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Biomedical subjects

M Denis

Publications and source records attributed to M Denis.

At least 19 recordsLinked to original sources
PubMed1992

Minocycline-induced cell-mediated hypersensitivity pneumonitis.

OBJECTIVE: To identify the cause of a hypersensitivity pneumonitis and to determine its pathogenesis. DESIGN: Case study. SETTING: Intensive care unit of a referral hospital. PATIENT: A 51-year-old man with chronic bronchitis who developed a hypersensitivity pneumonitis within 1 month after exposure to minocycline, amoxicillin, and erythromycin. INTERVENTION: Sequential bronchoalveolar lavages after reexposure to minocycline and amoxicillin. MEASUREMENTS: Immunologic analysis of the phenotype and function of alveolar lymphocytes. RESULTS: Reexposure to minocycline but not to amoxicillin was followed by an interstitial pneumonitis. Sequential bronchoalveolar lavages showed a transient rise of eosinophils and neutrophils and a persistent alveolar lymphocytosis. Alveolar lymphocytes consisted predominantly of CD8+ but also CD4+ cells. Two CD8+ lymphocyte subsets were identified: CD8+ D44+ cytotoxic T cells that increased rapidly after the drug was resumed and CD8+ CD57+ suppressor T cells that predominated 11 days after the drug's withdrawal. In-vitro assays showed the presence of a lymphocyte-mediated specific cytotoxicity against minocycline-bearing alveolar macrophages. CONCLUSION: These results support the hypothesis of a central role of T lymphocytes in the pathogenesis of drug-related hypersensitivity pneumonitis.

Alveolitis, Extrinsic Allergic↗
PubMed1992

Interleukin-6 is used as a growth factor by virulent Mycobacterium avium: presence of specific receptors.

In this paper, we examined the contribution of the lymphokine interleukin-6 (IL-6) to the growth of four virulent strains of Mycobacterium avium and the nature of the binding moieties on the mycobacteria. First, we showed that human or mouse recombinant interleukin-6 are potent growth factors for four strains of virulent M. avium. This was shown to occur in tissue culture medium, which does not support maximal growth of M. avium. Bioactive IL-6 was required, inasmuch as heat-activating IL-6 or adding an antibody against IL-6 blocked this growth-enhancing ability. The rapid uptake of IL-6 by M. avium was indicated by the fact that the incubation of IL-6 with the four M. avium strains led to a rapid removal of the bioactivity from the culture medium and a rapid removal of radiolabeled IL-6. Scatchard analysis of receptor interaction showed that the M. avium strains had a single receptor species with a Kd of 50 nM and the number of receptor sites was approximately 15,000 bacterium. Blocking experiments showed that the binding of radiolabeled IL-6 was fully displaceable with cold IL-6, but not with other lymphokines. These data suggest that IL-6 may play an important role in the pathogenesis of M. avium infections, notably by promoting growth of M. avium, and that some virulent M. avium strains bind IL-6 in a specific manner.

Binding, Competitive↗
PubMed1992

Reduction of carbon monoxide to formaldehyde by the terminal oxidase of the marine bacterium Pseudomonas nautica strain 617.

When exposed to CO, the aerobic respiratory system of the marine bacterium Pseudomonas nautica strain 617, previously reduced with dithionite, undergoes reoxidation. When dealing with the purified oxidase (dithionite reduced) exposure of the enzyme to CO induces its reoxidation (collapse of its alpha band). Under our experimental conditions, this form of the oxidase could not be reduced again by dithionite. Addition of formaldehyde to the native oxidized enzyme resulted in full inhibition of the oxidase reduction by dithionite, presumably due to complex formation. We hypothesized a reduction of CO into formaldehyde and a locking of the active site by the reaction product. By using flash photolysis, it was possible to turn over the enzyme, accumulate the reaction product and identify it as formaldehyde. When using the membrane-bound enzyme, formaldehyde accumulated without the help of flash photolysis. This unusual reduction of CO to formaldehyde could be related to the previously reported uncommon features of the P. nautica oxidase, in particular O2 reduction into H2O2 as end product [(1989) FEBS Lett. 247, 475-479].

Carbon Monoxide↗
PubMed1992

Mouse T cell clones against Mycobacterium avium: identification of clones that modify resistance against atypical mycobacteria infection.

Mouse T cell clones against live Mycobacterium avium were generated from the spleens of BALB/c mice infected with M. avium TMC 702. Eighth clones were of the L3T4+ subset, whereas two were of Lyt2+ subset. Six of the L3T4+ T cell clones were of the TH1 subset whereas two were of the TH2 subset, judged on the profile of cytokine release. One of the Lyt2+ clones exhibited significant cytotoxicity against M. avium-infected mouse macrophages. Transfer of clones to nude BALB/c mice infected with M. avium was associated with insignificant changes in resistance for seven clones. One clone, of the L3T4+/TH2 subset, transferred significant resistance to the infection, also associated with infusion of supernatants from the clone, which was fully inhibited by neutralizing with anti-interleukin 4. By contrast, infusion of one TH1 clone and the cytolytic Lyt2+ led to increased microbial growth in the spleens and livers of infected mice, which was not apparent on infusion with supernatants. Application of clones' supernatants on infected macrophages had marginal effects on M. avium growth and was not correlated with protective or suppressive activity. Overall, these results suggest that T cells may influence M. avium growth in vivo in a bidirectional manner and also suggest that interleukin 4 may be an important factor in host resistance to M. avium.

Animals↗
PubMed1992

Interleukin-6 in mouse hypersensitivity pneumonitis: changes in lung free cells following depletion of endogenous IL-6 or direct administration of IL-6.

In this study, we examined the role of interleukin-6 (IL-6) in the development of chronic lung inflammatory conditions, using a mouse model of hypersensitivity pneumonitis established by intranasal instillation of the thermophilic actinomycete Faeni rectivirgula. Challenged mice developed an early neutrophilic response at 24 h, followed by a macrophage/lymphocyte recruitment. The impact of IL-6 on the development of the inflammatory response was assessed by giving infusions of a monoclonal antibody against IL-6 so as to deplete endogenous levels of this cytokine or by giving exogenous IL-6 to challenged mice. Mice challenged intranasally with the actinomycete and given the anti-IL-6 antibody developed a strong, sustained neutrophilic response, with a significantly higher lung free cell number than control mice. Assessment of fibrosis by measuring lung hydroxyproline levels showed that challenged mice given anti-IL-6 developed more significant fibrosis than control mice. Conversely, infusions with IL-6 diminished F. rectivirgula-induced cell recruitments and the fibrotic response in the lungs. Moreover, alveolar macrophages from mice given 2 weeks of F. rectivirgula treatment released high levels of tumor necrosis factor alpha (TNF-alpha) bioactivity upon in vitro lipopolysaccharide challenge, compared to mice instilled with saline only. This TNF-alpha activity produced by macrophages was decreased by in vivo IL-6 treatment and enhanced by in vivo neutralization with anti-IL-6. These observations suggest that IL-6 may play a role in regulating the cellular recruitment in the lungs during an inflammatory response, with dramatic consequences for the cellular profile in the bronchoalveolar lavage and the subsequent fibrosis.

Alveolitis, Extrinsic Allergic↗
PubMed1992

Soluble interleukin 2 receptor (Tac chain) is not a reliable marker in kidney transplant recipient monitoring.

T lymphocyte expansion is triggered through interaction of interleukin 2 (IL-2) with its high-affinity receptor (IL-2R). This molecule is a heterodimer comprising an antigen-inducible component, the Tac chain (P55). Activation of T lymphocytes also generates a soluble form of this P55 called S-IL-2R. S-IL-2R is elevated in many T-cell-related pathologies (leukemia, autoimmunity, etc.). In graft recipients, rejection is a result of T-cell activation by graft antigens and therefore might induce a release of S-IL-2R in the circulation; this parameter is now said to be a good indicator of rejection. We have performed a study in renal graft recipients in order to assess the usefulness of circulating S-IL-2R particularly to discriminate the origin of renal failure in cases of rejection or of cyclosporin-A (CsA)-induced nephrotoxicity. We demonstrated that there are no differences between isolated values in the clinical groups at the time of diagnosis. Variations in S-IL-2R are increased compared to steady-state periods during rejection and cytomegalovirus infections, although not in CsA toxicity episodes. However, at the individual level there are too many false-positive and false-negative results, making this parameter no more meaningful than serum creatinine levels alone or even in association (as tested in logistic discriminant analysis). In addition, it seems that the variations in S-IL-2R are partly related to renal function itself, as suggested by the correlation between S-IL-2R levels and serum creatinine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers↗
PubMed1992

Different mental imagery abilities result in different regional cerebral blood flow activation patterns during cognitive tasks.

Using regional cerebral blood flow (rCBF) imaging, two populations having high and low imagery abilities were compared at rest and while performing two cognitive tasks: silent verb conjugation and mental imagery. The imagery task produced an rCBF increase in the left visual association and left frontal cortices in both groups. Differences between high and low imagers were observed on global and regional flow responses to cognitive tasks: low imagers showed a whole cortex CBF increase during both tasks; high imagers showed a right dominance in the visual association cortex in all conditions, and in the parietal association cortex at rest.

Adult↗
PubMed1992

Activated mouse macrophages kill Entamoeba histolytica trophozoites by releasing reactive nitrogen intermediates.

Mouse macrophages activated by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS) are highly cytotoxic for the enteric protozoan parasite Entamoeba histolytica. Herein, we show that this killing by activated macrophages is L-arginine dependent, inasmuch as it was blocked by exogenous arginase or NG-monomethyl-L-arginine. These two inhibitors had no effect on E. histolytica cytolytic activity against L929 fibroblasts. Also, macrophage killing of E. histolytica always correlated with nitrite presence in the supernatant fluids. Finally, it was shown that addition of excess iron or the reductant sodium dithionite to activated macrophages blocked their ability to kill E. histolytica. Overall, this suggests that killing of E. histolytica by activated macrophages depends on the production of reactive nitrogen intermediates which leads to critical iron loss and protozoan parasite death.

Animals↗
PubMed1992

Murine hypersensitivity pneumonitis: interleukin-4 administration partially abrogates the disease process.

C57BL-6 inbred mice were given intranasal instillations of Faeni rectivirgula (150 micrograms/day, 3 days a week for 3 weeks) to produce a lung inflammatory reaction which mimics Farmers' lung in humans. Challenged mice developed a strong inflammatory response in their lungs, based on various markers (lung index, bronchoalveolar cell number, fibrosis). The effect of interleukin-4 (IL-4) was studied by infusing mice intraperitoneally with 100, 1000 or 10,000 units of IL-4 weekly during the challenge period. It was shown that IL-4 infusion decreased the inflammatory response, as seen by a decreased lung index (1.7 in mice given F. rectivirgula and 10(3) U IL-4 and 1.31 in mice given antigen and 10(4) U IL-4 weekly versus 2.3 in mice instilled with F. rectivirgula). Interleukin-4 infusion also partially abrogated the F. rectivirgula-induced alveolitis, as seen by a decrease in cell numbers in the broncho-alveolar lavage (BAL) (1.3 x 10(5) cells in saline-instilled mice; 8.3 x 10(5) cells in mice given 10(3) U IL-4 and F. rectivirgula; 3.2 x 10(5) cells in mice given antigen and 10(4) U IL-4; 1.8 x 10(6) cells in mice given F. rectivirgula only). Also, it was apparent that IL-4 administration could partially block the appearance of the fibrosis induced by F. rectivirgula (220 micrograms of hydroxyproline/lung in challenged mice; 170 micrograms/lung in challenged mice given 10(3) U IL-4; 131 micrograms/lung in mice given antigen and 10(4) U IL-4 and c. 100 micrograms/lung in control animals). Infusion of 10(2) U IL-4 weekly had no statistical effect on any marker of inflammation.(ABSTRACT TRUNCATED AT 250 WORDS)

Alveolitis, Extrinsic Allergic↗
PubMed1992

Entamoeba histolytica extract and interferon-gamma activation of macrophage-mediated amoebicidal function.

The effect of recombinant murine interferon-gamma (IFN-gamma) and E. histolytica extract (E.h.E.) on macrophage (M phi) activation for amoebicidal activity was examined. Peritoneal macrophages were harvested from C57BL/6 and A/J mice and preincubated with IFN-gamma and/or E.h.E. It was found that amoebicidal activity could be induced in both C57BL/6 and A/J-derived macrophages by pretreatment with IFN-gamma and E.h.E. Pretreatment of the M phi with E. histolytica extract or IFN-gamma alone did not result in the activation of significant cytotoxic activity against E. histolytica trophozoites. In the presence of IFN-gamma, E.h.E. had a dose-dependent effect on the activation of M phi amoebicidal function.

Adjuvants, Immunologic↗
PubMed1992

Murine hypersensitivity pneumonitis: bidirectional role of interferon-gamma.

C57BL/6 mice were instilled intranasally with optimal doses [150 micrograms of antigen 3 days a week) of the actinomycete Faeni rectivirgula to induce an experimental hypersensitivity pneumonitis. Some control mice received normal rat IgG as controls, whereas other mice received 1 mg weekly of rat anti-murine interferon gamma (IFN-gamma) antibody by the intraperitoneal route and 200 micrograms by the intranasal route given 2 days before and during the challenge period before each instillation. Control mice developed a clear hypersensitivity pneumonitis characterized by an early neutrophilic response at 3 days and a later influx of mononuclear cells (nine- to tenfold increase in cell number. P less than 0.001 vs saline instilled mice at 4 weeks post-treatment). F. rectivirgula instillation determined a sharp increase in the lung index (80% increase in lung weight, P less than 0.005 vs saline treated mice), as well as a significant fibrosis at 4 weeks (twofold increase in lung hydroxyproline levels). Cytokine measurements showed that tumour necrosis factor alpha (TNF alpha) was present in the broncho-alveolar lavage (BAL) of challenged mice at 4 weeks when the BAL was obtained 8 hr after the last challenge (130 U/ml). Treatment of mice with the monoclonal antibody against IFN-gamma was associated with very few changes in the number of cells in the BAL of challenged mice. The lung index of challenged mice was significantly reduced by infusion of the anti-IFN-gamma antibody. Anti-IFN-gamma treatment resulted in decreased levels of TNF alpha in the BAL of F. rectivirgula after 4 weeks of treatment (56 U/ml, P less than 0.01). Moreover, depletion of endogenous IFN-gamma in F. rectivirgula-instilled mice resulted in a diminished lung fibrotic response (P less than 0.01 vs mice treated with F. rectivirgula and control antibody). We also studied the effect of exogenous IFN-gamma adminstration on the development of lung disease. Groups of mice received recombinant gamma interferon (IFN-gamma) (1000 U) intraperitoneally just before the first treatment and also daily, whereas controls received saline or IFN-gamma alone (no F. rectivirgula challenge). After 4 weeks of treatment, mice were killed and various markers of the disease were evaluated. As mentioned before, bronchoalveolar lavage (BAL) cell number was increased tenfold in mice treated with F. rectivirgula, whereas mice given F. rectivirgula and IFN-gamma had only a threefold increase in BAL cell number, determined mostly by a decrease in alveolar macrophage recruitment in the lungs.(ABSTRACT TRUNCATED AT 400 WORDS)

Actinomycetales↗
PubMed1992

In vivo activation of macrophages by IFN-gamma to kill Entamoeba histolytica trophozoites in vitro.

To determine the role of interferon-gamma (IFN-gamma) in the activation of macrophages to kill Entamoeba histolytica trophozoites in vitro, C57BL/6 mice were injected with various doses of recombinant IFN-gamma (rIFN-gamma) by either the intravenous, intraperitoneal or intramuscular routes. Mice were treated with doses of rIFN-gamma ranging from 10(1) to 10(5) units. Twenty hours later, peritoneal macrophages were harvested from the treated animals. Macrophage monolayers were prepared and their in vitro cytotoxic activity against a virulent strain of E. hystolytica (IP:0682:1) was determined. Amoebicidal activity was determined by counting the number of dead trophozoites by Trypan Blue exclusion in cultures containing macrophages and amoebic trophozoites which were incubated together for 4 h. Both intravenous and intraperitoneal treatment resulted in the recovery of macrophages from the peritoneal cavity which exhibited amoebicidal activity in vitro. Peritoneal macrophages harvested from mice that had been treated intraperitoneally or intravenously with rIFN-gamma, however, showed significantly more amoebicidal activity in comparison to macrophages harvested from animals treated intramuscularly. There was a dose dependent relationship between the concentration of rIFN-gamma used to activate macrophages in vivo and the number of dead trophozoites in vitro. In addition, these results confirm our previous observations that treatment in vitro with rIFN-gamma can activate murine peritoneal macrophages to kill amoebic trophozoites.

Animals↗
PubMed1992

Murine hypersensitivity pneumonitis: a study of cellular infiltrates and cytokine production and its modulation by cyclosporin A.

The progression of hypersensitivity pneumonitis (HP) was evaluated in mice repeatedly challenged with the actinomycete Faeni rectivirgula (Micropolyspora faeni) (90 or 180 micrograms), at the cellular level and at the mediator level. Instillation of F. rectivirgula by the intranasal route determined a granulomatous inflammation in the lungs of animals correlated with a dramatic increase (5- to 6-fold) in cellularity in the bronchoalveolar space and an increase in the percentage of lymphocytes. Disease in mice was also correlated with high spontaneous release of the cytokines interleukin-1 (IL-1) (60 U/ml), interleukin-6 (IL-6) (72 U/ml), and tumor necrosis factor-alpha (TNF-alpha) (56 U/ml) in the bronchoalveolar lavage (BAL) fluid, as well as by an enhanced capacity for cytokine release by macrophages upon stimulation with F. rectivirgula. It was also found that the pulmonary inflammation was correlated with a 60 to 70% increase in total lung weight after 4 wk and a significant lung fibrosis as seen by a 2-fold increase in lung hydroxyproline levels. Treatment of challenged mice with cyclosporin A (CyA) led to an abrogation of the disease as seen by an abrogation of the increase in lung index, lack of IL-1 and TNF-alpha release in the BAL. CyA did not, however, completely prevent the alveolitis as seen by the cellular infiltrate (2- to 3-fold in BAL cell increase). It also did not prevent the T-lymphocyte recruitment associated with HP, although these cells did not proliferate in response to the F. rectivirgula antigen, in contrast to BAL cells from F. rectivirgula-challenged mice treated with excipient only.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intranasal↗
PubMed1992

T cells in hypersensitivity pneumonitis: effects of in vivo depletion of T cells in a mouse model.

C57BL/6 mice were given intranasal instillation of optimal doses of the actinomycete Faeni rectivirgula 150 micrograms/mouse 3 days/wk), an important offending agent causing hypersensitivity pneumonitis. This instillation was associated with a very significant increase in the lung weight of the mice and also a large increase (10-fold) in the number of cells recovered from the bronchoalveolar lavage (BAL) of instilled mice. Also, this instillation was associated with a very significant fibrosis at 4 and 8 wk (2-fold increase in hydroxyproline levels in the lungs). We determined the effect of depleting certain T-cell subsets on the progression of this inflammatory disease. Elimination of the L3T4 subset did not significantly affect the increase in the lung index, the lung cellular influx, or its profile. Fibrosis was also unaffected by this depletion of L3T4+ cells. Similarly, depletion of Lyt2+ (CD8+) cells did not lead to significant changes in these disease parameters. Depletion of all T cells (Thyl+) was also ineffective at modifying the number of infiltrating cells and the lung index score. However, identification of cell types in BAL showed that mice depleted of Thyl+ cells had a cellular influx that was almost exclusively neutrophilic throughout the instillation period, whereas control mice developed only a transient neutrophilic response to F. rectivirgula instillation, which was replaced by a recruitment of mononuclear cells, mostly macrophages. Also, depletion of Thyl+ cells before and during F. rectivirgula challenge had no effect on tumor necrosis factor-alpha levels in the BAL of treated mice (63 +/- 13 U/ml in anti-Thy1. 2 antibodies treated versus 52 +/- 10 U/ml in the BAL of control mice given F. rectivirgula).(ABSTRACT TRUNCATED AT 250 WORDS)

Actinomycetales Infections↗
PubMed1992

Transforming growth factor-beta is generated in the course of hypersensitivity pneumonitis: contribution to collagen synthesis.

Mice of the C57BL/6 strain were instilled with optimal doses (150 micrograms/day for 3 days/wk) of the thermophilic actinomycete Faeni rectivirgula (also known as Saccharopolyspora rectivirgula or Micropolyspora faeni) to induce a hypersensitivity pneumonitis inflammation that mimics the human disease affecting certain occupational groups. This mouse model was characterized by a very significant alveolitis (3-fold increase in bronchoalveolar lavage [BAL] cell number at 48 h and a 10-fold increase at 3 wk). Also, total lung transforming growth factor (TGF-beta) was shown to be elevated in treated mice as early as 1 wk after the first instillation and increased gradually to 2.5 micrograms/lung at 3 wk (approximately 0.3 microgram/lung in saline-instilled controls). Intranasal instillation with F. rectivirgula was also associated with very significant increases in lung fibroblast collagen synthesis, starting at 2 wk. BAL macrophages from mice instilled with F. rectivirgula were found to release significantly more TGF-beta upon in vitro stimulation with zymosan beads than did BAL macrophages from saline-instilled mice. Finally, we show that supernatants from activated BAL macrophages of mice given F. rectivirgula increased quite significantly collagen synthesis in normal mouse lung fibroblasts. This increase could be abrogated by treating conditioned medium with a rabbit antibody against TGF-beta. Collectively, these data suggest that TGF-beta is generated in the course of experimental mouse hypersensitivity pneumonitis and contributes significantly to collagen synthesis.

Alveolitis, Extrinsic Allergic↗
PubMed1992

Murine hypersensitivity pneumonitis: production and importance of colony-stimulating factors in the course of a lung inflammatory reaction.

The release of colony-stimulating factors (CSFs) and their contribution to the inflammatory response in the lungs of mice exposed by the intranasal route to the actinomycete Faeni rectivirgula (150 micrograms/day, 3 days/wk), an important thermophilic actinomycete that determines farmer's lung in humans, was examined. Bronchoalveolar lavages (BAL) and lung homogenates of normal mice or saline-instilled mice contained undetectable levels (less than 0.5 U/ml) of the cytokines interleukin-3 (IL-3), colony-stimulating factor-1 (CSF-1), and granulocyte/macrophage colony-stimulating factor (GM-CSF). Mice instilled with F. rectivirgula developed a CSF cytokine response early (24 h) after the instillation that increased and plateaued 2 wk later, and stayed high thereafter. Similarly, lung homogenates of F. rectivirgula-challenged mice contained significant levels of all three CSFs from 24 h after treatment until termination of the experiment. The offending agent itself, F. rectivirgula, was found to directly induce the secretion of IL-3 and GM-CSF from isolated mouse BAL cells and mouse splenocytes, at doses ranging from 1 to 100 micrograms/ml. This was not due to contaminating endotoxin, as inclusion of polymyxin B did not modify this release. Instillation of antibodies against the CSFs in mice challenged with F. rectivirgula did not modify the increase in BAL cell number determined by the challenge (11-fold increase in BAL cell number in F. rectivirgula-instilled mice at 3 wk, whether given anti-CSFs or not). Moreover, direct intratracheal infusion of CSFs (5,000 U of IL-3/CSF-1/GM-CSF) every week did not change the cellular response seen in challenged mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alveolitis, Extrinsic Allergic↗