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4.
Respiration ; 99(4): 307-315, 2020.
Article in English | MEDLINE | ID: mdl-32222710

ABSTRACT

BACKGROUND: Genome-wide association studies (GWAS) have accelerated our understanding of the genetic underpinnings of chronic obstructive pulmonary disease (COPD); however, GWAS populations have typically consisted of European descent, with ∼1% of Latin American ancestry. OBJECTIVE: To overcome this limitation, we conducted a GWAS in a rural Chilean population with increased COPD risk to investigate genetic variation of COPD risk in this understudied minority population. METHOD: We carried out a case-control study of 214 COPD patients (defined by the GOLD criteria) and 193 healthy controls in Talca, Chile. DNA was extracted from venous blood and genotyped on the Illumina Global Screening Array (n = 754,159 markers). After exclusion based on Hardy-Weinberg equilibrium (p ≤ 0.001), call rates (<95%), and minor allele frequencies (<0.5%) in controls, 455,564 markers were available for logistic regression. RESULTS: PRDM15 rs1054761 C allele (p = 2.22 × 10-7) was associated with decreased COPD risk. Three PRDM15 SNPs located on chromosome 21 were significantly associated with COPD risk (p < 10-6). Two of these SNPs, rs1054761 and rs4075967, were located on a noncoding transcript variant region of the gene. CONCLUSION: PRDM15 overexpression may play a role in the B-cell dysregulation in COPD pathogenesis. To the best of our knowledge, the association between PRDM15 and COPD risk was not previously found in GWAS studies in largely European populations, highlighting the importance of investigating novel variants associated with COPD risk among ethnically diverse populations.


Subject(s)
DNA-Binding Proteins/genetics , Pulmonary Disease, Chronic Obstructive/genetics , Transcription Factors/genetics , Aged , Air Pollution, Indoor/statistics & numerical data , Biomass , Case-Control Studies , Chile/epidemiology , Female , Forced Expiratory Volume , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Logistic Models , Male , Polymorphism, Single Nucleotide , Pulmonary Diffusing Capacity , Rural Population , Severity of Illness Index , Smoking/epidemiology , Vital Capacity
5.
PLoS One ; 14(7): e0219349, 2019.
Article in English | MEDLINE | ID: mdl-31260505

ABSTRACT

[This corrects the article DOI: 10.1371/journal.pone.0217803.].

6.
PLoS One ; 14(6): e0217803, 2019.
Article in English | MEDLINE | ID: mdl-31170225

ABSTRACT

COPD patients are prone to acute infectious exacerbations that impair their quality of life and hamper prognosis. The purpose of the present study was to investigate the in situ IFN-ß response in the lungs of stable COPD and non-COPD patients. Lung samples from 70 subjects (9 control never smokers, 19 control smokers without COPD, 21 patients with moderate COPD and 21 patients with very severe COPD) were studied for the expression of IFN-ß, its main transcription factor, IRF-7, and two products of its autocrine function, namely RIG-I and MDA-5, by immunohistochemical techniques and quantitative real-time PCR. IFN-ß, IRF-7, RIG-I and MDA-5 were widely detected in most lung cell types. In epithelial tissues and alveolar macrophages, IFN-ß and IRF-7 labeling scores were decreased up to 65% and 74%, respectively, for COPD patients, paralleling an analogous reduction (43% and 65%, respectively) in the amount of their lung mRNA. Moreover, this decreased production of IFN-ß in COPD patients correlated with a similar decrease in the expression of RIG-I and MDA-5, two essential members of the innate immune system. Our study indicates that most lung cells from stable COPD patients show a constitutive decreased expression of IFN-ß, IRF-7, RIG-I and MDA-5, suggesting that this deficiency is the main cause of their acute viral exacerbations.


Subject(s)
Interferon-beta/metabolism , Lung/metabolism , Pulmonary Disease, Chronic Obstructive/metabolism , DEAD Box Protein 58/metabolism , Female , Humans , Interferon Regulatory Factor-7/metabolism , Interferon-Induced Helicase, IFIH1/metabolism , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/pathology , Receptors, Immunologic , Signal Transduction
7.
Rev Med Chil ; 143(9): 1162-71, 2015 Sep.
Article in Spanish | MEDLINE | ID: mdl-26530199

ABSTRACT

Approximately 3 million people in the world die every year as a consequence of COPD, which is associated with an abnormal inflammatory response of the lung to noxious particles and gases. This inflammatory pattern causes pathological changes leading to a narrowing of small airways and destruction of lung parenchyma, also known as emphysema. Classically, these changes were associated to macrophages and neutrophils, although T CD8+ lymphocytes were latter added to the equation to explain the origin of emphysematous lesions. However, in recent years, multiple evidences have arisen indicating that inflammatory response in COPD is much more complex. These findings point to a key role for mast cells, dendritic cells, T CD4+ and B cells. The aim of this article is to review such evidence and report what is known so far about those cells involved in the inflammatory response in COPD.


Subject(s)
Inflammation/physiopathology , Pulmonary Disease, Chronic Obstructive/physiopathology , B-Lymphocytes/physiology , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Dendritic Cells/physiology , Humans , Macrophages, Alveolar/physiology , Mast Cells/physiology , Neutrophils/physiology
8.
Rev. méd. Chile ; 143(9): 1162-1171, set. 2015. ilus
Article in Spanish | LILACS | ID: lil-762687

ABSTRACT

Approximately 3 million people in the world die every year as a consequence of COPD, which is associated with an abnormal inflammatory response of the lung to noxious particles and gases. This inflammatory pattern causes pathological changes leading to a narrowing of small airways and destruction of lung parenchyma, also known as emphysema. Classically, these changes were associated to macrophages and neutrophils, although T CD8+ lymphocytes were latter added to the equation to explain the origin of emphysematous lesions. However, in recent years, multiple evidences have arisen indicating that inflammatory response in COPD is much more complex. These findings point to a key role for mast cells, dendritic cells, T CD4+ and B cells. The aim of this article is to review such evidence and report what is known so far about those cells involved in the inflammatory response in COPD.


Subject(s)
Humans , Inflammation/physiopathology , Pulmonary Disease, Chronic Obstructive/physiopathology , B-Lymphocytes/physiology , /physiology , /physiology , Dendritic Cells/physiology , Macrophages, Alveolar/physiology , Mast Cells/physiology , Neutrophils/physiology
9.
Respir Med ; 104(9): 1310-8, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20359875

ABSTRACT

BACKGROUND: In COPD, although histological lesions at both the small airways (wall thickening and tissue remodeling) and lung parenchyma (emphysematous destruction) are definitely different, the inflammatory cells involved in both processes are the same. Our study aims to determine if these histopathological phenotypes are related to two different lymphocyte profiles. METHODS: Distribution and cell density of CD3(+), CD4(+), CD8(+) and B lymphocytes were compared in small airways and parenchymal interstitium of 9 non-smokers, 18 smokers without COPD, 16 smokers with moderate COPD and 16 patients with very severe COPD undergoing lung transplantation. Spatial distribution of lymphocytes in periemphysematous parenchyma was also assessed. RESULTS: CD3(+) and B cell densities were significantly higher in small airways than parenchyma interstitium of very severe COPD patients. Furthermore, CD8(+) cells were increased in the epithelium of airways of moderate COPD patients compared to non-smokers. Although CD8(+) cell density was increased in parenchyma of COPD patients, CD8(+) and B cell densities were similar when comparing periemphysematous and non-emphysematous alveolar interstitium. CONCLUSIONS: In COPD, it is true that the small airways' wall shows a clear inflammatory pattern, with a high mononuclear infiltration and tissue remodeling. However, parenchymal interstitium shows a milder CD8(+) infiltration which, moreover, is not spatially related to emphysematous destroyed areas.


Subject(s)
CD8-Positive T-Lymphocytes/pathology , Lung/pathology , Pulmonary Disease, Chronic Obstructive/pathology , CD8-Positive T-Lymphocytes/immunology , Female , Humans , Lung/immunology , Lymphocyte Count , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/immunology , Smoking/immunology , Smoking/pathology
10.
Chest ; 130(3): 702-9, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16963666

ABSTRACT

STUDY OBJECTIVES: To conduct a detailed morphologic and ultrastructural study of pleural adhesions following talc pleurodesis. METHODS: Talc with a main particle size of 8.36 +/- 0.2 mum (mean +/- SEM) and at a dose of 200 mg/kg in a 2-mL slurry was instilled via a small catheter into the pleural cavity of 10 male rabbits. Five rabbits were killed at 1 week, and five rabbits were killed at 1 month after instillation. At autopsy, after macroscopically observing the pleural cavity, adhesions were excised from opposing pleural surfaces and processed for histopathologic, immunocytochemical, and ultrastructural study. RESULTS: At 1 week, all adhesions examined were mesothelium-covered fibrovascular bands containing well-developed blood and lymphatic vessels establishing a structural continuity between both pleural layers. Nerves were present in adhesions from 20% of the rabbits. They consisted of a single fascicle containing 5 to 20 thin myelinated axons of various diameters (1 to 6 microm) uniformly distributed throughout the nerve section. The anatomic location of the adhesion did not appear to influence its overall morphology. CONCLUSIONS: As early as at 1 week, adhesions are well-formed structures more resembling newly formed pleural tissue than a simple scar. Nerve fibers in pleural adhesions are reported for the first time, which suggests that these adhesions are potentially capable of conducting pain stimuli. Further studies are required in order to confirm our results in human pleural adhesions.


Subject(s)
Pleura/innervation , Pleural Diseases/chemically induced , Pleurodesis/adverse effects , Talc/adverse effects , Animals , Disease Models, Animal , Epithelium/pathology , Extracellular Matrix/pathology , Lymphangiogenesis , Male , Neovascularization, Pathologic/pathology , Nerve Fibers, Myelinated/pathology , Pain/etiology , Pain/physiopathology , Pleura/blood supply , Pleura/physiopathology , Pleural Cavity/pathology , Pleural Diseases/pathology , Pleural Diseases/physiopathology , Rabbits , Tissue Adhesions/chemically induced , Tissue Adhesions/complications , Tissue Adhesions/physiopathology
11.
Dis Aquat Organ ; 66(1): 33-40, 2005 Aug 09.
Article in English | MEDLINE | ID: mdl-16175966

ABSTRACT

Trophozoite, prezoosporangium and zoospore are the 3 main developmental stages that form the life cycle of protozoa of the genus Perkinsus. Several studies have shown that the differentiation of Perkinsus species from the trophozoite to the prezoosporangium stage involves a substantial modification of the antigenic characteristics of these molluscan parasites. With the aim of determining the presence and distribution of antigenic determinants conserved during trophozoite to prezoosporangium differentiation, a polyclonal serum was raised against trophozoites of P. atlanticus purified from parasitized gills of the clam Tapes semidecussatus. Immunocytochemical analyses showed that the serum generated against P. atlanticus trophozoites strongly cross-reacted with the prezoosporangium stage. Immunogold electron microscopy studies revealed that the granular component of the nucleolus, chromatin, cell wall, plasmalemma, lomasomes and vacuolar membrane are the main subcellular structures where the immunodominant epitopes consistently expressed by trophozoites and prezoosporangia are located. Furthermore, analysis of the immunogold staining pattern revealed that the labelling density obtained for prezoosporangia in the nucleolus, cell wall, plasmalemma and lomasomes was significantly higher than that obtained for trophozoites. The most immunoreactive structure in trophozoites was the granular component of the nucleolus, whereas in prezoosporangia it was the lomasome. Interestingly, the main antigenic compartment of P. atlanticus, considering both developmental stages, was the lomasome of the prezoosporangium. These findings show that P. atlanticus trophozoite to prezoosporangium differentiation is accompanied by significant qualitative and quantitative changes in the ultrastructural distribution of the immunodominant antigens shared by these 2 developmental stages.


Subject(s)
Bivalvia/parasitology , Epitopes/metabolism , Eukaryota/growth & development , Eukaryota/immunology , Eukaryota/ultrastructure , Life Cycle Stages , Animals , Fluorescent Antibody Technique , Immunohistochemistry , Microscopy, Electron , Spain
12.
Am J Respir Crit Care Med ; 168(3): 348-55, 2003 Aug 01.
Article in English | MEDLINE | ID: mdl-12773332

ABSTRACT

This study was designed to ascertain, in a rabbit model, extrapleural talc deposition and the related inflammatory response after talc slurry pleurodesis with two clinical doses, 200 and 50 mg/kg. Histopathologic evaluations revealed that whereas numerous rabbits receiving a high dose had talc in the ipsilateral (70%) and contralateral (55%) lung, mediastinum (90%), pericardium (30%), and liver (25%), a small number of animals treated with a low dose showed talc in the ipsilateral lung (10%) and mediastinum (20%) and none in the contralateral lung, pericardium, or liver. Hematologic and immunocytochemical analyses showed that a systemic inflammatory response develops shortly after pleurodesis with a high talc dose involving massive accumulation of neutrophils and macrophages in lung tissue. Zymography also revealed that the pulmonary expression of matrix metalloproteinases 2 and 9 was up-regulated in both lungs in a dose-dependent manner soon after talc instillation. Furthermore, microscopic examination of lung specimens revealed that the higher the dose of talc, the greater the development of both fibrotic visceral pleural thickening and foreign-body granulomas. These findings show pleurodesis with a high talc dose to be associated with an increased risk of extrapleural talc deposition, which may originate undesirable acute and chronic inflammatory responses.


Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Dose-Response Relationship, Drug , Mediastinitis/chemically induced , Pericarditis/chemically induced , Pleurisy/chemically induced , Pleurodesis/adverse effects , Pneumonia/chemically induced , Talc/administration & dosage , Talc/adverse effects , Acute Disease , Animals , Chemical and Drug Induced Liver Injury/pathology , Disease Models, Animal , Male , Mediastinitis/pathology , Pericarditis/pathology , Pleurisy/pathology , Pneumonia/pathology , Rabbits , Talc/pharmacokinetics , Time Factors
13.
Chest ; 122(3): 1018-27, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12226049

ABSTRACT

BACKGROUND: Cases of acute respiratory failure reported after talc pleurodesis have raised concerns about its safety. It has been speculated that this pulmonary inflammatory syndrome is secondary to the extrapleural dissemination of the talc particles. STUDY OBJECTIVES: To test the hypothesis that particle size influences extrapleural talc deposition and pleural inflammation after talc slurry pleurodesis. DESIGN: Thirty rabbits underwent pleurodesis as follows: 10 rabbits received 200 mg/kg of the talc used for human pleurodesis, normal talc (NT); 10 rabbits received 200 mg/kg of talc with particles of larger size, large talc (LT); and 10 rabbits received saline solution. Samples from the ipsilateral lung, chest wall, diaphragm, mediastinal pleura, heart, liver, spleen, and right kidney were obtained at 24 h and 7 days and processed for optic and electron microscopy and energy-dispersive x-ray analysis. RESULTS: Visceral pleural thickening was greater with NT than with LT, but no differences were observed in the macroscopic score of adhesions. There was more talc in the lungs of the rabbits that received NT than in those that received LT. Talc particles were detected in mediastinum (100%) and pericardium (20%), irrespective of the talc used. Three animals, all receiving NT, had talc particles in the liver. CONCLUSIONS: Our study shows that while both talcs were equally effective in achieving pleurodesis, the intrapleural injection of NT elicits greater pulmonary and systemic talc particle deposition than LT. Moreover, pleural inflammation was greater with NT than with LT.


Subject(s)
Pleurodesis/methods , Animals , Foreign-Body Reaction/pathology , Male , Microscopy, Electron, Scanning , Particle Size , Pleura/pathology , Rabbits , Sodium Chloride , Talc/administration & dosage , Talc/pharmacokinetics , Talc/toxicity , Tissue Distribution
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