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1.
Am J Respir Cell Mol Biol ; 68(1): 62-74, 2023 01.
Article in English | MEDLINE | ID: mdl-36108173

ABSTRACT

The gain-of-function minor allele of the MUC5B (mucin 5B, oligomeric mucus/gel-forming) promoter (rs35705950) is the strongest risk factor for idiopathic pulmonary fibrosis (IPF), a devastating fibrotic lung disease that leads to progressive respiratory failure in adults. We have previously demonstrated that Muc5b overexpression in mice worsens lung fibrosis after bleomycin exposure and have hypothesized that excess Muc5b promotes endoplasmic reticulum (ER) stress and apoptosis, stimulating fibrotic lung injury. Here, we report that ER stress pathway members ATF4 (activating transcription factor 4) and ATF6 coexpress with MUC5B in epithelia of the distal IPF airway and honeycomb cyst and that this is more pronounced in carriers of the gain-of-function MUC5B promoter variant. Similarly, in mice exposed to bleomycin, Muc5b expression is temporally associated with markers of ER stress. Using bulk and single-cell RNA sequencing in bleomycin-exposed mice, we found that pathologic ER stress-associated transcripts Atf4 and Ddit3 (DNA damage inducible transcript 3) were elevated in alveolar epithelia of SFTPC-Muc5b transgenic (SFTPC-Muc5bTg) mice relative to wild-type (WT) mice. Activation of the ER stress response inhibits protein translation for most genes by phosphorylation of Eif2α (eukaryotic translation initiation factor 2 alpha), which prevents guanine exchange by Eif2B and facilitates translation of Atf4. The integrated stress response inhibitor (ISRIB) facilitates interaction of phosphorylated Eif2α with Eif2B, overcoming translation inhibition associated with ER stress and reducing Atf4. We found that a single dose of ISRIB diminished Atf4 translation in SFTPC-Muc5bTg mice after bleomycin injury. Moreover, ISRIB resolved the exaggerated fibrotic response of SFTPC-Muc5bTg mice to bleomycin. In summary, we demonstrate that MUC5B and Muc5b expression is associated with pathologic ER stress and that restoration of normal translation with a single dose of ISRIB promotes lung repair in bleomycin-injured Muc5b-overexpressing mice.


Subject(s)
Idiopathic Pulmonary Fibrosis , Mucin-5B , Mice , Animals , Mucin-5B/genetics , Mucin-5B/metabolism , Eukaryotic Initiation Factor-2B , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/metabolism , Endoplasmic Reticulum Stress , Bleomycin
2.
Am J Physiol Lung Cell Mol Physiol ; 321(2): L440-L450, 2021 08 01.
Article in English | MEDLINE | ID: mdl-34160296

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF, yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis 3 wk after intratracheal bleomycin administration. Although we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.


Subject(s)
Bleomycin/adverse effects , Gene Expression Regulation/drug effects , Idiopathic Pulmonary Fibrosis , Mucin-5B , Respiratory Mucosa , Animals , Bleomycin/pharmacology , Idiopathic Pulmonary Fibrosis/chemically induced , Idiopathic Pulmonary Fibrosis/genetics , Idiopathic Pulmonary Fibrosis/metabolism , Lung Injury/chemically induced , Lung Injury/genetics , Lung Injury/metabolism , Lung Injury/pathology , Male , Mice , Mucin-5B/biosynthesis , Mucin-5B/genetics , Respiratory Mucosa/metabolism , Respiratory Mucosa/pathology
4.
Transfus Clin Biol ; 26(4): 356-358, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31262628

ABSTRACT

We report the case of a French woman with acquired von Willebrand syndrome who presents recurrent subarachnoid and intra-cerebral hemorrhage since 2012. She had no family or personal bleeding history. In the biologic explorations, APTT was abnormally high with no anticoagulant drugs (it was normal, historically). Two monoclonal IgG and IgM kappa proteins were detected without any lymphoproliferative disorder. Intravenous infusion of immunoglobulin is very effective in AVWS with immunoglobulin G monoclonal gammapathie of undetermined significance. We had a satisfactory correction of coagulation factors for about 30 days. The exploration of APTT is surely essential for the diagnosis and treatment.


Subject(s)
Cerebral Hemorrhage/etiology , Monoclonal Gammopathy of Undetermined Significance/immunology , von Willebrand Diseases/diagnosis , Aged , Autoantibodies/immunology , Blood Coagulation Tests , Cerebral Hemorrhage/diagnostic imaging , Cerebral Hemorrhage/prevention & control , Epistaxis/etiology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin M/blood , Immunoglobulin kappa-Chains/blood , Immunoglobulins, Intravenous/therapeutic use , Magnetic Resonance Imaging , Monoclonal Gammopathy of Undetermined Significance/complications , Neuroimaging , Paraproteins/analysis , Recurrence , Subarachnoid Hemorrhage/diagnostic imaging , Subarachnoid Hemorrhage/etiology , von Willebrand Diseases/etiology , von Willebrand Diseases/immunology , von Willebrand Diseases/therapy , von Willebrand Factor/therapeutic use
5.
Oncogene ; 36(14): 2030-2044, 2017 04 06.
Article in English | MEDLINE | ID: mdl-27721404

ABSTRACT

The predisposition of patients with Hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) involves components of viral infection, inflammation and time. The development of multifocal, genetically distinct tumours is suggestive of a field defect affecting the entire liver. The molecular susceptibility mediating such a field defect is not understood. One potential mediator of long-term cellular reprogramming is heritable (epigenetic) regulation of transcription, exemplified by DNA methylation. We studied epigenetic and transcriptional changes in HCV-infected livers in comparison with control, uninfected livers and HCC, allowing us to identify pre-neoplastic epigenetic and transcriptional events. We find the HCV-infected liver to have a pattern of acquisition of DNA methylation targeted to candidate enhancers active in liver cells, enriched for the binding sites of the FOXA1, FOXA2 and HNF4A transcription factors. These enhancers can be subdivided into those proximal to genes implicated in liver cancer or to genes involved in stem cell development, the latter distinguished by increased CG dinucleotide density and polycomb-mediated repression, manifested by the additional acquisition of histone H3 lysine 27 trimethylation (H3K27me3). Transcriptional studies on our samples showed that the increased DNA methylation at enhancers was associated with decreased local gene expression, results validated in independent samples from The Cancer Genome Atlas. Pharmacological depletion of H3K27me3 using the EZH2 inhibitor GSK343 in HepG2 cells suppressed cell growth and also revealed that local acquired DNA methylation was not dependent upon the presence of polycomb-mediated repression. The results support a model of HCV infection influencing the binding of transcription factors to cognate sites in the genome, with consequent local acquisition of DNA methylation, and the added repressive influence of polycomb at a subset of CG-dense cis-regulatory sequences. These epigenetic events occur before neoplastic transformation, resulting in what may be a pharmacologically reversible epigenetic field defect in HCV-infected liver.


Subject(s)
Epigenesis, Genetic , Hepacivirus/physiology , Hepatitis C/complications , Liver/virology , Polycomb-Group Proteins/metabolism , Precancerous Conditions , Promoter Regions, Genetic , Binding Sites/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/virology , DNA Methylation/genetics , Gene Expression Regulation, Neoplastic , Hep G2 Cells , Hepatitis C/genetics , Hepatitis C/metabolism , Humans , Liver/metabolism , Liver/pathology , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Liver Neoplasms/virology , Mutation/physiology , Precancerous Conditions/genetics , Precancerous Conditions/metabolism , Precancerous Conditions/pathology , Precancerous Conditions/virology , Promoter Regions, Genetic/genetics , Protein Binding , Transcription, Genetic
9.
Contact Dermatitis ; 2(6): 301-4, 1976 Dec.
Article in English | MEDLINE | ID: mdl-1032122

ABSTRACT

This is a report of two patients suspected of having allergic dermato-conjunctivitis due to corticosteroids. Both were tested with the constituents of the ointments they were using, that is, corticosteroids, antibacterial agents, preservatives, and other active ingredients of the ointment bases. Both patients showed positive allergic patch test reactions to the respective corticosteroid betamethasone valerate, and one to hydrocortisone, neomycin, and a rubber additive. The importance of routine patch testing in ophthalmic practice to detect sensitizers in cases of allergy is mentioned. Hydrocortisone (25%) in petrolatum is recommended for patch testing.


Subject(s)
Anti-Inflammatory Agents/adverse effects , Conjunctivitis/etiology , Dermatitis, Contact/etiology , Administration, Topical , Aged , Dermatitis, Atopic/etiology , Female , Folliculitis/drug therapy , Glucocorticoids , Humans , Hydrocortisone , Male , Middle Aged , Neomycin/adverse effects , Patch Tests , Rubber/adverse effects , Skin Ulcer/drug therapy
10.
Contact Dermatitis ; 2(3): 147-50, 1976 Jun.
Article in English | MEDLINE | ID: mdl-139271

ABSTRACT

A patient with chronic open-angle glaucoma was suspected of having allergic dermatitis and conjunctivitis to epinephrine. He was tested with epinephrine and other active substances, the preservatives and antioxidants usually used in the preparation of eye drops. He was also tested with other possible contactants with which he had had contact. The patient showed positive allergic patch test reactions to the chloride solution of epinephrine. The patient showed an unexpected positive reaction when tested with di-isopropyl fluorophosphate (DFP). The importance of routine patch testing in ophthalmic practice to detect sensitizers in cases of contact allergy is stressed.


Subject(s)
Conjunctivitis/chemically induced , Dermatitis, Contact/etiology , Drug Eruptions/etiology , Epinephrine/adverse effects , Aged , Drug Eruptions/diagnosis , Epinephrine/therapeutic use , Glaucoma/drug therapy , Humans , Male , Patch Tests
11.
Br J Vener Dis ; 53(2): 88-92, 1977 Apr.
Article in English | MEDLINE | ID: mdl-870145

ABSTRACT

Chlamydia trachomatis was isolated from 26% of urethral swabs taken from 509 men with urethritis. The highest yield of 68% was obtained from a selected group of men with nonspecific urethritis (NSU) who had a frank urethral discharge. This is a higher than in previous reports, and is significantly higher than the isolation of C. trachomatis from men with less severe urethritis. The higher yield was similar to C. trachomatis isolation rates reported among patients with severe trachoma in hyperendemic areas. Men with a previous history of NSU had low isolation rates. Overall, 30% of 385 men with NSU had positive chlamydial culture results, 7% of 59 men with gonococcal urethritis alone were Chlamydia-positive, 15% of 59 men with gonorrhoea followed by NSU (post-gonococcal urethritis) were Chlamydia-positive, and only 3% of 61 men without urethritis harboured Chlamydia. Swabs taken from the cervical os of 28 of 108 female contacts of men with NSU had a positive result for C. trachomatis. Significantly more pairs of sexual partners had the same chlamydial culture result than had different results. The chlamydial isolation rate was higher among men admitting a casual sexual contact than in men claiming only regular partnerships. The findings provide further evidence for the sexual transmission of C. trachomatis and for its aetiological role in NSU.


Subject(s)
Chlamydia trachomatis/isolation & purification , Urethra/microbiology , Chlamydia Infections/microbiology , Chlamydia Infections/transmission , Humans , Male , Urethritis/microbiology
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