar to mature lymphostimulatory dendritic cells present in lymphoid organs. LC in LCH granulomas intensely expressed B7-1 and B7-2 molecules, whereas normal pulmonary LC and LC accumulating in other pathologic lung disorders did not express these costimulatory molecules. The presence of B7+ LC in LCH granulomas was associated with the expression in these lesions, but not at other sites in the lung, of a unique profile of cytokines (presence of GM-CSF, TNF-alpha, and IL-1beta and the absence of IL-10) that is known to promote the in vitro differentiation of LC into cells expressing a lymphostimulatory phenotype. Finally, LCH granulomas were the only site where CD154-positive T cells could be identified in close contact with LC intensely expressing CD40 Ags. Taken together, these results strongly support the idea that an abnormal immune response initiated by LC may participate in the pathogenesis of pulmonary LCH, and suggest that therapeutic strategies aimed at modifying the lymphostimulatory phenotype of LC may be useful in the treatment of this disorder.

Adult↗
PubMed1999

In situ expression of B7 and CD40 costimulatory molecules by normal human lung macrophages and epithelioid cells in tuberculoid granulomas.

Normal alveolar macrophages (AM) are not efficient in inducing the proliferation of resting T lymphocytes, and, rather, tend to inhibit pulmonary immune responses. In contrast, epithelioid cells (EC), activated macrophages that play an essential role in the course of granulomatous responses, appear to stimulate T cell proliferation efficiently. The inability of macrophages to deliver potent costimulatory signals through the B7/CD28 and CD40/CD40L pathways could explain their weak accessory cell activity. Using MoAbs and immunohistochemical techniques, however, we found that essentially all AM in normal human lung tissue expressed B7-1, B7-2 and CD40 molecules, and most of these cells were strongly positive. Pulmonary macrophages in other compartments also expressed these costimulatory molecules; no differences in expression were observed comparing macrophages from smokers and non-smokers. Most AM recovered by bronchoalveolar lavage from normal lung segments also strongly expressed B7-1, B7-2 and CD40 molecules. In comparison, resting blood monocytes were B7-1- and only moderately positive for B7-2. Activation of monocytes with lipopolysaccharide (LPS) induced expression of these costimulatory molecules to levels similar to that of AM from the control subjects. EC in granulomatous lesions also expressed easily detectable levels of B7-1, B7-2 and CD40. T lymphocytes within and surrounding the granulomas expressed CD28, the counter-receptor for B7, and many of these T cells also expressed B7-1 and B7-2. These findings suggest that both AM and EC can deliver costimulatory signals through B7-1, B7-2 and CD40 molecules, and indicate that the impairment in accessory cell activity observed for normal AM cannot be attributed to the absence of expression of these costimulatory molecules.

Adult↗
PubMed1999

[Pathogenesis of adult pulmonary Langerhans-cell histiocytosis].

Pulmonary Langerhans cell histiocytosis (LCH) is an uncommon disorder occurring most often in young smokers. Histologically, the disease is characterized by granulomatous lesions containing LC that destroy distal bronchioles. The etiology of the disease remains unknown, but progress has been made in understanding its pathogenesis. Modifications in the bronchiolar epithelium induced by smoking, such as the increased secretion of GM-CSF by these cells, are probably responsible for the initial accumulation of large numbers of LC. However, given the rarity of pulmonary LCH compared with the frequency of smoking, an as yet unidentified genetic predisposition may also be necessary for the development of the disease. Although LC in LCH granulomas may be clonal in origin, several observations argue against the idea that the disease, which can regress spontaneously, is a malignant process. Cells of dendritic cell lineage (including LC), are potent antigen presenting cells, suggesting that pulmonary LCH results from an uncontrolled immune response initiated by LC. Consistent with this idea, LC and T-cells are the predominant cell populations found in the early lesions of pulmonary LCH, and unlike LC in the normal bronchial mucosa and those accumulating in other pathologic situations, LC in pulmonary LCH granulomas express surface molecules important for the activation of T-lymphocytes. A number of mediators are produced in the microenvironment of granulomas that probably influence the outcome of the local immune and inflammatory reaction. Ultimately, precise knowledge of the pathogenesis of this disorder should permit the development of specific treatment. In the interim, therapies aimed at modifying the state of activation of LC in the granulomatous lesions may prove useful.

Adult↗
PubMed1998

Expression of three members of the TNF-R family of receptors (4-1BB, lymphotoxin-beta receptor, and Fas) in human lung.

Receptors belonging to the tumour necrosis factor receptor (TNF-R) superfamily are implicated in a variety of important biological processes. Although messenger ribonucleic acid coding for many of these receptors has been detected in lung, little is known about their expression in this organ. In this study, immunohistochemical techniques were used to evaluate the expression of three receptors of this family (4-1BB, lymphotoxin-beta receptor (LTbeta-R), and Fas) in normal human lung, lung carcinomas and by tuberculous and sarcoid granulomas. The 4-1BB receptor was uniformly expressed by endothelial cells of small vessels and by basal epithelial cells within pseudostratified bronchial epithelium. LTbeta-R expression by parenchymal cells was limited to those of epithelial origin (bronchial and bronchiolar epithelium, hyperplastic alveolar epithelium and lung carcinomas). Fas was present on both fibroblasts and epithelial cells (bronchial and alveolar epithelium and most, but not all, carcinomas), but not on endothelial cells. A subpopulation of T-lymphocytes expressed these receptors, but only Fas was detected on normal alveolar macrophages and epithelioid cells. Thus, 4-1BB, LTbeta-R, and Fas have characteristic and only partially overlapping patterns of expression in the lung. The findings should facilitate further evaluation of their role in lung homeostasis and pathology.

Adenocarcinoma↗