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1.
Sci Rep ; 11(1): 12965, 2021 06 21.
Artículo en Inglés | MEDLINE | ID: mdl-34155270

RESUMEN

Secretory leukocyte peptidase inhibitor (SLPI) is a biomarker present in the respiratory tract that protects against tissue destruction and aids in wound healing. We examined whether SLPI in pleural effusion can be used to distinguish benign asbestos pleural effusion (BAPE) from early-stage malignant pleural mesothelioma (MPM) and other diseases. We measured the levels of SLPI, hyaluronic acid (HA), soluble mesothelin-related peptides (SMRP), CCL2, galectin-3, and CYFRA21-1 in 51 patients with BAPE, 37 patients with early-stage MPM, 77 patients with pleural effusions due to non-small-cell lung cancer (LCa), and 74 patients with other pleural effusions. SLPI levels in the pleural fluid of patients with BAPE were significantly lower than those in patients with MPM, LCa, and other pleural effusions (p < 0.0001). The area under the curve (AUC) for SLPI's ability to distinguish BAPE from MPM was 0.902, with a sensitivity of 82.4% and a specificity of 86.5%. This AUC was not only favourable but was better than the AUC for the ability of CYFRA21-1 to distinguish BAPE (0.853). The combination of SLPI and CYFRA21-1 achieved an AUC of 0.965 for the differentiation between BAPE and MPM. Pleural fluid SLPI as well as CYFRA21-1 and HA is useful as a biomarker to diagnose BAPE, which needs to be distinguished from early-stage MPM.


Asunto(s)
Asbestosis/diagnóstico , Asbestosis/metabolismo , Biomarcadores , Derrame Pleural/diagnóstico , Derrame Pleural/metabolismo , Inhibidor Secretorio de Peptidasas Leucocitarias/metabolismo , Área Bajo la Curva , Asbestosis/complicaciones , Biomarcadores de Tumor , Diagnóstico Diferencial , Humanos , Mesotelioma Maligno/diagnóstico , Mesotelioma Maligno/etiología , Mesotelioma Maligno/metabolismo , Derrame Pleural/etiología , Derrame Pleural Maligno/diagnóstico , Derrame Pleural Maligno/metabolismo , Curva ROC
2.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L1084-L1096, 2020 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-32209025

RESUMEN

Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased lung fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene (mtOgg1tg) are protected against lung fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary fibrosis that was accompanied by reduced lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout (Pink1-KO) mice are more susceptible to asbestos-induced lung fibrosis and have increased lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and lung fibrosis. Given the key role of AEC apoptosis in pulmonary fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.


Asunto(s)
Células Epiteliales Alveolares/efectos de los fármacos , Asbestosis/genética , ADN Glicosilasas/genética , Pulmón/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Proteínas Quinasas/genética , Fibrosis Pulmonar/genética , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Amianto/administración & dosificación , Asbestosis/etiología , Asbestosis/metabolismo , Asbestosis/patología , Bleomicina/administración & dosificación , Daño del ADN , ADN Glicosilasas/deficiencia , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Femenino , Regulación de la Expresión Génica , Peróxido de Hidrógeno/farmacología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/metabolismo , Cultivo Primario de Células , Proteínas Quinasas/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Transducción de Señal , Titanio/administración & dosificación
3.
JCI Insight ; 4(16)2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31434799

RESUMEN

Macrophage activation is implicated in the development of pulmonary fibrosis by generation of profibrotic molecules. Although NADPH oxidase 4 (NOX4) is known to contribute to pulmonary fibrosis, its effects on macrophage activation and mitochondrial redox signaling are unclear. Here, we show that NOX4 is crucial for lung macrophage profibrotic polarization and fibrotic repair after asbestos exposure. NOX4 was elevated in lung macrophages from subjects with asbestosis, and mice harboring a deletion of NOX4 in lung macrophages were protected from asbestos-induced fibrosis. NOX4 promoted lung macrophage profibrotic polarization and increased production of profibrotic molecules that induce collagen deposition. Mechanistically, NOX4 further augmented mitochondrial ROS production and induced mitochondrial biogenesis. Targeting redox signaling and mitochondrial biogenesis prevented the profibrotic polarization of lung macrophages by reducing the production of profibrotic molecules. These observations provide evidence that macrophage NOX4 is a potentially novel therapeutic target to halt the development of asbestos-induced pulmonary fibrosis.


Asunto(s)
Asbestosis/metabolismo , Macrófagos Alveolares/fisiología , Macrófagos/fisiología , NADPH Oxidasa 4/metabolismo , Biogénesis de Organelos , Adulto , Anciano , Animales , Línea Celular , Polaridad Celular , Femenino , Fibrosis , Humanos , Masculino , Ratones , Persona de Mediana Edad , Fenotipo , Especies Reactivas de Oxígeno/metabolismo
4.
Dis Markers ; 2017: 9645940, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28757678

RESUMEN

BACKGROUND: The identification of diagnostic/prognostic biomarkers for asbestos-related diseases is relevant for early diagnosis and patient survival and may contribute to understanding the molecular mechanisms underlying the disease development and progression. AIMS: To identify a pattern of miRNAs as possible diagnostic biomarkers for patients with malignant pleural mesothelioma (MPM) and asbestosis (ASB) and as prognostic biomarkers for MPM patients. METHODS: miRNA-16, miRNA-17, miRNA-126, and miRNA-486 were quantified in plasma and formalin-fixed paraffin-embedded samples to evaluate their diagnostic and prognostic roles compared to patients with other noncancerous pulmonary diseases (controls). Results. The expression of all the miRNAs was significantly lower in patients with MPM and ASB than that in controls. miRNA-16, miRNA-17, and miRNA-486 in plasma and tissue of MPM patients were significantly correlated. Furthermore, the expression of miRNA-16 in plasma and tissue, and miRNA-486 only in tissue, was positively related with cumulative survival in MPM patients. CONCLUSIONS: All the miRNA levels were decreased in patients with MPM or ASB, supporting the role of circulating miRNAs as a potential tool for diseases associated with exposure to asbestos fibers. miRNA-16 was directly related to MPM patient prognosis, suggesting its possible use as a prognostic marker in MPM patients.


Asunto(s)
Asbestosis/sangre , Neoplasias Pulmonares/sangre , Mesotelioma/sangre , MicroARNs/sangre , Anciano , Asbestosis/metabolismo , Asbestosis/patología , Estudios de Casos y Controles , Femenino , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/metabolismo , Mesotelioma/patología , Mesotelioma Maligno , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Proyectos Piloto
5.
FASEB J ; 31(7): 3072-3083, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28351840

RESUMEN

Fibrosis in multiple organs, including the liver, kidney, and lung, often occurs secondary to environmental exposure. Asbestos exposure is one important environmental cause of lung fibrosis. The mechanisms that mediate fibrosis is not fully understood, although mitochondrial oxidative stress in alveolar macrophages is critical for fibrosis development. Mitochondrial Ca2+ levels can be associated with production of reactive oxygen species. Here, we show that patients with asbestosis have higher levels of mitochondrial Ca2+ compared with normal patients. The mitochondrial calcium uniporter (MCU) is a highly selective ion channel that transports Ca2+ into the mitochondrial matrix to modulate metabolism. Asbestos exposure increased mitochondrial Ca2+ influx in alveolar macrophages from wild-type, but not MCU+/-, mice. MCU expression polarized macrophages to a profibrotic phenotype after exposure to asbestos, and the profibrotic polarization was regulated by MCU-mediated ATP production. Profibrotic polarization was abrogated when MCU was absent or its activity was blocked. Of more importance, mice that were deficient in MCU were protected from pulmonary fibrosis. Regulation of mitochondrial Ca2+ suggests that MCU may play a pivotal role in the development of fibrosis and could potentially be a therapeutic target for pulmonary fibrosis.-Gu, L., Larson-Casey, J. L., Carter, A. B. Macrophages utilize the mitochondrial calcium uniporter for profibrotic polarization.


Asunto(s)
Asbestosis/metabolismo , Canales de Calcio/metabolismo , Regulación de la Expresión Génica/fisiología , Macrófagos/fisiología , Adolescente , Adulto , Animales , Calcio/metabolismo , Canales de Calcio/genética , Haplotipos , Humanos , Ratones , Persona de Mediana Edad , Fibrosis Pulmonar , Especies Reactivas de Oxígeno , Adulto Joven
6.
Respir Res ; 18(1): 38, 2017 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-28222740

RESUMEN

BACKGROUND: Myofibroblasts play a major role in the synthesis of extracellular matrix (ECM) and the stimulation of these cells is thought to play an important role in the development of silicosis. The present study was undertaken to investigate the anti-fibrotic effects of dibutyryl-cAMP (db-cAMP) on rats induced by silica. METHODS: A HOPE MED 8050 exposure control apparatus was used to create the silicosis model. Rats were randomly divided into 4 groups: 1)controls for 16 w; 2)silicosis for 16 w; 3)db-cAMP pre-treatment; 4) db-cAMP post-treatment. Rat pulmonary fibroblasts were cultured in vitro and divided into 4 groups as follows: 1) controls; 2) 10-7mol/L angiotensin II (Ang II); 3) Ang II +10-4 mol/L db-cAMP; and 4) Ang II + db-cAMP+ 10-6 mol/L H89. Hematoxylin-eosin (HE), Van Gieson staining and immunohistochemistry (IHC) were performed to observe the histomorphology of lung tissue. The levels of cAMP were detected by enzyme immunoassay. Double-labeling for α-SMA with Gαi3, protein kinase A (PKA), phosphorylated cAMP-response element-binding protein (p-CREB), and p-Smad2/3 was identified by immunofluorescence staining. Protein levels were detected by Western blot analysis. The interaction between CREB-binding protein (CBP) and Smad2/3 and p-CREB were measured by co-immunoprecipitation (Co-IP). RESULTS: Db-cAMP treatment reduced the number and size of silicosis nodules, inhibited myofibroblast differentiation, and extracellular matrix deposition in vitro and in vivo. In addition, db-cAMP regulated Gαs protein and inhibited expression of Gαi protein, which increased endogenous cAMP. Db-cAMP increased phosphorylated cAMP-response element-binding protein (p-CREB) via protein kinase A (PKA) signaling, and decreased nuclear p-Smad2/3 binding with CREB binding protein (CBP), which reduced activation of p-Smads in fibroblasts induced by Ang II. CONCLUSIONS: This study showed an anti-silicotic effect of db-cAMP that was mediated via PKA/p-CREB/CBP signaling. Furthermore, the findings offer novel insight into the potential use of cAMP signaling for therapeutic strategies to treat silicosis.


Asunto(s)
Asbestosis/tratamiento farmacológico , Asbestosis/metabolismo , Proteína de Unión a CREB/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , CMP Cíclico/análogos & derivados , Proteínas de la Membrana/metabolismo , Miofibroblastos/efectos de los fármacos , Fosfoproteínas/metabolismo , Animales , Asbestosis/patología , Diferenciación Celular/efectos de los fármacos , CMP Cíclico/administración & dosificación , Masculino , Miofibroblastos/patología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Resultado del Tratamiento
7.
Am J Physiol Lung Cell Mol Physiol ; 310(11): L1071-7, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27106292

RESUMEN

Libby amphibole (LA) causes a unique progressive lamellar pleural fibrosis (LPF) that is associated with pulmonary function decline. Pleural fibrosis among the LA-exposed population of Libby, MT, has been associated with the production of anti-mesothelial cell autoantibodies (MCAA), which induce collagen production from cultured human mesothelial cells. We hypothesized that the progressive nature of LPF could be at least partially attributed to an autoimmune process and sought to demonstrate that LA-induced MCAA trigger collagen deposition in vivo. C57BL/6 mice were exposed to LA for 7 mo, and serum was tested for MCAA by cell-based ELISA on primary mouse mesothelial cells. When treated in vitro with serum from mice exposed to LA, mesothelial cells upregulated collagen matrix production. This effect was lost when the serum was cleared of IgG using protein G beads, implicating IgG autoantibodies. Using the peritoneal cavity as a surrogate for the pleural cavity, groups of naïve (non-asbestos-exposed) mice were injected intraperitoneally with 1) control serum, 2) one dose of serum from LA-exposed mice (LA serum), 3) two doses of LA serum, or 4) two doses of LA serum cleared of IgG. After 1 mo, analysis of collagen in peritoneal walls using two-photon confocal microscopy (SHG analysis) and a hydroxyproline assay demonstrated significant increases in collagen by LA serum but not control or cleared serum. These data support the hypothesis that MCAA in LA-exposed mice induce fibrotic responses in vivo, demonstrating that an autoimmune component may be contributing to the progressive pleural fibrosis seen in LA-exposed patients.


Asunto(s)
Asbestos Anfíboles/toxicidad , Asbestosis/inmunología , Autoanticuerpos/inmunología , Células Epiteliales/inmunología , Colágenos Fibrilares/metabolismo , Animales , Asbestosis/metabolismo , Células Cultivadas , Epitelio/inmunología , Epitelio/patología , Pulmón/inmunología , Pulmón/patología , Ratones Endogámicos C57BL , Enfermedades Pleurales/inmunología , Enfermedades Pleurales/metabolismo , Cultivo Primario de Células
8.
J Environ Pathol Toxicol Oncol ; 34(4): 277-85, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26756421

RESUMEN

We tested the postulate that iron homeostasis is altered among patients diagnosed to have asbestosis. Lung tissue from six individuals diagnosed to have had asbestosis at autopsy was stained for iron, ferritin, divalent metal transporter 1 (DMT1), and ferroportin 1 (FPN1). Slides from six individuals having pneumonectomy for lung cancer were employed as controls. Lung tissue from those patients with asbestosis demonstrated stainable iron, whereas control lung tissue did not. Staining for this metal was observed predominantly in airway and alveolar macrophages. Expression of the iron-related proteins ferritin, DMT1, and FPN1 was elevated in lung tissue from the six asbestosis patients relative to controls. This increased expression of iron-transport and iron-storage proteins was evident in both airway and alveolar epithelial cells. Asbestos bodies were abundant in lung tissue from patients diagnosed to have had asbestosis. While staining for iron, ferruginous bodies did not demonstrate uptake of antibodies for ferritin, DMT1, and FPN1. We conclude that iron homeostasis is altered in lung disease among those diagnosed to have asbestosis with an accumulation of the metal and a modified expression of iron-related proteins being evident.


Asunto(s)
Asbestosis/metabolismo , Proteínas Reguladoras del Hierro/metabolismo , Hierro/metabolismo , Pulmón/patología , Asbestosis/patología , Estudios de Casos y Controles , Fibrosis , Homeostasis , Humanos , Inmunohistoquímica , Proteínas Reguladoras del Hierro/genética , Pulmón/metabolismo
9.
J Biol Chem ; 289(48): 33391-403, 2014 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-25324550

RESUMEN

Although the mechanisms for fibrosis development remain largely unknown, recent evidence indicates that endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) may act as an important fibrotic stimulus in diseased lungs. ER stress is observed in lungs of patients with idiopathic pulmonary fibrosis. In this study we evaluated if ER stress and the UPR was present in macrophages exposed to chrysotile asbestos and if ER stress in macrophages was associated with asbestos-induced pulmonary fibrosis. Macrophages exposed to chrysotile had elevated transcript levels of several ER stress genes. Macrophages loaded with the Ca(2+)-sensitive dye Fura2-AM showed that cytosolic Ca(2+) increased significantly within minutes after chrysotile exposure and remained elevated for a prolonged time. Chrysotile-induced increases in cytosolic Ca(2+) were partially inhibited by either anisomycin, an inhibitor of passive Ca(2+) leak from the ER, or 1,2-bis(2-aminophenoxyl)ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM), an intracellular Ca(2+) chelator known to deplete ER Ca(2+) stores. Anisomycin inhibited X-box-binding protein 1 (XBP1) mRNA splicing and reduced immunoglobulin-binding protein (BiP) levels, whereas BAPTA-AM increased XBP1 splicing and BiP expression, suggesting that ER calcium depletion may be one factor contributing to ER stress in cells exposed to chrysotile. To evaluate ER stress in vivo, asbestos-exposed mice showed fibrosis development, and alveolar macrophages from fibrotic mice showed increased expression of BiP. Bronchoalveolar macrophages from asbestosis patients showed increased expression of several ER stress genes compared with normal subjects. These findings suggest that alveolar macrophages undergo ER stress, which is associated with fibrosis development.


Asunto(s)
Asbestos Serpentinas/toxicidad , Asbestosis/metabolismo , Calcio/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Fibrosis Pulmonar/metabolismo , Adolescente , Adulto , Animales , Asbestosis/patología , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Macrófagos Alveolares/patología , Masculino , Ratones , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/patología , Empalme del ARN/efectos de los fármacos , Factores de Transcripción del Factor Regulador X , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box
10.
Toxicol Appl Pharmacol ; 276(1): 28-46, 2014 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-24480151

RESUMEN

Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (>20 µm) cleared quickly with T(½) estimated as 30 and 33 days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T(½)>1000 days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91 days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation.


Asunto(s)
Asbestos Serpentinas/toxicidad , Asbestosis/prevención & control , Polvo , Exposición por Inhalación/efectos adversos , Pulmón/efectos de los fármacos , Vehículos a Motor , Equipos de Seguridad/efectos adversos , Animales , Asbesto Crocidolita/análisis , Asbesto Crocidolita/química , Asbesto Crocidolita/farmacocinética , Asbesto Crocidolita/toxicidad , Asbestos Serpentinas/análisis , Asbestos Serpentinas/química , Asbestos Serpentinas/farmacocinética , Asbestosis/inmunología , Asbestosis/metabolismo , Asbestosis/patología , Fenómenos Químicos , Modelos Animales de Enfermedad , Polvo/análisis , Semivida , Industrias , Pulmón/química , Pulmón/inmunología , Pulmón/ultraestructura , Masculino , Ensayo de Materiales , Enfermedades Profesionales/inducido químicamente , Enfermedades Profesionales/inmunología , Enfermedades Profesionales/patología , Enfermedades Profesionales/prevención & control , Ratas , Ratas Wistar , Mucosa Respiratoria/química , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/ultraestructura , Distribución Tisular , Pruebas de Toxicidad Aguda
13.
Sci Rep ; 3: 1123, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23350030

RESUMEN

Asbestos is a potent carcinogen associated with malignant mesothelioma and lung cancer but its carcinogenic mechanisms are still poorly understood. Asbestos toxicity is ascribed to its particular physico-chemical characteristics, and one of them is the presence of and ability to adsorb iron, which may cause an alteration of iron homeostasis in the tissue. This observational study reports a combination of advanced synchrotron-based X-ray imaging and micro-spectroscopic methods that provide correlative morphological and chemical information for shedding light on iron mobilization features during asbestos permanence in lung tissue. The results show that the processes responsible for the unusual distribution of iron at different stages of interaction with the fibres also involve calcium, phosphorus and magnesium. It has been confirmed that the dominant iron form present in asbestos bodies is ferritin, while the concurrent presence of haematite suggests alteration of iron chemistry during asbestos body permanence.


Asunto(s)
Amianto/metabolismo , Carcinógenos/metabolismo , Hierro/metabolismo , Pulmón/metabolismo , Anciano , Anciano de 80 o más Años , Amianto/química , Asbestosis/metabolismo , Asbestosis/patología , Calcio/química , Calcio/metabolismo , Carcinógenos/química , Femenino , Ferritinas/metabolismo , Humanos , Hierro/química , Pulmón/patología , Magnesio/química , Magnesio/metabolismo , Masculino , Microscopía Electrónica de Rastreo , Fósforo/química , Fósforo/metabolismo , Espectroscopía de Absorción de Rayos X
14.
Crit Rev Toxicol ; 43(2): 154-83, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23346982

RESUMEN

This review provides a basis for substantiating both kinetically and pathologically the differences between chrysotile and amphibole asbestos. Chrysotile, which is rapidly attacked by the acid environment of the macrophage, falls apart in the lung into short fibers and particles, while the amphibole asbestos persist creating a response to the fibrous structure of this mineral. Inhalation toxicity studies of chrysotile at non-lung overload conditions demonstrate that the long (>20 µm) fibers are rapidly cleared from the lung, are not translocated to the pleural cavity and do not initiate fibrogenic response. In contrast, long amphibole asbestos fibers persist, are quickly (within 7 d) translocated to the pleural cavity and result in interstitial fibrosis and pleural inflammation. Quantitative reviews of epidemiological studies of mineral fibers have determined the potency of chrysotile and amphibole asbestos for causing lung cancer and mesothelioma in relation to fiber type and have also differentiated between these two minerals. These studies have been reviewed in light of the frequent use of amphibole asbestos. As with other respirable particulates, there is evidence that heavy and prolonged exposure to chrysotile can produce lung cancer. The importance of the present and other similar reviews is that the studies they report show that low exposures to chrysotile do not present a detectable risk to health. Since total dose over time decides the likelihood of disease occurrence and progression, they also suggest that the risk of an adverse outcome may be low with even high exposures experienced over a short duration.


Asunto(s)
Asbestos Anfíboles/efectos adversos , Asbestos Serpentinas/efectos adversos , Asbestosis/etiología , Asbestos Anfíboles/farmacocinética , Asbestos Serpentinas/farmacocinética , Asbestosis/metabolismo , Asbestosis/patología , Relación Dosis-Respuesta a Droga , Humanos , Exposición por Inhalación , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Tamaño de la Partícula , Neoplasias Pleurales/epidemiología , Neoplasias Pleurales/etiología
15.
Annu Rev Pathol ; 8: 161-87, 2013 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-23347351

RESUMEN

Asbestos causes asbestosis and malignancies by molecular mechanisms that are not fully understood. The modes of action underlying asbestosis, lung cancer, and mesothelioma appear to differ depending on the fiber type, lung clearance, and genetics. After reviewing the key pathologic changes following asbestos exposure, we examine recently identified pathogenic pathways, with a focus on oxidative stress. Alveolar epithelial cell apoptosis, which is an important early event in asbestosis, is mediated by mitochondria- and p53-regulated death pathways and may be modulated by the endoplasmic reticulum. We review mitochondrial DNA (mtDNA)-damage and -repair mechanisms, focusing on 8-oxoguanine DNA glycosylase, as well as cross talk between reactive oxygen species production, mtDNA damage, p53, OGG1, and mitochondrial aconitase. These new insights into the molecular basis of asbestos-induced lung diseases may foster the development of novel therapeutic targets for managing degenerative diseases (e.g., asbestosis and idiopathic pulmonary fibrosis), tumors, and aging, for which effective management is lacking.


Asunto(s)
Amianto/envenenamiento , Amianto/toxicidad , Asbestosis/etiología , Asbestosis/patología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/patología , Animales , Apoptosis/efectos de los fármacos , Amianto/química , Asbestosis/genética , Asbestosis/metabolismo , Daño del ADN , ADN Mitocondrial/efectos de los fármacos , Humanos , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/metabolismo , Neoplasias Pulmonares/etiología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mesotelioma/etiología , Mesotelioma/genética , Mesotelioma/metabolismo , Mesotelioma/patología , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo
16.
Hum Pathol ; 44(5): 895-907, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23253490

RESUMEN

It has been proposed that an epithelial injury may be one of the multiple primary events in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The aim of this study was to characterize the tight junction and adherens junction proteins in normal human lung, IPF, cryptogenic organizing pneumonia, and asbestosis. We determined the immunohistochemical cell-specific expression of tight junction proteins claudin-1, claudin-2, claudin-3, claudin-4, claudin-5, and claudin-7, as well as 3 adherens junction proteins, E-cadherin, N-cadherin, and ß-catenin. We further analyzed the expression of claudin-1, claudin-3, and claudin-4 and E-cadherin, N-cadherin, and ß-catenin at the transcriptional level by quantitative real-time reverse transcriptase polymerase chain reaction. The expression levels of both tight junction and adherens junction proteins were elevated in regenerative alveolar epithelium in pulmonary fibrosis as compared with the expression of these proteins in normal alveolar epithelium. In particular, the expression levels of claudins-1 and claudin-3 were clearly elevated in all diseases. Furthermore, the amounts of adherens junction proteins messenger RNAs (mRNAs) were also all increased in pulmonary fibroses in comparison with healthy controls, with N-cadherin showing the greatest increase in mRNA levels in all diseases. However, the amounts of claudin-1, claudin-3, and claudin-4 mRNAs in fibrotic lung were similar to or even lower than those measured in the healthy controls. It is possible that the diminished capacity to produce claudin mRNAs may be one explanation for poor repair capacity of alveolar epithelial cells in IPF.


Asunto(s)
Uniones Adherentes/química , Asbestosis/metabolismo , Claudinas/análisis , Fibrosis Pulmonar/metabolismo , Uniones Estrechas/química , Cadherinas/análisis , Epitelio/metabolismo , Humanos , Inmunohistoquímica , Pulmón/química , Alveolos Pulmonares/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
17.
Ind Health ; 50(4): 299-306, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22785421

RESUMEN

Leukotrienes (LTs) are involved in the pathogenesis of lung fibrosis and were increased in exhaled breath condensate (EBC) of the patients with pneumoconiosis. However the possible influence of extra-pulmonary disorders on the EBC markers is not known. Therefore in parallel with EBC, LTs' levels in the plasma and urine were measured in patients with pneumoconiosis (45 × asbestos exposure, 37 × silica exposure) and in 27 controls. Individual LTs B4, C4, D4 and E4 were measured by liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS). In EBC, LT D4 and LT E4 were increased in both groups of patients (p<0.001 and p<0.05), comparing with the controls. Both LT B4 and cysteinyl LTs were elevated in asbestos-exposed subjects (p<0.05). Asbestosis with more severe radiological signs (s1/s2-t3/u2) and lung functions impairment has shown higher cysteinyl LTs and LT C4 in the EBC (p<0.05) than mild asbestosis (s1/s0-s1/s1). In addition, in the subjects with asbestosis, cysteinyl LTs in EBC correlated with TLC (-0.313, p<0.05) and TLCO/Hb (-0.307, p<0.05), and LT C4 with TLC (-0.358, p<0.05). In pneumoconioses, EBC appears the most useful from the 3 fluids studied.


Asunto(s)
Asbestosis/metabolismo , Pruebas Respiratorias , Leucotrienos/análisis , Silicosis/metabolismo , Anciano , Asbestosis/diagnóstico por imagen , Femenino , Humanos , Leucotrieno B4/análisis , Leucotrieno B4/sangre , Leucotrieno B4/orina , Leucotrieno C4/análisis , Leucotrieno C4/sangre , Leucotrieno C4/orina , Leucotrieno D4/análisis , Leucotrieno D4/sangre , Leucotrieno D4/orina , Leucotrieno E4/análisis , Leucotrieno E4/sangre , Leucotrieno E4/orina , Leucotrienos/sangre , Leucotrienos/orina , Masculino , Persona de Mediana Edad , Radiografía , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Silicosis/diagnóstico por imagen
18.
J Toxicol Environ Health A ; 74(17): 1111-32, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21797767

RESUMEN

Increased incidences of asbestosis have been reported in workers from Libby, MT, associated with exposures to amphibole-contaminated vermiculite. In this study pulmonary and histopathological changes were investigated following Libby amphibole (LA) exposure in a rat model. Rat respirable fractions of LA and amosite (aerodynamic diameter <2.5 µm) were prepared by water elutriation. Male F344 rats were exposed to single doses of either saline (SAL), amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal instillation. At times from 1 d to 3 mo after exposure, bronchoalveolar lavage (BAL) was performed and right and left lungs were removed for reverse-transcription polymerase chain reaction (RT-PCR) and histopathological analysis, respectively. Data indicated that 0.65 mg amosite resulted in a higher degree of pulmonary injury, inflammation, and fibrotic events than LA at the same mass dose. Exposure to either amosite or high dose LA resulted in higher levels of cellular permeability and injury, inflammatory enzymes, and iron binding proteins in both BAL fluid and lung tissue at most time points when compared to SAL controls. However, mRNA expression for some growth factors (e.g., platelet-derived growth factor [PDGF]-A and transforming growth factor [TGF]-1ß), which contribute to fibrosis, were downregulated at several time points. Furthermore, histopathological examination showed notable thickening of interstitial areas surrounding the alveolar ducts and terminal bronchioles. On a mass dose basis, amosite produced a greater acute and persistent lung injury for at least 3 mo after exposure. However, further testing and analysis of LA are needed with regard to the dose metric to fully evaluate its potential fibrogenicity and carcinogenicity.


Asunto(s)
Contaminantes Ocupacionales del Aire/toxicidad , Silicatos de Aluminio/toxicidad , Asbestos Anfíboles/toxicidad , Asbestosis/inmunología , Asbestosis/patología , Pulmón/efectos de los fármacos , Contaminantes Ocupacionales del Aire/química , Silicatos de Aluminio/química , Animales , Asbestos Anfíboles/química , Asbestosis/metabolismo , Biomarcadores/análisis , Biomarcadores/metabolismo , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo/efectos de los fármacos , Proteínas de Unión a Hierro/genética , Proteínas de Unión a Hierro/metabolismo , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Masculino , Fibras Minerales/análisis , Fibras Minerales/toxicidad , Tamaño de la Partícula , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , ARN Mensajero/metabolismo , Distribución Aleatoria , Ratas , Ratas Endogámicas F344 , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Factor de Crecimiento Transformador beta1/genética , Factor de Crecimiento Transformador beta1/metabolismo
19.
J Toxicol Environ Health B Crit Rev ; 14(1-4): 76-121, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21534086

RESUMEN

Lung carcinomas and pulmonary fibrosis (asbestosis) occur in asbestos workers. Understanding the pathogenesis of these diseases is complicated because of potential confounding factors, such as smoking, which is not a risk factor in mesothelioma. The modes of action (MOA) of various types of asbestos in the development of lung cancers, asbestosis, and mesotheliomas appear to be different. Moreover, asbestos fibers may act differentially at various stages of these diseases, and have different potencies as compared to other naturally occurring and synthetic fibers. This literature review describes patterns of deposition and retention of various types of asbestos and other fibers after inhalation, methods of translocation within the lung, and dissolution of various fiber types in lung compartments and cells in vitro. Comprehensive dose-response studies at fiber concentrations inhaled by humans as well as bivariate size distributions (lengths and widths), types, and sources of fibers are rarely defined in published studies and are needed. Species-specific responses may occur. Mechanistic studies have some of these limitations, but have suggested that changes in gene expression (either fiber-catalyzed directly or by cell elaboration of oxidants), epigenetic changes, and receptor-mediated or other intracellular signaling cascades may play roles in various stages of the development of lung cancers or asbestosis.


Asunto(s)
Amianto/toxicidad , Asbestosis/metabolismo , Carcinoma/inducido químicamente , Exposición por Inhalación/efectos adversos , Neoplasias Pulmonares/inducido químicamente , Pulmón/efectos de los fármacos , Material Particulado/toxicidad , Animales , Amianto/administración & dosificación , Amianto/química , Amianto/farmacocinética , Transporte Biológico , Carga Corporal (Radioterapia) , Carcinógenos Ambientales/administración & dosificación , Carcinógenos Ambientales/química , Carcinógenos Ambientales/farmacocinética , Carcinógenos Ambientales/toxicidad , Carcinoma/genética , Carcinoma/metabolismo , Fenómenos Químicos , Humanos , Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Fibras Minerales/análisis , Fibras Minerales/toxicidad , Mutágenos/administración & dosificación , Mutágenos/química , Mutágenos/farmacocinética , Mutágenos/toxicidad , Material Particulado/administración & dosificación , Material Particulado/química , Material Particulado/farmacocinética , Distribución Tisular
20.
J Toxicol Environ Health B Crit Rev ; 14(1-4): 179-245, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21534089

RESUMEN

The cellular and molecular mechanisms of how asbestos fibers induce cancers and other diseases are not well understood. Both serpentine and amphibole asbestos fibers have been shown to induce oxidative stress, inflammatory responses, cellular toxicity and tissue injuries, genetic changes, and epigenetic alterations in target cells in vitro and tissues in vivo. Most of these mechanisms are believe to be shared by both fiber-induced cancers and noncancerous diseases. This article summarizes the findings from existing literature with a focus on genetic changes, specifically, mutagenicity of asbestos fibers. Thus far, experimental evidence suggesting the involvement of mutagenesis in asbestos carcinogenicity is more convincing than asbestos-induced fibrotic diseases. The potential contributions of mutagenicity to asbestos-induced diseases, with an emphasis on carcinogenicity, are reviewed from five aspects: (1) whether there is a mutagenic mode of action (MOA) in fiber-induced carcinogenesis; (2) mutagenicity/carcinogenicity at low dose; (3) biological activities that contribute to mutagenicity and impact of target tissue/cell type; (4) health endpoints with or without mutagenicity as a key event; and finally, (5) determinant factors of toxicity in mutagenicity. At the end of this review, a consensus statement of what is known, what is believed to be factual but requires confirmation, and existing data gaps, as well as future research needs and directions, is provided.


Asunto(s)
Amianto/toxicidad , Carcinógenos Ambientales/toxicidad , Fibras Minerales/toxicidad , Neoplasias/inducido químicamente , Animales , Amianto/administración & dosificación , Amianto/química , Asbestosis/metabolismo , Carcinógenos Ambientales/administración & dosificación , Carcinógenos Ambientales/química , Fenómenos Químicos , Daño del ADN , Humanos , Fibras Minerales/análisis , Mitosis/efectos de los fármacos , Mutación/efectos de los fármacos , Neoplasias/metabolismo , Enfermedades Pleurales/inducido químicamente , Enfermedades Pleurales/metabolismo
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