[Corticoids and lung diseases: conclusions, synthesis and perspectives].
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Acute Disease↗
Biomedical subjects
A Magnan
Publications and source records attributed to A Magnan.
Altered compartmentalization of transforming growth factor-beta in asthmatic airways.
BACKGROUND: Asthma is characterized by alterations of the bronchial epithelium associated with inflammatory cell infiltrates and sub-epithelial fibrosis. Transforming Growth Factor-beta (TGF-beta) is an anti-inflammatory and fibrosing cytokine normally present in bronchial epithelial cells and also potentially produced by inflammatory cells. Thus, TGF-beta could play a role in the asthmatic process, and its expression could be modified in asthmatic airways. OBJECTIVE: To test this latter hypothesis, we studied the bronchial distribution of TGF-beta in asthmatic patients. METHODS: TGF-beta 1, 2, 3 distribution was studied by immunohistochemistry in bronchial biopsies from 12 asthmatic patients and 10 non-asthmatic subjects. RESULTS: Bronchial epithelial cells from asthmatics were negative or faintly positive while a bright staining was detected in these from non-asthmatics (P < 0.01). In both groups, when inflammatory cells were present beneath the basement membrane, they were stained by the anti-TGF-beta antibody. CONCLUSION: This study shows an altered compartimentalization of TGF-beta in asthma. (a) TGF-beta is scarse in asthmatic bronchial epithelial cells, which could favour the perennization of the bronchial inflammation, and (b) TGF-beta is present in inflammatory cells beneath the basement membrane, where it could be involved in the frequent sub-epithelial fibrosis.
Adult↗
[Allergies: determinants of T2 lymphocyte polarization and desensitization mechanisms].
Distinguishing two populations amongst T lymphocytes, namely Th1 and Th2, has enabled a better understanding of the pathophysiology of inflammatory diseases most notably immunoallergic disorders. These two populations, initially described in mice, are defined by the profile of cytokines which they produce. Th1 lymphocytes secrete amongst others IL-2 and IFN-gamma and the action exercised by these cytokines are involved in cellular reactions. Th2 lymphocytes are involved in humoral responses and immediate hypersensitivity secreting IL-4 and IL-5. In man the distinction between the two populations is more subtle than in the mouse, in particular for the same cell there is a possibility to pass from one type of cytokine to another. Thus the importance of factors which influence the orientation towards Th1 or Th2 type amongst the T lymphocytes. What are these factors? Can one use these to change the response to achieve a therapeutic goal? These are the questions that we propose to touch on in this analysis broaching the induction of the Th2 response. Certain responses are linked to the individual and concern their heredity. Others are the cells themselves which are involved in antigen presentation, the presenting cell and the HLA molecules, peptide antigen and T cell receptor. Again there are others which influence the presentation without being directly involved: these are the cytokines already present in the biological milieu and engaged co-receptors. All these factors act in concert, perhaps with others which are not yet known and account for the complexity of the response. Desensitisation is a treatment whose efficacy is recognised in certain precise indications. During the course of treatment, there is a diminution of IgE to the benefit of IgG and a diminution of the eosinophil count induced by specific provocation. These effects may be related to a decrease in the production of IL-4 and IL-5 respectively, which has been found in several recent studies. Desensitisation also shows that in spite of its complexity, one can reorientate towards a Th1 response based on spontaneous Th2 response. In this respect desensitisation constitutes a human model for the study of orientation of the Th2 immune response. In the future better understanding of the mechanisms of the allergic reaction will enable new treatments to be developed based on the use of antigenic peptides or using cytokines and inhibitors of cytokines.
Animals↗
Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation.
RANTES (regulated upon activation, normally T expressed and secreted) is a chemoattractant for macrophages, memory T lymphocytes, and eosinophils. We investigated whether intrapulmonary production of the chemokine RANTES contributes to the recruitment of immune cells during lung transplantation complications. RANTES concentration was measured in bronchoalveolar lavage (BAL) fluids using an ELISA assay. It was significantly higher during CMV pneumonitis (36.2 +/- l6 pg/ml, n=12, P=0.031) and allograft rejection (31.1 +/- 8.5 pg/ml, n=27, P=0.013) than in patients without complications (9.1 +/- 2.3 pg/ml, n=22). At least some of the RANTES was produced by lung macrophages: BAL macrophages cultured for 24 hr spontaneously released larger amount of RANTES during CMV pneumonitis (140 +/- 53 pg/ml, n=8, P=0.002) and allograft rejection (84 +/- 44 pg/ml, n=11, P=0.037) than in control patients (15.2 +/- 6.5 pg/ml, n=21). Moreover, macrophages in transbronchial biopsies were labeled by an anti-RANTES mAb. RANTES production by BAL macrophages was followed in 2 patients with CMV pneumonitis. It remained high as long as CMV-induced cytopathic effects or clinical symptoms were present, but it returned to baseline as the infection was controlled. These results suggest that the intrapulmonary production of the chemokine RANTES by activated macrophages contributes to the intrapulmonary accumulation of immune cells during complications of lung transplantation.
Antiviral Agents↗
Balance between alveolar macrophage IL-6 and TGF-beta in lung-transplant recipients. Marseille and Montréal Lung Transplantation Group.
Acute inflammation in the lung is characterized by a phase of tissue injury followed by a phase of tissue repair. When the latter is excessive, fibrosis occurs. Alveolar macrophages (AM) can produce cytokines involved in both phases of acute lung inflammation, notably interleukin-6 (IL-6), involved in injury and transforming growth factor-beta (TGF-beta), mediating repair. We hypothesized that AM were activated in both phases, and studied IL-6 and TGF-beta production by AM during complications of lung transplantation, acute rejection (AR), and cytomegalovirus pneumonitis (CMVP). In addition, we analyzed these cytokines in bronchiolitis obliterans (BO), a fibrotic complication of lung transplantation linked to previous AR and CMVP. At the onset of AR and CMVP, IL-6 secretion increased, whereas AM TGF-beta content was increased, but not its secretion. In contrast, with time, IL-6 reached control value whereas TGF-beta secretion rose significantly. In BO, IL-6 was not oversecreted, but TGF-beta increased, notably before functional abnormalities occurred. These results show that during acute complications of lung transplantation, AM display an early activation with oversecretion of IL-6, which is involved in tissue injury, counterbalanced by a late activation in which TGF-beta predominates, mediating tissue repair. The results provide new insights into the pathogenesis of BO, which is linked to acute complications of lung transplantation through this biphasic AM activation.
Adolescent↗
Early T-cell development in CD3-deficient mice.
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Animals↗
[Lung transplantation and respiratory function tests. Functional outcome in the presence and absence of chronic rejection].
Between may 1988 and march 1993, twenty five double lung transplants were performed and five heart/lung transplants. Lung function tests (EFR) were performed on these patients for a period of 19.2 +/- 3.4 months. The aim of this study was two-fold. First, to report our overall results and to estimate the role of the single breath nitrogen washout test (N2 slope) in the early detection of chronic rejection (RC). Secondly, to assess the diagnostic value of EFR in the discrimination of acute rejection (RA) and of cytomegalovirus pneumonitis (PCMV). There were 41 episodes of RA and 21 episodes of PCMV and they were analysed as a function of the presence or absence of RC. In the absence of RC, RA produced no change in EFR and PCMV was accompanied by a pure restrictive ventilatory defect. On the otherhand, RA and PCMV lead to a worsening of obstruction and an hypoxaemia which characterises RC. The diagnosis of RC was made, on average, 14.4 +/- 2.9 months after surgery. However, from the sixth month the nitrogen slope was significantly increased and other parameters of EFR (particular maximal flows at low lung volume) remained normal. Thus, our results suggest that the N2 slope, measured in the absence of any evidence of acute rejection, constitutes an early test for chronic rejection. When its pathological rise is compared to the results of histology (presence or absence of RC), it shows a sensitivity of 0.94 and a specificity of 0.93.
Acute Disease↗
[AIDS: a model for the study of atopy?].
The drug intolerance and allergic manifestations linked to infection with the Human Immunodeficiency Virus (HIV) are often misunderstood. However, in the light of recent advances in immunopathology, these manifestations perhaps give an indication as to more general mechanisms of allergy. Drug intolerance is frequent during the course of AIDS, and is largely due to sulphamides; more rarely to pentamidine or amoxycillin associated with clavulanic acid. Other allergic manifestations are frequent in subjects suffering from AIDS, and occur all the more so in those subjects who are atopic before their immunodepression occurred. Metabolic anomalies occurring during the course of the disease perhaps partially explain certain aspects of drug intolerance. However, it seems that it is particularly the immunological changes which are at the origin of allergic manifestations to these diseases. AIDS is characterised by polyclonal activation of B-lymphocytes which leads to hyper-gammaglobulinaemia. This excess of antibody confronted with an excess of antigen in association with the administration of high doses of long-term antibiotics would favour the formation of antigen antibody complexes which may be responsible for the manifestations of a type of "serum sickness". Besides, there is a specific dysregulation of IgE synthesis as evident by a rise of serum IgE in subjects suffering from AIDS. That would explain the progressive increase in the expression of interleukine-4 and interleukine-10 during the course of the disease at the expense of the expression of interleukine-2 and interferon gamma. The shift from a Th1 cytokine secretion profile to that of a Th2 profile could be a consequence of decreased IL12 production by HIV infected monocyte/macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)
Acquired Immunodeficiency Syndrome↗
[The relation between rhinitis and allergic asthma. The action of antihistaminics on bronchial hyperreactivity].
The connections which maintain rhinitis and allergic asthma are less simple than it appears. If there is an indisputable relationship between rhinitis and asthma it is far from systematic. Several factors regulate this relationship. The sensitivity towards perennial allergens is more readily associated with asthma or non-specific bronchial hyper-reactivity than the sensitisation to seasonal allergens while both are connected to rhinitis. Several explanations can be touched upon: the size of the allergen dose, the duration of exposure, and polysensitisation. On the other hand the risk of developing asthma is much greater if there is an increase in the total IgE level. Finally the intensity of nasal inflammation may itself alter the intensity of the bronchial hyperreactivity. In spite of these connections and the efficacy of the recent anti-histamines on rhinitis, the known effects of anti-histamines on the bronchi remain marginal.
Allergens↗
[Asthma-allergy. Altitude: a study model].
Several epidemiological studies have now established the relationship between atopy and bronchial asthma. The study of the role of altitude in sensitization, bronchial reactivity, clinical symptoms and allergen exposure in asthma is a good model for understanding the disease. It is now demonstrated that in altitude there is a major decrease in the number of mites (one of the major aeroallergens) and a low mite antigenic load (measured with monoclonal antibodies). In altitude, the climatic factor which has by far the greatest effect on the development of mites is indoor relative humidity which is much lower that at sea level. These findings explain the clinical improvement of some asthmatic patients and help understand the association between the presence of indoor allergens and asthma.
Allergens↗
Emergence of inflammatory alveolar macrophages during rejection or infection after lung transplantation.
Local activation of macrophages may play an important role in immune complications following lung transplantation. To document such a phenomenon, we have investigated the possible changes of alveolar macrophage surface antigen expression after lung transplantation. Using immunocytofluorometry, we have analyzed the phenotype of alveolar macrophages from 41 bronchoalveolar lavage fluids obtained from 19 lung transplant recipients displaying various complications. The strong expression of HLA-DR observed on almost all alveolar macrophages was similar among groups I (no complication), II (minimal acute rejection), and III (mild to severe acute rejection), but was enhanced in group IV (bronchial infection) (P < 0.03). We observed no significant variation in the monocyte lineage CD14 antigen expression among the 4 groups, and about 83% of alveolar macrophages expressed this marker strongly. Membrane expression of the 27E10 antigen that characterizes infiltrating macrophages in acute inflammatory lesions was significantly higher during mild to severe rejection episodes than in controls (P < 0.02) and during bronchial infections (P < 0.05) but not during minimal rejection. Double staining experiments confirmed that 27E10-positive cells in groups III and IV belonged to the macrophage lineage. In addition, the expression of the 27E10 antigen on cultured alveolar macrophages was found to be increased after stimulation by bacterial lipopolysaccharide or IFN-gamma. These results indicate that a particular alveolar macrophage subpopulation is activated during immune events after lung transplantation. This population, recognized by the 27E10 mAb, might be involved in cytokine production during severe acute rejection and infection episodes.
Adolescent↗
Perforin and granzyme B gene-expressing cells in bronchoalveolar lavage fluids from lung allograft recipients displaying cytomegalovirus pneumonitis.
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Bronchoalveolar Lavage Fluid↗
Transforming growth factor beta in normal human lung: preferential location in bronchial epithelial cells.
BACKGROUND: Transforming growth factor beta (TGF-beta) is an immunomodulatory cytokine regulating the proliferation and differentiation of various cell types. It also contributes to the maintenance of tissue architecture by influencing the production of extracellular matrix components. TGF-beta has been detected in bronchoalveolar lavage fluid from normal human lung, but the nature and distribution of cells containing TGF-beta in this organ remain unknown. METHODS: Fourteen normal human lung specimens were studied by immunohistochemistry with a monoclonal antibody recognizing TGF-beta 1, TGF-beta 2 and TGF-beta 3. RESULTS: TGF-beta was detected in all cases. Bronchial epithelial cells contained the largest amounts of TGF-beta. In these cells the staining was brightest at the apical pole. Macrophages and smooth muscle cells also contained TGF-beta, although less than epithelial cells. No TGF-beta was detected in other cell populations, including endothelial cells, fibroblasts, and pneumocytes. CONCLUSIONS: The bronchial epithelial compartment appears to be the main location of TGF-beta in the normal human lung, suggesting that this cytokine has a pivotal role in the immunological properties of the bronchial mucosa.
Adult↗
Soluble TNF receptors (TNF-sR55 and TNF-sR75) in lung allograft recipients displaying cytomegalovirus pneumonitis.
Two distinct types of tumor necrosis factor receptors (TNF-R) have been identified (TNF-R55 and TNF-R75). Both TNF-R also exist in soluble forms (TNF-sR), resulting from the release of the extracellular domains (TNF-sR55 and TNF-sR75). TNF-sR may play an important role in vivo as they can bind to TNF alpha and prevent ligand binding to the cellular TNF-R, thus acting as naturally occurring inhibitors of TNF alpha. Sera from lung allograft recipients with cytomegalovirus (CMV) pneumonitis (12 patients) were assayed for TNF-sR55 and TNF-sR75. The concentrations were compared with those from either control lung recipients displaying neither rejection nor infection (12 patients), or lung recipients with allograft rejection (12 patients). Serum TNF-sR55 and TNF-sR75 concentrations were measured by enzyme-linked immunologic binding assay. Serum TNF-sR55 and TNF-sR75 concentrations were significantly higher during CMV pneumonitis (mean +/- SEM: 13.7 +/- 4.7 ng/ml, and 11.7 +/- 2.7 ng/ml, respectively) than during allograft rejection (3.7 +/- 0.3 ng/ml, p < 0.001, and 2.6 +/- 0.6 ng/ml, p < 0.001, respectively). They were also higher than in control subjects (3.6 +/- 0.3 ng/ml, p < 0.001, and 1.9 +/- 0.5 ng/ml, p < 0.001, respectively). Serum TNF alpha concentration was low in case of rejection or in control subjects (< 20 pg/ml). Conversely increased levels of TNF alpha were detected in the serum of six out of the 12 patients with CMV pneumonitis (p < 0.03 versus rejection and control subjects). Ganciclovir treatment of CMV pneumonitis led to a dramatic decrease of TNF alpha, TNF-sR55, and TNF-sR75 serum levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Monitoring of alveolar macrophage production of tumor necrosis factor-alpha and interleukin-6 in lung transplant recipients. Marseille and Montreal Lung Transplantation Group.
Bronchiolitis obliterans (BO), a common complication in lung transplant recipients, is a fibrotic process probably related to acute rejection (AR) and cytomegalovirus pneumonitis (CMVP). Because the pathogenesis of pulmonary fibrotic diseases involves activation of alveolar macrophages (AM), the present study was carried out to determine if AM were activated during AR, CMVP, and BO. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were measured in 157 AM supernatants obtained from 29 transplant recipients by immunoradiometric assay. Five groups were analyzed: AR (n = 21), CMVP (n = 12), BO (n = 15), bacterial pneumonia (BP) (n = 8), and control subjects (n = 70). Cytokines were also assayed 15 d (n = 15) and 30 d (n = 9) after AR and 30 d (n = 9) after CMVP. Cytokine secretion was elevated during AR (TNF-alpha = 3,709 +/- 1,409 pg/10(6) cells, IL-6 = 5,482 +/- 2,058 pg/10(6) cells, p < 0.005), and they returned to control values within 15 d. A similar pattern was observed during CMVP (TNF-alpha = 5,000 +/- 2,773 pg/10(6) cells, IL-6 = 12,280 +/- 3,939 pg/10(6) cells, p < 0.005), and values returned to control levels within 30 d. During BP, cytokine production values were higher than control values, but to a lesser extent than in AR and CMVP (TNF-alpha = 2,502 +/- 1,072, p < 0.05; IL-6 = 3,734 +/- 1,440, p < 0.005). In contrast, cytokine secretion during BO was not statistically different from that of control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
End-tidal CO2 analysis in sleep apnea syndrome. Conditions for use.
The diagnosis of sleep apnea syndrome (SAS) requires expensive and complex instrumentation. The purpose of the present study was to determine the value of end-tidal CO2 (EtCO2) in screening for sleep apneas. Thirty-nine patients referred to our sleep laboratory because of suspected SAS and ten normal subjects were studied. The EtCO2 was measured using an infrared spectrometer (POET) designed for simultaneous measurement of CO2 and pulse oximetry. In 29 subjects, expired gas was sampled with a nasobuccal mask (Respiron) with lateral orifices. In the other 20 subjects, sampling was done with nasobuccal prongs (Criticare) comprising a four-channel plastic tube to the mouth and the nostrils. Data from an 8-h night were transferred the following day to a microcomputer (Apple Macintosh) for processing. Apnea was defined as an absence of detection of CO2 for more than 10 s. Conventional polysomnography was performed (Respisomnographe). The number of apneas in 8 h and the apnea index (number of apneas in 1 h) were calculated after visual analysis on the screen of the polysomnograph and also with EtCO2 analysis. For recordings made with a nasobuccal mask, the regression curve between the apnea indices computed with EtCO2 and polysomnography was an order 2 polynomial curve (r = 0.76; p < 0.001), with an inflection point at 39 apneas per hour. For recordings with nasobuccal prongs, the correlation was very significant (r = 0.95; p < 0.0001), and the regression curve was linear. The EtCO2 with nasobuccal prongs appears to be a simple and reliable method for screening for SAS.
Adult↗
[Respiratory failure in a HIV seropositive heroin addict female].
A 31-year-old woman, heroin addict since ten years, and infected by the human immunodeficiency virus (HIV) since one year, was admitted to the intensive care unit for respiratory failure (PaO2 = 40 mmHg and PaCO2 = 14.8 mmHg, despite breathing pure oxygen). She had been followed up for 6 months for increasing dyspnoea due to chronic cor pulmonale for which no satisfactory explanation had been put forward. Artificial ventilation with 8 cmH2O positive end-expiratory pressure and 100% oxygen was completely inefficient. She died within a few hours. Postmortem lung biopsy revealed talc particles within interalveolar walls and alveolar macrophages as well as the expected alterations in blood vessels. Pulmonary hypertension due to talc microemboli is a well-known cause of respiratory failure in heroin addicts. Such a diagnosis should not be overlooked in a patient infected with HIV. Respiratory failure may not be only due to opportunist infections, or tumours related to the HIV infection.
Adult↗
[Visceral leishmaniasis associated with Hodgkin's disease: diagnostic difficulties].
A case of Hodgkin's disease associated from the start with visceral leishmaniasis in the absence of antitumoral treatment shows that leishmaniasis is a severe opportunistic infection in endemic areas and can be masked by the tumoral syndrome of an underlying pathology. Conversely, patients with visceral leishmaniasis must be investigated for a cause of immunosuppression with, in particular, biopsy of accessible lymph nodes. The exceptionally favourable course of this particular case deserved to be high-lighted.
Adult↗