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1.
Nutrients ; 15(22)2023 Nov 14.
Article in English | MEDLINE | ID: mdl-38004174

ABSTRACT

Between 2021 and 2023, the Scientific Council of Dietplus®, a group specialized in overweight and obesity management, conducted a clinical study on 170 volunteer subjects with a BMI > 29 Kg/m2 consecutively recruited. The Dietplus® program comprises nutritional education, intensive, personalized coaching, and consuming food supplements rich in plant derivatives. The aim of this study was to assess the effect of the Dietplus® program on biometric, behavioral, and biological parameters. A control group of 30 obese patients was followed for a similar 12-week period. Mean weight loss reached 9 ± 2.1 kg in the Dietplus® test group versus a 1 ± 0.1 kg weight gain in the control group. Excess weight loss reached 33 ± 13%, and fat mass loss was 7.6% (p < 0.001); waist circumference was reduced by 30%. Quality of Life, Nutriscore, and Prochaska di Clemente scale significantly improved (p < 0.001). Biological parameters showed substantial improvements in the carbohydrate profile and insulin resistance (HOMA index) and in the lipid profile with lower plasma triglyceride (p < 0.01) and VLDL (p < 0.01) concentrations. Inflammatory parameters (orosomucoid, ultrasensitive C-reactive protein, and PINI indices) were also substantially reduced. These results indicate a substantial benefit in subjects who followed the Dietplus® program. (Dietplus® 116 Rue Robert Bunsen, 57460 Behren-lès-Forbach, France is active in France Belgium and Spain. Plant Derived Food Supplements are produced in France). Indeed, improvements were observed in all biometric, behavioral, and metabolic parameters.


Subject(s)
Insulin Resistance , Quality of Life , Humans , Body Mass Index , Obesity/metabolism , Dietary Supplements , Weight Loss
2.
Cell Mol Life Sci ; 79(5): 260, 2022 Apr 27.
Article in English | MEDLINE | ID: mdl-35474501

ABSTRACT

Osteoarthritis (OA) synovial membrane is mainly characterized by low-grade inflammation, hyperplasia with increased cell proliferation and fibrosis. We previously underscored a critical role for CEMIP in fibrosis of OA cartilage. However, its role in OA synovial membrane remains unknown. An in vitro model with fibroblast-like synoviocytes from OA patients and an in vivo model with collagenase-induced OA mice were used to evaluate CEMIP-silencing effects on inflammation, hyperplasia and fibrosis. Our results showed that i. CEMIP expression was increased in human and mouse inflamed synovial membrane; ii. CEMIP regulated the inflammatory response pathway and inflammatory cytokines production in vitro and in vivo; iii. CEMIP induced epithelial to mesenchymal transition pathway and fibrotic markers in vitro and in vivo; iv. CEMIP increased cell proliferation and synovial hyperplasia; v. CEMIP expression was increased by inflammatory cytokines and by TGF-ß signaling; vi. anti-fibrotic drugs decreased CEMIP expression. All these findings highlighted the central role of CEMIP in OA synovial membrane development and underscored that targeting CEMIP could be a new therapeutic approach.


Subject(s)
Epithelial-Mesenchymal Transition , Hyaluronoglucosaminidase , Osteoarthritis , Animals , Cytokines/metabolism , Fibrosis , Humans , Hyaluronoglucosaminidase/metabolism , Hyperplasia/metabolism , Inflammation/pathology , Mice , Osteoarthritis/metabolism , Synovial Membrane/metabolism , Synovial Membrane/pathology
3.
J Clin Med ; 10(22)2021 Nov 16.
Article in English | MEDLINE | ID: mdl-34830613

ABSTRACT

Osteoarthritis (OA) is recognized as being a cellular senescence-linked disease. Intra-articular injections of glucocorticoids (GC) are frequently used in knee OA to treat synovial effusion but face controversies about toxicity. We investigated the influence of GC on cellular senescence hallmarks and senescence induction in fibroblast-like synoviocytes (FLS) from OA patients and mesenchymal stem cells (MSC). METHODS: Cellular senescence was assessed via the proliferation rate, ß-galactosidase staining, DNA damage and CKI expression (p21, p16INK4A). Experimental senescence was induced by irradiation. RESULTS: The GC prednisolone did not induce an apparent senescence phenotype in FLS, with even higher proliferation, no accumulation of ß-galactosidase-positive cells nor DNA damage and reduction in p21mRNA, only showing the enhancement of p16INK4A. Prednisolone did not modify experimental senescence induction in FLS, with no modulation of any senescence parameters. Moreover, prednisolone did not induce a senescence phenotype in MSC: despite high ß-galactosidase-positive cells, no reduction in proliferation, no DNA damage and no CKI enhancement was observed. CONCLUSIONS: We provide reassuring in vitro data about the use of GC regarding cellular senescence involvement in OA: the GC prednisolone did not induce a senescent phenotype in OA FLS (the proliferation ratio was even higher) and in MSC and did not worsen cellular senescence establishment.

5.
Int J Mol Sci ; 23(1)2021 Dec 31.
Article in English | MEDLINE | ID: mdl-35008858

ABSTRACT

An inflamed synovial membrane plays a major role in joint destruction and is characterized by immune cells infiltration and fibroblast proliferation. This proteomic study considers the inflammatory process at the molecular level by analyzing synovial biopsies presenting a histological inflammatory continuum throughout different arthritis joint diseases. Knee synovial biopsies were obtained from osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) or rheumatoid arthritis (RA; n = 8) patients. The histological inflammatory score was determined using a semi-quantitative scale based on synovial hyperplasia, lymphocytes, plasmocytes, neutrophils and macrophages infiltration. Proteomic analysis was performed by liquid chromatography-mass spectrometry (LC-MS/MS). Differentially expressed proteins were confirmed by immunohistochemistry. Out of the 1871 proteins identified and quantified by LC-MS/MS, 10 proteins (LAP3, MANF, LCP1, CTSZ, PTPRC, DNAJB11, EML4, SCARA5, EIF3K, C1orf123) were differentially expressed in the synovial membrane of at least one of the three disease groups (RA, OA and CPPA). Significant increased expression of the seven first proteins was detected in RA and correlated to the histological inflammatory score. Proteomics is therefore a powerful tool that provides a molecular pattern to the classical histology usually applied for synovitis characterization. Except for LCP1, CTSZ and PTPRC, all proteins have never been described in human synovitis.


Subject(s)
Arthritis/immunology , Arthritis/pathology , Proteins/metabolism , Synovial Membrane/immunology , Synovial Membrane/pathology , Aged , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Biopsy , Chondrocalcinosis , Female , Humans , Immunohistochemistry , Male , Mass Spectrometry , Middle Aged , Proteomics
6.
Cancers (Basel) ; 12(11)2020 Oct 31.
Article in English | MEDLINE | ID: mdl-33142864

ABSTRACT

Loss of skeletal muscle mass in cancer cachexia is recognized as a predictor of mortality. This study aimed to characterize the changes in the muscle secretome associated with cancer cachexia to gain a better understanding of the mechanisms involved and to identify secreted proteins which may reflect this wasting process. The changes in the muscle proteome of the C26 model were investigated by label-free proteomic analysis followed by a bioinformatic analysis in order to identify potentially secreted proteins. Multiple reaction monitoring and Western blotting were used to verify the presence of candidate proteins in the circulation. Our results revealed a marked increased muscular production of several acute phase reactants (APR: Haptoglobin, Serine protease inhibitor A3N, Complement C3, Serum amyloid A-1 protein) which are released in the circulation during C26 cancer cachexia. This was confirmed in other models of cancer cachexia as well as in cancer patients. Glucocorticoids and proinflammatory cytokines are responsible for an increased production of APR by muscle cells. Finally, their muscular expressions are strongly positively correlated with body weight loss as well as the muscular induction of atrogens. Our study demonstrates therefore a marked increased production of APR by the muscle in cancer cachexia.

7.
Immunity ; 46(3): 457-473, 2017 03 21.
Article in English | MEDLINE | ID: mdl-28329706

ABSTRACT

Living in a microbe-rich environment reduces the risk of developing asthma. Exposure of humans or mice to unmethylated CpG DNA (CpG) from bacteria reproduces these protective effects, suggesting a major contribution of CpG to microbe-induced asthma resistance. However, how CpG confers protection remains elusive. We found that exposure to CpG expanded regulatory lung interstitial macrophages (IMs) from monocytes infiltrating the lung or mobilized from the spleen. Trafficking of IM precursors to the lung was independent of CCR2, a chemokine receptor required for monocyte mobilization from the bone marrow. Using a mouse model of allergic airway inflammation, we found that adoptive transfer of IMs isolated from CpG-treated mice recapitulated the protective effects of CpG when administered before allergen sensitization or challenge. IM-mediated protection was dependent on IL-10, given that Il10-/- CpG-induced IMs lacked regulatory effects. Thus, the expansion of regulatory lung IMs upon exposure to CpG might underlie the reduced risk of asthma development associated with a microbe-rich environment.


Subject(s)
Chemotaxis, Leukocyte/immunology , DNA, Bacterial/immunology , Hypersensitivity/immunology , Macrophages, Alveolar/immunology , Respiratory Hypersensitivity/immunology , Animals , Disease Models, Animal , Flow Cytometry , Macrophage Activation/immunology , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Oligodeoxyribonucleotides/immunology , Spleen/immunology
8.
J Clin Invest ; 126(9): 3279-95, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27548519

ABSTRACT

Increases in eosinophil numbers are associated with infection and allergic diseases, including asthma, but there is also evidence that eosinophils contribute to homeostatic immune processes. In mice, the normal lung contains resident eosinophils (rEos), but their function has not been characterized. Here, we have reported that steady-state pulmonary rEos are IL-5-independent parenchymal Siglec-FintCD62L+CD101lo cells with a ring-shaped nucleus. During house dust mite-induced airway allergy, rEos features remained unchanged, and rEos were accompanied by recruited inflammatory eosinophils (iEos), which were defined as IL-5-dependent peribronchial Siglec-FhiCD62L-CD101hi cells with a segmented nucleus. Gene expression analyses revealed a more regulatory profile for rEos than for iEos, and correspondingly, mice lacking lung rEos showed an increase in Th2 cell responses to inhaled allergens. Such elevation of Th2 responses was linked to the ability of rEos, but not iEos, to inhibit the maturation, and therefore the pro-Th2 function, of allergen-loaded DCs. Finally, we determined that the parenchymal rEos found in nonasthmatic human lungs (Siglec-8+CD62L+IL-3Rlo cells) were phenotypically distinct from the iEos isolated from the sputa of eosinophilic asthmatic patients (Siglec-8+CD62LloIL-3Rhi cells), suggesting that our findings in mice are relevant to humans. In conclusion, our data define lung rEos as a distinct eosinophil subset with key homeostatic functions.


Subject(s)
Eosinophils/cytology , Lung/cytology , Adult , Aged , Allergens/immunology , Animals , Antigens, CD/metabolism , Dendritic Cells/cytology , Female , Homeostasis , Humans , Hypersensitivity/metabolism , Inflammation , Interleukin-5/metabolism , L-Selectin/metabolism , Male , Membrane Glycoproteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Middle Aged , Phagocytosis , Pyroglyphidae , Th2 Cells/cytology , Transcriptome
9.
J Control Release ; 187: 91-100, 2014 Aug 10.
Article in English | MEDLINE | ID: mdl-24845126

ABSTRACT

Inhalation aerosols offer a targeted therapy for respiratory diseases. However, the therapeutic efficacy of inhaled biopharmaceuticals is limited by the rapid clearance of macromolecules in the lungs. The aim of this research was to study the effects of the PEGylation of antibody fragments on their local residence time after administration to the respiratory tract. We demonstrate that the conjugation of a two-armed 40-kDa polyethylene glycol (PEG) chain to anti-interleukin-17A (IL-17A) F(ab')2 and anti-IL-13 Fab' greatly prolonged the presence of these fragments within the lungs of mice. The content of PEGylated antibody fragments within the lungs plateaued up to 4h post-delivery, whereas the clearance of unconjugated proteins started immediately after administration. Forty-eight hours post-delivery, F(ab')2 and Fab' contents in the lungs had decreased to 10 and 14% of the dose initially deposited, respectively. However, this value was 40% for both PEG40-F(ab')2 and PEG40-Fab'. The prolonged pulmonary residency of the anti-IL-17A PEG40-F(ab')2 translated into an improved efficacy in reducing lung inflammation in a murine model of house dust mite-induced lung inflammation. We demonstrate that PEGylated proteins were principally retained within the lung lumen rather than the nasal cavities or lung parenchyma. In addition, we report that PEG increased pulmonary retention of antibody fragments through mucoadhesion and escape from alveolar macrophages rather than increased hydrodynamic size or improved enzymatic stability. The PEGylation of proteins might find broad application in the local delivery of therapeutic proteins to diseased airways.


Subject(s)
Immunoglobulin Fab Fragments/administration & dosage , Immunoglobulin Fab Fragments/chemistry , Polyethylene Glycols/chemistry , Respiratory System/metabolism , Allergens/immunology , Animals , Bronchoalveolar Lavage Fluid , Female , Interleukin-13/immunology , Interleukin-17/immunology , Male , Mice , Mice, Inbred BALB C , Pneumonia/drug therapy , Pneumonia/metabolism , Pyroglyphidae/immunology
10.
J Immunol ; 189(8): 4135-43, 2012 Oct 15.
Article in English | MEDLINE | ID: mdl-22962682

ABSTRACT

A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness.


Subject(s)
ADAM Proteins/toxicity , Antigens, Dermatophagoides/administration & dosage , Bronchial Hyperreactivity/immunology , Inflammation Mediators/administration & dosage , ADAM Proteins/biosynthesis , ADAM Proteins/deficiency , ADAMTS Proteins , Animals , Antigens, Dermatophagoides/immunology , Bronchial Hyperreactivity/genetics , Bronchial Hyperreactivity/pathology , Disease Models, Animal , Humans , Immunophenotyping , Inflammation Mediators/antagonists & inhibitors , Inflammation Mediators/immunology , Male , Mice , Mice, 129 Strain , Mice, Knockout , Ovalbumin/administration & dosage , Ovalbumin/antagonists & inhibitors , Ovalbumin/immunology
11.
Am J Respir Cell Mol Biol ; 47(5): 709-17, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22904197

ABSTRACT

IL-13 is a prototypic T helper type 2 cytokine and a central mediator of the complex cascade of events leading to asthmatic phenotype. Indeed, IL-13 plays key roles in IgE synthesis, bronchial hyperresponsiveness, mucus hypersecretion, subepithelial fibrosis, and eosinophil infiltration. We assessed the potential efficacy of inhaled anti-IL-13 monoclonal antibody Fab' fragment on allergen-induced airway inflammation, hyperresponsiveness, and remodeling in an experimental model of allergic asthma. Anti-IL-13 Fab' was administered to mice as a liquid aerosol generated by inExpose inhalation system in a tower allowing a nose-only exposure. BALB/c mice were treated by PBS, anti-IL-13 Fab', or A33 Fab' fragment and subjected to ovalbumin exposure for 1 and 5 weeks (short-term and long-term protocols). Our data demonstrate a significant antiasthma effect after nebulization of anti-IL-13 Fab' in a model of asthma driven by allergen exposure as compared with saline and nonimmune Fab fragments. In short- and long-term protocols, administration of the anti-IL-13 Fab' by inhalation significantly decreased bronchial responsiveness to methacholine, bronchoalveolar lavage fluid eosinophilia, inflammatory cell infiltration in lung tissue, and many features of airway remodeling. Levels of proinflammatory mediators and matrix metalloprotease were significantly lower in lung parenchyma of mice treated with anti-IL-13 Fab'. These data demonstrate that an inhaled anti-IL-13 Fab' significantly reduces airway inflammation, hyperresponsiveness, and remodeling. Specific neutralization of IL-13 in the lungs using an inhaled anti-IL-13 Fab' could represent a novel and effective therapy for the treatment of asthma.


Subject(s)
Anti-Asthmatic Agents/administration & dosage , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Asthma/drug therapy , Immunoglobulin Fab Fragments/administration & dosage , Administration, Inhalation , Airway Remodeling/drug effects , Airway Resistance/drug effects , Allergens/immunology , Animals , Asthma/immunology , Bronchoalveolar Lavage Fluid , Bronchoconstrictor Agents/pharmacology , Inflammation Mediators/metabolism , Interleukin-13/immunology , Lung/drug effects , Lung/pathology , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Methacholine Chloride/pharmacology , Mice , Mice, Inbred BALB C , Nebulizers and Vaporizers , Ovalbumin/immunology , STAT6 Transcription Factor/metabolism
12.
J Proteome Res ; 10(9): 4291-301, 2011 Sep 02.
Article in English | MEDLINE | ID: mdl-21751807

ABSTRACT

As asthma physiopathology is complex and not fully understood to date; it is expected that new key mediators are still to be unveiled in this disease. The main objective of this study was to discover potential new target proteins with a molecular weight >20 kDa by using two-dimensional differential in-gel electrophoresis (2D-DIGE) on lung parenchyma extracts from control or allergen-exposed mice (ovalbumin). Two different mouse models leading to the development of acute airway inflammation (5 days allergen exposure) and airway remodeling (10 weeks allergen exposure) were used. This experimental setting allowed the discrimination of 33 protein spots in the acute inflammation model and 31 spots in the remodeling model displaying a differential expression. Several proteins were then identified by MALDI-TOF/TOF MS. Among those differentially expressed proteins, PDIA6, GRP78, Annexin A6, hnRPA3, and Enolase display an increased expression in lung parenchyma from mice exposed to allergen for 5 days. Conversely, Apolipoprotein A1 was shown to be decreased after allergen exposure in the same model. Analysis on lung parenchyma of mice exposed to allergens for 10 weeks showed decreased calreticulin levels. Changes in the levels of those different mediators were confirmed by Western blot and immunohistochemical analysis. Interestingly, alveolar macrophages isolated from lungs in the acute inflammation model displayed enhanced levels of GRP78. Moreover, intratracheal instillation of anti-GRP78 siRNA in allergen-exposed animals led to a decrease in eosinophilic inflammation and bronchial hyperresponsiveness. This study unveils new mediators of potential importance that are up- and down-regulated in asthma. Among up-regulated mediators, GRP-78 appears as a potential new therapeutic target worthy of further investigations.


Subject(s)
Asthma/metabolism , Drug Discovery/methods , Proteome/analysis , Proteomics , Two-Dimensional Difference Gel Electrophoresis , Airway Remodeling/physiology , Allergens/immunology , Animals , Blotting, Western , Disease Models, Animal , Drug Delivery Systems , Endoplasmic Reticulum Chaperone BiP , Heat-Shock Proteins/metabolism , Immunohistochemistry , Macrophages, Alveolar/metabolism , Male , Mice , Pneumonia/metabolism , Proteome/chemistry , Proteome/metabolism , Reproducibility of Results , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
13.
Eur J Immunol ; 41(2): 380-91, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21268008

ABSTRACT

Asthma is a complex disease linked to various pathophysiological events including the activity of proteinases. The multifunctional A disintegrin and metalloproteinases (ADAMs) displaying the ability to cleave membrane-bound mediators or cytokines appear to be key mediators in various inflammatory processes. In the present study, we investigated ADAM-8 expression and production in a mouse model of allergen-induced airway inflammation. In allergen-exposed animals, increased expression of ADAM-8 was found in the lung parenchyma and in DC purified from the lungs. The potential role of ADAM-8 in the development of allergen-induced airway inflammation was further investigated by the use of an anti-ADAM-8 antibody and ADAM-8 knockout animals. We observed a decrease in allergen-induced acute inflammation both in BALF and the peribronchial area in anti-ADAM-8 antibody-treated mice and in ADAM-8-deficient mice (ADAM-8(-/-) ) after allergen exposure. ADAM-8 depletion led to a significant decrease of the CD11c(+) lung DC. We also report lower levels of CCL11 and CCL22 production in antibody-treated mice and ADAM-8- deficient mice that might be explained by decreased eosinophilic inflammation and lower numbers of DC, respectively. In conclusion, ADAM-8 appears to favour allergen-induced acute airway inflammation by promoting DC recruitment and CCL11 and CCL22 production.


Subject(s)
ADAM Proteins/metabolism , Antigens, CD/metabolism , Asthma/metabolism , Membrane Proteins/metabolism , ADAM Proteins/antagonists & inhibitors , ADAM Proteins/genetics , ADAM Proteins/immunology , Animals , Antibodies/immunology , Antibodies/pharmacology , Antibodies/therapeutic use , Antigens, CD/genetics , Antigens, CD/immunology , Asthma/immunology , Asthma/pathology , Bronchoalveolar Lavage Fluid/cytology , Cell Count , Cell Movement/genetics , Cell Movement/immunology , Chemokine CCL11/metabolism , Chemokine CCL22/metabolism , Cytokines/metabolism , Eosinophils/metabolism , Eosinophils/pathology , Gene Expression/genetics , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Inflammation/prevention & control , Lung/drug effects , Lung/metabolism , Lung/pathology , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/pathology , Male , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/immunology , Vaccination
14.
Am J Respir Cell Mol Biol ; 43(3): 286-95, 2010 Sep.
Article in English | MEDLINE | ID: mdl-19843707

ABSTRACT

Matrix metalloproteinases (MMPs) recently appeared as key regulators of inflammation, allowing the recruitment and clearance of inflammatory cells and modifying the biological activity of many peptide mediators by cleavage. MMP-19 is newly described, and it preferentially cleaves matrix proteins such as collagens and tenascin-C. The role of MMP-19 in asthma has not been described to date. The present study sought to assess the expression of MMP-19 in a murine asthma model, and to address the biological effects of MMP-19 deficiency in mice. Allergen-exposed, wild-type mice displayed increased expression of MMP-19 mRNA and an increased number of MMP-19-positive cells in the lungs, as detected by immunohistochemistry. After an allergen challenge of MMP-19 knockout (MMP-19(-/-)) mice, exacerbated eosinophilic inflammation was detected in bronchoalveolar lavage fluid and bronchial tissue, along with increased airway responsiveness to methacholine. A shift toward increased T helper-2 lymphocyte (Th2)-driven inflammation in MMP-19(-/-) mice was demonstrated by (1) increased numbers of cells expressing the IL-33 receptor T(1)/ST(2) in lung parenchyma, (2) increased IgG(1) levels in serum, and (3) higher levels of IL-13 and eotaxin-1 in lung extracts. Tenascin-C was found to accumulate in peribronchial areas of MMP-19(-/-) after allergen challenges, as assessed by Western blot and immunohistochemistry analyses. We conclude that MMP-19 is a new mediator in asthma, preventing tenascin-C accumulation and directly or indirectly controlling Th2-driven airway eosinophilia and airway hyperreactivity. Our data suggest that MMP-19 may act on Th2 inflammation homeostasis by preventing the accumulation of tenascin protein.


Subject(s)
Allergens/pharmacology , Asthma/metabolism , Eosinophils/metabolism , Lung/metabolism , Matrix Metalloproteinases, Secreted/deficiency , Tenascin/metabolism , Adult , Animals , Asthma/pathology , Blotting, Western , Bone Marrow/metabolism , Bronchial Hyperreactivity/immunology , Bronchial Hyperreactivity/metabolism , Bronchoalveolar Lavage Fluid , Cells, Cultured , Eosinophils/immunology , Eosinophils/pathology , Female , Flow Cytometry , Humans , Immunoenzyme Techniques , Interleukin-13/pharmacology , Lung/pathology , Male , Mice , Mice, Knockout , Myocytes, Smooth Muscle/metabolism , RNA, Messenger/genetics , Respiratory System/metabolism , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/metabolism , Tenascin/genetics , Th2 Cells/metabolism
15.
Respir Res ; 10: 127, 2009 Dec 24.
Article in English | MEDLINE | ID: mdl-20034386

ABSTRACT

Lungs are exposed to the outside environment and therefore to toxic and infectious agents or allergens. This may lead to permanent activation of innate immune response elements. A Disintegrin And Metalloproteinases (ADAMs) and ADAMs with Thrombospondin motifs (ADAMTS) are proteinases closely related to Matrix Metalloproteinases (MMPs). These multifaceted molecules bear metalloproteinase and disintegrin domains endowing them with features of both proteinases and adhesion molecules. Proteinases of the ADAM family are associated to various physiological and pathological processes and display a wide spectrum of biological effects encompassing cell fusion, cell adhesion, "shedding process", cleavage of various substrates from the extracellular matrix, growth factors or cytokines... This review will focus on the putative roles of ADAM/ADAMTS proteinases in airway diseases such as asthma and COPD.


Subject(s)
ADAM Proteins/metabolism , Lung Diseases/metabolism , Lung/metabolism , Models, Biological , Animals , Humans
16.
Inflamm Res ; 58(12): 845-54, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19506803

ABSTRACT

OBJECTIVE: Animal models of asthma mimic major features of human disease. Since the genetic background of experimental animals might affect hyperresponsiveness and inflammation, we studied its potential influence and the mechanisms leading to differences in strains. METHODS: We applied a mouse model of allergic asthma to BALB/c and C57BL/6 mice. RESULTS: BALB/c mice displayed greater levels of airway reactivity to methacholine than C57BL/6 mice. Moreover, BALB/c mice exhibited higher numbers of mast cells in lung tissue when compared to C57BL/6. On the contrary, eosinophil and neutrophil counts in bronchoalveolar lavage fluid (BALF) as well as peribronchial eosinophilia were greater in C57BL/6. IL (Interleukin)-4, IL-5, IL-13, and CCL11 levels measured in whole-lung extracts were higher in BALB/c, while, in sharp contrast, CCL11 and CCL5 levels were higher in BALF of C57BL/6 mice. CONCLUSIONS: We observed phenotypic differences between C57BL/6 and BALB/c mice in an asthma model with different distributions of pro-inflammatory cytokines and inflammatory cells.


Subject(s)
Asthma/immunology , Bronchial Hyperreactivity/immunology , Cytokines , Disease Models, Animal , Inflammation/immunology , Mice, Inbred BALB C/immunology , Mice, Inbred C57BL/immunology , Animals , Asthma/genetics , Bronchoalveolar Lavage Fluid/cytology , Bronchoalveolar Lavage Fluid/immunology , Cytokines/biosynthesis , Cytokines/immunology , Humans , Immunoglobulin E/immunology , Lung/cytology , Lung/immunology , Lung/pathology , Methacholine Chloride/administration & dosage , Methacholine Chloride/immunology , Mice , Mice, Inbred BALB C/genetics , Mice, Inbred C57BL/genetics , Ovalbumin/immunology
17.
Proteomics ; 9(8): 2163-70, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19322781

ABSTRACT

Asthma is a complex inflammatory disease of airways. A network of reciprocal interactions between inflammatory cells, peptidic mediators, extracellular matrix components, and proteases is thought to be involved in the installation and maintenance of asthma-related airway inflammation and remodeling. To date, new proteic mediators displaying significant activity in the pathophysiology of asthma are still to be unveiled. The main objective of this study was to uncover potential target proteins by using surface-enhanced laser desorption/ionization-time of flight-mass spectrometry (SELDI-TOF-MS) on lung samples from mouse models of allergen-induced airway inflammation and remodeling. In this model, we pointed out several protein or peptide peaks that were preferentially expressed in diseased mice as compared to controls. We report the identification of different five proteins: found inflammatory zone 1 or RELM alpha (FIZZ-1), calcyclin (S100A6), clara cell secretory protein 10 (CC10), Ubiquitin, and Histone H4.


Subject(s)
Asthma/metabolism , Biomarkers/metabolism , Bronchi/metabolism , Inflammation/metabolism , Animals , Asthma/physiopathology , Bronchi/chemistry , Bronchi/physiopathology , Cell Cycle Proteins/metabolism , Histones/metabolism , Inflammation/physiopathology , Intercellular Signaling Peptides and Proteins/metabolism , Mass Spectrometry , Mice , Protein Array Analysis , S100 Calcium Binding Protein A6 , S100 Proteins/metabolism , Ubiquitin/metabolism , Uteroglobin/metabolism
18.
Am J Respir Cell Mol Biol ; 41(4): 449-58, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19213876

ABSTRACT

Among proteases, metalloproteases are implicated in tissue remodeling, as shown in numerous diseases including allergy. ADAMs (A Disintegrin And Metalloprotease) metalloproteases are implicated in physiologic processes such as cytokine and growth factor shedding, cell migration, adhesion, or repulsion. Our aim was to measure ADAM-12 expression in airway epithelium and to define its role during the allergic response. To raise this question, we analyzed the ADAM-12 expression ex vivo after allergen exposure in patients with allergic rhinitis and in vitro in cultured primary human airway epithelial cells (AEC). Clones of BEAS-2B cells transfected with the full-length form of ADAM-12 were generated to study the consequences of ADAM-12 up-regulation on AEC function. After allergen challenge, a strong increase of ADAM-12 expression was observed in airway epithelium from patients with allergic rhinitis but not from control subjects. In contrast with the other HB-epidermal growth factor sheddases, ADAM-10 and -17, TNF-alpha in vitro increased the expression of ADAM-12 by AEC, an effect amplified by IL-4 and IL-13. Up-regulation of ADAM-12 in AEC increased the expression of alpha3 and alpha4 integrins and to the modulation of cell migration on fibronectin but not on collagen. Moreover, overexpression of ADAM-12 in BEAS-2B enhanced the secretion of CXCL1 and CXCL8 and their capacity to recruit neutrophils. CD47 was strongly decreased by ADAM-12 overexpression, a process associated with a reduced adhesion of neutrophils. These effects were mainly dependent on epidermal growth factor receptor activation. In summary, ADAM-12 is produced during allergic reaction by AEC and might increase neutrophil recruitment within airway mucosa.


Subject(s)
ADAM Proteins/physiology , Bronchi/pathology , Membrane Proteins/physiology , Neutrophils/physiology , Rhinitis, Allergic, Perennial/pathology , Rhinitis, Allergic, Seasonal/pathology , ADAM Proteins/genetics , ADAM12 Protein , Allergens/pharmacology , CD47 Antigen/biosynthesis , CD47 Antigen/genetics , Cell Adhesion , Cells, Cultured/enzymology , Cells, Cultured/pathology , Chemokine CXCL1/metabolism , Chemotaxis, Leukocyte/physiology , Epithelial Cells/enzymology , ErbB Receptors/physiology , Gene Expression Regulation , Humans , Integrins/biosynthesis , Integrins/genetics , Interleukin-8/metabolism , Membrane Proteins/genetics , Recombinant Fusion Proteins/physiology , Transfection , Tumor Necrosis Factor-alpha/pharmacology
19.
Cancer Res ; 68(22): 9541-50, 2008 Nov 15.
Article in English | MEDLINE | ID: mdl-19010931

ABSTRACT

ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorage-independent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1-overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor beta (TGF-beta), and interleukin-1beta (IL-1beta). Neutralizing antibodies against TGF-beta and IL-1beta blocked the chemotactic effect of medium conditioned by ADAMTS-1-expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1-induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling.


Subject(s)
ADAM Proteins/physiology , Neoplasms/etiology , ADAM Proteins/genetics , ADAMTS1 Protein , Animals , Chemotaxis , Collagen/biosynthesis , Fibroblasts/physiology , Humans , Matrix Metalloproteinase 13/physiology , Mice , Mice, SCID , RNA, Messenger/analysis , Rats , Stromal Cells/physiology , Transfection
20.
Mol Med ; 12(7-8): 171-9, 2006.
Article in English | MEDLINE | ID: mdl-17088949

ABSTRACT

ADAMs (a disintegrin and metalloprotease) constitute a family of cell surface proteins containing disintegrin and metalloprotease domains which associate features of adhesion molecules and proteases. ADAMTSs (a disintegrin and metalloprotease with thrombospondin motifs) bear thrombospondin type I motifs in C-terminal extremity, and most of them are secreted proteins. Because genetic studies have shown that ADAM-33 gene polymorphisms are associated with asthma, we designed this study to assess mRNA expression profile of several ADAM and ADAMTS proteases in sputum from patients with asthma and to investigate the relationship between expression of these proteases and asthma-associated inflammation and airway obstruction. mRNA expression profile of selected ADAM and ADAMTS proteinases (ADAM-8, -9, -10, -12, -15, -17, and -33; ADAMTS-1, -2, -15, -16, -17, -18, and -19), their physiological inhibitors TIMP-1 and TIMP-3, and RECK, a membrane-anchored MMP activity regulator, was obtained by RT-PCR analysis performed on cells collected by sputum induction from 21 patients with mild to moderate asthma and 17 healthy individuals. mRNA levels of ADAM-8, ADAM-9, ADAM-12, TIMP-1, and TIMP-3 were significantly increased, whereas mRNA levels coding for ADAMTS-1, ADAMTS-15, and RECK were significantly decreased in patients with asthma compared with control patients. ADAM-8 expression was negatively correlated with the forced expiratory volume at the first second (FEV(1)) (r = -0.57, P < 0.01), whereas ADAMTS-1 and RECK expressions were positively correlated to FEV(1) (r = 0.45, P < 0.05, and r = 0.55, P = 0.01, respectively). We conclude that expression of ADAMs and ADAMTSs and their inhibitors is modulated in airways from patients with asthma and that these molecules may play a role in the pathogenesis of asthma.


Subject(s)
ADAM Proteins/antagonists & inhibitors , ADAM Proteins/genetics , Asthma/genetics , Asthma/metabolism , Sputum/metabolism , Tissue Inhibitor of Metalloproteinases/genetics , ADAM Proteins/metabolism , Adult , Aged , Blotting, Western , Case-Control Studies , Cell Count , Female , GPI-Linked Proteins , Gene Expression Regulation , Humans , Immunohistochemistry , Inflammation , Lipopolysaccharides/metabolism , Male , Membrane Glycoproteins/metabolism , Middle Aged , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, IgE/immunology , Reverse Transcriptase Polymerase Chain Reaction , Sputum/cytology , Subcellular Fractions , Tissue Inhibitor of Metalloproteinases/metabolism
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