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1.
Lung ; 195(4): 507-515, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28536739

RESUMEN

INTRODUCTION: The current understanding of associations between lung disease and military deployment to Southwest Asia, including Iraq and Afghanistan, is both controversial and limited. We sought to clarify the relation between military deployment and biopsy-proven lung disease. METHODS: Retrospective data were analyzed for military personnel with non-neoplastic lung biopsies evaluated at the Armed Forces Institute of Pathology or Joint Pathology Center (January 2005 to December 2012). RESULTS: Of 391 subjects, 137 (35.0%) had deployed to Southwest Asia prior to biopsy. Compared to non-deployed subjects, those deployed were younger (median age 37 vs. 51 years) with higher representation of African Americans (30.0 vs. 16.9%). Deployed patients were more likely diagnosed with non-necrotizing granulomas (OR 2.4). Non-deployed subjects had higher frequency of idiopathic interstitial pneumonias, particularly organizing pneumonia. Prevalence of small airways diseases including constrictive bronchiolitis was low. CONCLUSIONS: This study provides a broader understanding of diversity of biopsy-proven non-neoplastic lung disease as it relates to military deployment to Southwest Asia and importantly did not show an increased prevalence of small airway disease to include constrictive bronchiolitis.


Asunto(s)
Enfermedades Pulmonares/patología , Pulmón/patología , Personal Militar , Adolescente , Adulto , Negro o Afroamericano , Biopsia , Bronquiolitis Obliterante/etnología , Bronquiolitis Obliterante/patología , Distribución de Chi-Cuadrado , Femenino , Granuloma del Sistema Respiratorio/etnología , Granuloma del Sistema Respiratorio/patología , Humanos , Neumonías Intersticiales Idiopáticas/etnología , Neumonías Intersticiales Idiopáticas/patología , Modelos Logísticos , Enfermedades Pulmonares/etnología , Masculino , Persona de Mediana Edad , Medio Oriente , Análisis Multivariante , Oportunidad Relativa , Valor Predictivo de las Pruebas , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Estados Unidos/epidemiología , Población Blanca , Adulto Joven
2.
HPB Surg ; 2012: 270372, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22675237

RESUMEN

Pulmonary complications after liver transplantation (LT) often cause mortality. This study investigated whether small-for-size LT increases acute pulmonary injury and whether NIM811 which improves small-for-size liver graft survival attenuates LT-associated lung injury. Rat livers were reduced to 50% of original size, stored in UW-solution with and without NIM811 (5 µM) for 6 h, and implanted into recipients of the same or about twice the donor weight, resulting in half-size (HSG) and quarter-size grafts (QSG), respectively. Liver injury increased and regeneration was suppressed after QSG transplantation as expected. NIM811 blunted these alterations >75%. Pulmonary histological alterations were minimal at 5-18 h after LT. At 38 h, neutrophils and monocytes/macrophage infiltration, alveolar space exudation, alveolar septal thickening, oxidative/nitrosative protein adduct formation, and alveolar epithelial cell/capillary endothelial apoptosis became overt in the lungs of QSG recipients, but these alterations were mild in full-size and HSG recipients. Liver pretreatment with NIM811 markedly decreased pulmonary injury in QSG recipients. Hepatic TNFα and IL-1ß mRNAs and pulmonary ICAM-1 expression were markedly higher after QSG transplantation, which were all decreased by NIM811. Together, dysfunctional small-for-size grafts produce toxic cytokines, leading to lung inflammation and injury. NIM811 decreased toxic cytokine formation, thus attenuating pulmonary injury after small-for-size LT.

3.
Chest ; 141(6): 1512-1521, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22207675

RESUMEN

BACKGROUND: Reports of pulmonary fibrosis, emphysema, and, more recently, pulmonary alveolar proteinosis (PAP) in indium workers suggested that workplace exposure to indium compounds caused several different lung diseases. METHODS: To better understand the pathogenesis and natural history of indium lung disease, a detailed, systematic, multidisciplinary analysis of clinical, histopathologic, radiologic, and epidemiologic data for all reported cases and workplaces was undertaken. RESULTS: Ten men (median age, 35 years) who produced, used, or reclaimed indium compounds were diagnosed with interstitial lung disease 4-13 years after first exposure (n = 7) or PAP 1-2 years after first exposure (n = 3). Common pulmonary histopathologic features in these patients included intraalveolar exudate typical of alveolar proteinosis (n = 9), cholesterol clefts and granulomas (n = 10), and fibrosis (n = 9). Two patients with interstitial lung disease had pneumothoraces. Lung disease progressed following cessation of exposure in most patients and was fatal in two. Radiographic data revealed that two patients with PAP subsequently developed fibrosis and one also developed emphysematous changes. Epidemiologic investigations demonstrated the potential for exposure to respirable particles and an excess of lung abnormalities among coworkers. CONCLUSIONS: Occupational exposure to indium compounds was associated with PAP, cholesterol ester crystals and granulomas, pulmonary fibrosis, emphysema, and pneumothoraces. The available evidence suggests exposure to indium compounds causes a novel lung disease that may begin with PAP and progress to include fibrosis and emphysema, and, in some cases, premature death. Prospective studies are needed to better define the natural history and prognosis of this emerging lung disease and identify effective prevention strategies.


Asunto(s)
Indio/toxicidad , Enfermedades Pulmonares/inducido químicamente , Enfermedades Profesionales/inducido químicamente , Exposición Profesional/efectos adversos , Adulto , Biomarcadores/análisis , Broncoscopía , Diagnóstico Diferencial , Progresión de la Enfermedad , Humanos , Enfermedades Pulmonares/diagnóstico , Masculino , Enfermedades Profesionales/diagnóstico , Proteínas Asociadas a Pancreatitis , Pruebas de Función Respiratoria , Factores de Riesgo , Tomografía Computarizada por Rayos X
5.
Am J Cardiol ; 102(11): 1514-7, 2008 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-19026306

RESUMEN

We examined whether the risk factors for increased brachial pulse pressure (PP) are similar for blacks and whites. Many studies have reported the strong association of increased brachial PP and the prevalence of cardiovascular disease. Participants were from 4 major epidemiologic studies in the United States (26,083 subjects): Charleston Heart Study, Evans County Heart Study, the National Health and Nutrition Examination Survey (NHANES) I study, and the NHANES II study. At baseline, there was no history or clinical evidence of coronary heart disease (CHD). The CHD mortality as a function of brachial PP and the association of traditional risk factors for CHD with PP were analyzed for each of the 4 studies and for the 4 studies combined. Multiple regression analysis showed that the most significant predictors of high brachial PP are body mass index > or =30 kg/m(2) (regression coefficient 3.79, p <0.0001), diabetes mellitus (5.14, p <0.0001), serum total cholesterol > or =240 mg/dl (0.51, p <0.0157), age (0.60, p <0.0001), gender (-1.77, p <0.0001), and race (3.75, p <0.0001). In conclusion, the same risk factors for CHD (namely, increase in body mass index > or =30 kg/m(2), diabetes mellitus, hypercholesterolemia, and age) are significantly associated with high brachial PP for blacks and whites. These risk factors were stronger in whites compared with blacks. However, female gender and age variables were even more associated with brachial PP in blacks. Smoking was significant but not reflected in peripheral brachial PP as it is in aortic PP.


Asunto(s)
Negro o Afroamericano , Presión Sanguínea , Arteria Braquial , Enfermedades Cardiovasculares/fisiopatología , Hipertensión/fisiopatología , Población Blanca , Adolescente , Adulto , Factores de Edad , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Encuestas Nutricionales , Obesidad , Prevalencia , Análisis de Regresión , Factores de Riesgo , Fumar/efectos adversos , Estados Unidos/epidemiología , Adulto Joven
6.
Am J Forensic Med Pathol ; 28(2): 116-20, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17525560

RESUMEN

Neuroleptic malignant syndrome (NMS) is a diagnosis of exclusion difficult to make due to a lack of pathognomonic features. Diagnosing NMS by postmortem examination becomes increasingly challenging when possible underlying brain pathology is obscured. The diagnosis is based on clinical history and laboratory findings. Autopsy and histologic findings, if any, usually are reflective of hyperthermia or complications (eg, aspiration pneumonia) of NMS. The authors describe a case of a 36-year-old Hispanic woman with a presumptive diagnosis of pseudoseizures, treated with various combinations of neuroleptic medications over a 6-week period prior to her sudden, unexpected, in-hospital death. Neuroleptic malignant syndrome is likely to have contributed to this patient's death. Confounding factors and medicolegal issues of a postmortem diagnosis of NMS are discussed.


Asunto(s)
Síndrome Neuroléptico Maligno/diagnóstico , Lesión Renal Aguda/etiología , Adulto , Anticonvulsivantes/efectos adversos , Encéfalo/patología , Creatina Quinasa/sangre , Deshidratación/etiología , Femenino , Fiebre/etiología , Medicina Legal , Humanos , Hipovolemia/etiología , Fallo Hepático Agudo/etiología , Rigidez Muscular/etiología , Psicotrópicos/efectos adversos , Temblor/etiología
7.
Am J Forensic Med Pathol ; 28(2): 137-40, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17525564

RESUMEN

Verapamil blocks the rapid influx of calcium into the cardiac myocytes of the cardiac conduction system and smooth muscle of the vasculature, resulting in decreased myocardial contractility, prolonged conduction time, and vascular relaxation. A sustained-release form, verapamil SR (or ER), is available that contains higher levels of medication and requires only once-daily dosing. The majority of reported fatal cases of verapamil toxicity are due to massive, intentional overdoses. Herein, we present an unusual case of fatal verapamil SR toxicity in a 57-year-old female that resulted from accidental overdose of only 3 tablets (720 mg), as witnessed by the decedent's daughter. In spite of the low dose ingested, the postmortem cardiac blood verapamil level was clearly toxic (6000 ng/mL, or 6 mg/L). Her preexisting medical conditions included hypercholesterolemia, hypertension, iron deficiency anemia, diabetes mellitus, and associated mild chronic renal failure. Complicating factors, which likely include the decedent's preexisting renal and cardiac disease, and a review of the available literature will be discussed.


Asunto(s)
Bloqueadores de los Canales de Calcio/efectos adversos , Verapamilo/efectos adversos , Accidentes , Antihipertensivos/administración & dosificación , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/sangre , Combinación de Medicamentos , Sobredosis de Droga , Femenino , Toxicología Forense , Humanos , Hipercolesterolemia/complicaciones , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Indoles/administración & dosificación , Fallo Renal Crónico/complicaciones , Persona de Mediana Edad , Verapamilo/administración & dosificación , Verapamilo/sangre
8.
Am J Forensic Med Pathol ; 26(4): 343-8, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16304468

RESUMEN

Hypertrophic cardiomyopathy (HCM) is a disease process which results in a large, heavy heart, with hypertrophy of the interventricular septum (IVS) and left ventricle. HCM accounts for a significant number of cases of sudden cardiac death each year, most infamously in young athletes. The prevalence of the disease has increased over the past several years due to advances in clinical diagnosis and molecular genetic studies. Over this same period, new forms of treatment also have emerged. One such treatment is alcohol septal ablation (ASA). ASA is a procedure performed by a cardiologist, via cardiac catheterization, by injecting pure ethanol into selected arteries which supply the IVS, resulting in a targeted myocardial infarction. This infarct then retracts and forms a scar, decreasing the outflow obstruction and improving the patient's clinical symptoms.The authors report 2 cases of death following ASA treatment of HCM. The first, a 56-year-old male, had his ASA procedure 10 days prior to death. The second decedent, a 76-year-old female, had her procedure only 30 hours before death. These case reports are followed by a discussion about HCM, including pathology, treatments, and treatment-related pathology, before closing with a discussion about death certification in the cases presented and therapy-related deaths in general.


Asunto(s)
Antiinfecciosos Locales/efectos adversos , Cardiomiopatía Hipertrófica/terapia , Ablación por Catéter/efectos adversos , Etanol/efectos adversos , Infarto del Miocardio/inducido químicamente , Anciano , Antiinfecciosos Locales/administración & dosificación , Estenosis de la Válvula Aórtica/patología , Calcinosis/patología , Cateterismo Cardíaco , Trombosis Coronaria/patología , Etanol/administración & dosificación , Femenino , Fibrosis , Tabiques Cardíacos/patología , Humanos , Masculino , Persona de Mediana Edad , Válvula Mitral/patología , Infarto del Miocardio/patología , Isquemia Miocárdica/patología , Miocardio/patología
9.
J Histochem Cytochem ; 53(9): 1159-66, 2005 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-15923363

RESUMEN

Sphingosine kinase 1 (SK1) is a key enzyme critical to the sphingolipid metabolic pathway responsible for catalyzing the formation of the bioactive lipid sphingosine-1-phosphate. SK1-mediated production of sphingosine-1-phosphate has been shown to stimulate such biological processes as cell growth, differentiation, migration, angiogenesis, and inhibition of apoptosis. In this study, cell type-specific immunolocalization of SK1 was examined in the bronchus/terminal bronchiole of the lung. Strong immunopositive staining was evident at the apical surface of pseudostratified epithelial cells of the bronchus and underlying smooth muscle cells, submucosal serous glands, immature chondrocytes, type II alveolar cells, foamy macrophages, endothelial cells of blood vessels, and neural bundles. Immunohistochemical screening for SK1 expression was performed in 25 samples of normal/tumor patient matched non-small-cell lung cancer tissue and found that 25 of 25 tumor samples (carcinoid [5 samples], squamous [10 samples], and adenocarcinoma tumors [10 samples]), exhibited overwhelmingly positive immunostaining for SK1 as compared with patient-matched normal tissue. In addition, an approximately 2-fold elevation of SK1 mRNA expression was observed in lung cancer tissue versus normal tissue, as well as in several other solid tumors. Taken together, these findings define the localization of SK1 in lung and provide clues as to how SK1 may play a role in normal lung physiology and the pathophysiology of lung cancer.


Asunto(s)
Adenocarcinoma/enzimología , Tumor Carcinoide/enzimología , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Células Escamosas/enzimología , Neoplasias Pulmonares/enzimología , Pulmón/enzimología , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Animales , Especificidad de Anticuerpos , Bronquios/enzimología , Humanos , Inmunohistoquímica , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/inmunología , ARN Mensajero/metabolismo , Conejos
10.
Pediatr Dev Pathol ; 8(1): 115-23, 2005.
Artículo en Inglés | MEDLINE | ID: mdl-15803218

RESUMEN

Partial trisomy of 1q is rare. Only 32 cases of isolated partial trisomy 1q have been previously reported. From these cases, a characteristic phenotype is beginning to emerge. We present a case of mosaic duplication of 1q [46,XX,dup (1)(q11q44)/46,XX]. Many features of our patient have been described in previous patients, thus supporting the emerging phenotype. Two particular features, however, have not been previously described. The present case demonstrated extensive mineralization of the extraplacental membranes and bilateral nephromegaly, with an extreme form of diffusely hyperplastic perilobar nephroblastomatosis. Clinical comparison is made between our case and previously reported cases, and the clinical significance of the unique findings are reviewed and discussed.


Asunto(s)
Calcinosis/patología , Cromosomas Humanos Par 1/genética , Membranas Extraembrionarias/patología , Neoplasias Renales/genética , Mosaicismo , Trisomía , Tumor de Wilms/genética , Anomalías Múltiples , Adulto , Bandeo Cromosómico , Resultado Fatal , Femenino , Humanos , Recién Nacido , Neoplasias Renales/patología , Embarazo , Tumor de Wilms/patología
11.
Am J Forensic Med Pathol ; 26(1): 92-5, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15725785

RESUMEN

The incidence of amniotic fluid embolism during pregnancy is approximately 1/50,000 and has a mortality rate in excess of 80%. The postmortem diagnosis of amniotic fluid embolism can be challenging for forensic investigators and pathologists. At autopsy, usually signs of disseminated intravascular coagulation suggest an amniotic fluid embolism. A definitive diagnosis of amniotic fluid embolism cannot be made until ancillary studies are performed on the decedent's tissues. We report a case of a 37-year-old G3P2 white female who was 36 weeks gestation when her membranes spontaneously ruptured. She suddenly became breathless, went into cardiogenic shock, and died. The autopsy revealed gross and microscopic findings of amniotic fluid embolism, which was confirmed with ancillary studies consisting of special stains, immunohistochemistry, and a serum tryptase level. The authors hope this case report, including gross and microscopic autopsy findings with procedural and ancillary studies, and review of the literature will help investigators and pathologists in the diagnosis of amniotic fluid embolism.


Asunto(s)
Embolia de Líquido Amniótico/diagnóstico , Adulto , Autopsia , Diagnóstico Diferencial , Disnea/etiología , Embolia de Líquido Amniótico/complicaciones , Embolia de Líquido Amniótico/patología , Femenino , Humanos , Embarazo , Tercer Trimestre del Embarazo
12.
Am J Physiol Lung Cell Mol Physiol ; 288(1): L190-201, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15447940

RESUMEN

Thrombin activates protease-activated receptor (PAR)-1 and induces a myofibroblast phenotype in normal lung fibroblasts that resembles the phenotype of scleroderma lung fibroblasts. We now demonstrate that PAR-1 expression is dramatically increased in lung tissue from scleroderma patients, where it is associated with inflammatory and fibroproliferative foci. We also observe that thrombin induces resistance to apoptosis in normal lung fibroblasts, and this process is regulated by protein kinase C (PKC)-epsilon but not by PKC-alpha. Overexpression of a constitutively active (c-a) form of PAR-1 or PKC-epsilon significantly inhibits Fas ligand-induced apoptosis in lung fibroblasts, whereas scleroderma lung fibroblasts are resistant to apoptosis de novo. Thrombin translocates p21Cip1/WAF1, a signaling molecule downstream of PKC, from the nucleus to cytoplasm in normal lung fibroblasts mimicking the localization of p21Cip1/WAF1 in scleroderma lung fibroblasts. Overexpression of c-a PKC-alpha or PKC-epsilon results in accumulation of p21Cip1/WAF1 in the cytoplasm. Depletion of PKC-alpha or inhibition of mitogen-activated protein kinase (MAPK) blocks thrombin-induced DNA synthesis in lung fibroblasts. Inhibition of PKC by calphostin or PKC-alpha, but not PKC-epsilon, by antisense oligonucleotides prevents thrombin-induced MAPK phosphorylation and accumulation of G(1) phase regulatory protein cyclin D1, suggesting that PKC-alpha, MAPK, and cyclin D1 mediate lung fibroblast proliferation. These data demonstrate that two distinct PKC isoforms mediate thrombin-induced resistance to apoptosis and proliferation and suggest that p21Cip1/WAF1 promotes both phenomena.


Asunto(s)
ADN/biosíntesis , Fibroblastos , Miocitos del Músculo Liso , Proteína Quinasa C/metabolismo , Esclerodermia Sistémica/patología , Trombina/farmacología , Anciano , Apoptosis/efectos de los fármacos , Proteínas de Ciclo Celular/metabolismo , Supervivencia Celular , Células Cultivadas , Ciclina D1/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteína Ligando Fas , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Humanos , Isoenzimas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Glicoproteínas de Membrana/farmacología , Persona de Mediana Edad , Miocitos del Músculo Liso/patología , Fosforilación/efectos de los fármacos , Proteína Quinasa C-alfa , Proteína Quinasa C-epsilon , Receptor PAR-1/metabolismo
13.
Am J Pathol ; 163(4): 1467-79, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14507654

RESUMEN

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinical syndrome characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intraalveolar fibrosis. We have developed an animal model of BOOP where CBA/J mice infected with 1 x 10(6) plaque-forming units (PFU) reovirus 1/L develop follicular bronchiolitis and intraalveolar fibrosis similar to human BOOP. In this report, we demonstrate a role for T cells in the development of intraluminal fibrosis associated with BOOP. Corticosteroid treatment of reovirus 1/L-infected mice both inhibited the development of fibrotic lesions when administered early in the time-course and promoted the resolution of fibrotic lesions when corticosteroid administration was delayed. Further, the depletion of either CD4(+) or CD8(+) T cells before reovirus 1/L infection also inhibited fibrotic lesion development. Both corticosteroid treatment and depletion of CD4(+) or CD8(+) T cells also resulted in decreased expression of the proinflammatory and profibrotic cytokines, interferon (IFN)-gamma and monocyte chemoattractant protein-1 (MCP-1). Further, treatment of mice with a neutralizing monoclonal antibody to IFN-gamma also significantly inhibited the development of fibrosis. Taken together, these results suggest a significant role for T cells in the development of reovirus 1/L-induced BOOP fibrotic lesions in CBA/J mice and suggests that T(H)1-derived cytokines, especially IFN-gamma, may play a key role in fibrotic lesion development.


Asunto(s)
Neumonía en Organización Criptogénica/fisiopatología , Orthoreovirus de los Mamíferos , Fibrosis Pulmonar/fisiopatología , Fibrosis Pulmonar/virología , Infecciones por Reoviridae/complicaciones , Linfocitos T , Animales , Líquido del Lavado Bronquioalveolar/citología , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/patología , Quimiocinas/metabolismo , Neumonía en Organización Criptogénica/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Fibrosis , Glucocorticoides/farmacología , Humanos , Inflamación/patología , Leucaféresis , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Metilprednisolona/farmacología , Ratones , Ratones Endogámicos CBA , Cavidad Nasal/virología , Fibrosis Pulmonar/patología
14.
Am J Physiol Lung Cell Mol Physiol ; 285(2): L334-43, 2003 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12665468

RESUMEN

Activated fibroblasts, or myofibroblasts, are crucial players in tissue remodeling, wound healing, and various fibrotic disorders, including interstitial lung fibrosis associated with scleroderma. Here we characterize the signaling pathways in normal lung fibroblasts exposed to thrombin as they acquire two of the main features of myofibroblasts: smooth muscle (SM) alpha-actin organization and collagen gel contraction. Our results show that the small G protein Rho is involved in lung myofibroblast differentiation. Thrombin induces Rho-35S-labeled guanosine 5'-O-(3-thiotriphosphate) binding in a dose-dependent manner. It potently stimulates Rho activity in vivo and initiates protein kinase C (PKC)-epsilon-Rho complex formation. Toxin B, which inactivates Rho by ADP ribosylation, inhibits thrombin-induced SM alpha-actin organization, collagen gel contraction, and PKC-epsilon-SM alpha-actin and PKC-epsilon-RhoA coimmunoprecipitation. However, it has no effect on PKC-epsilon activation or translocation of PKC-epsilon to the membrane. Overexpression of constitutively active PKC-epsilon and constitutively active RhoA induces collagen gel contraction or SM alpha-actin organization, whereas, individually, they do not perform these functions. We therefore conclude that the contractile activity of myofibroblasts induced by thrombin is mediated via PKC-epsilon- and RhoA-dependent pathways and that activation of both of these molecules is required. We postulate that PKC-epsilon-RhoA complex formation is an early event in thrombin activation of lung fibroblasts, followed by PKC-epsilon-SM alpha-actin coimmunoprecipitation, which leads to the PKC-epsilon-RhoA-SM alpha-actin ternary complex formation.


Asunto(s)
Actinas/fisiología , Pulmón/fisiología , Contracción Muscular/fisiología , Trombina/fisiología , Activación Enzimática/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Proteína Quinasa C/metabolismo , Proteína Quinasa C-epsilon , Trombina/farmacología , Proteína de Unión al GTP rhoA/metabolismo
15.
Am J Respir Cell Mol Biol ; 28(2): 208-17, 2003 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-12540488

RESUMEN

Bronchiolitis obliterans organizing pneumonia (BOOP) and Acute Respiratory Distress Syndrome (ARDS) are two pulmonary diseases with fibrotic components. BOOP is characterized by perivascular/peribronchiolar leukocyte infiltration leading to the development of intra-alveolar fibrosis. ARDS is a biphasic disease that includes an acute phase, consisting of severe leukocyte infiltration, edema, hemorrhage, and the formation of hyaline membranes, and a chronic phase, which is characterized by persistent intra-alveolar and interstitial fibrosis. CBA/J mice infected with 1 x 10(6) plaque-forming units (pfu) reovirus 1/L develop follicular bronchiolitis and intra-alveolar fibrosis similar to BOOP. In contrast, CBA/J mice infected with 1 x 10(7) pfu reovirus 1/L develop histologic characteristics of ARDS including diffuse alveolar damage, hyaline membranes, and intra-alveolar fibrosis. In this report, we demonstrate a differential role for T lymphocytes in the development of fibrosis associated with BOOP versus ARDS. Neonatally thymectomized CBA/J mice infected with 1 x 10(7) pfu (ARDS) reovirus 1/L still develop the hallmark characteristics of ARDS, including a severe viral pneumonia with cellular infiltrates comprised mainly of macrophages and neutrophils, hyaline membrane formation, and hemorrhage during the acute phase of the disease and persistent intra-alveolar fibrosis during the chronic phase of the disease. In contrast, neonatally thymectomized CBA/J mice infected with 1 x 10(6) pfu (BOOP) reovirus 1/L do not develop intra-alveolar fibrosis associated with BOOP. Therefore, while T cells are necessary for the development of intraluminal fibrosis associated with BOOP, they are not necessary for the development of intraluminal fibrosis associated with ARDS. Furthermore, we suggest that interferon-gamma plays a key role in the fibrotic process and that elevated levels of interferon-gamma are associated with a continuum from least to more severe fibrosis.


Asunto(s)
Neumonía en Organización Criptogénica/etiología , Orthoreovirus de los Mamíferos/patogenicidad , Síndrome de Dificultad Respiratoria/etiología , Linfocitos T/inmunología , Animales , Quimiocinas/genética , Neumonía en Organización Criptogénica/inmunología , Neumonía en Organización Criptogénica/patología , Citocinas/genética , Fibrosis , Expresión Génica , Humanos , Interferón gamma/metabolismo , Ratones , Ratones Endogámicos CBA , ARN Mensajero/genética , ARN Mensajero/metabolismo , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/patología
16.
Clin Immunol ; 103(3 Pt 1): 284-95, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12173303

RESUMEN

Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by diffuse alveolar damage (DAD) secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or noninfectious insult. We have previously described a unique animal model in which CBA/J mice infected with reovirus 1/L develop ARDS. This model recapitulates the histopathological changes observed in human ARDS, which consist of the overlapping phases of exudation, including the formation of hyaline membranes, regeneration, and healing via repair with fibrosis. In this report, we show that the development of DAD in the acute phase of the disease and intraalveolar fibrosis in the late phase of the disease was not modulated by treatment with methylprednisolone (MPS). In the presence or absence of MPS, the majority of cells infiltrating the lungs after reovirus 1/L infection were polymorphonuclear leukocytes and macrophages. A number of key proinflammatory and anti-inflammatory cytokines/chemokines that are observed in the BAL fluid of ARDS patients were also found in the lungs of mice after reovirus 1/L infection and were not modulated by MPS. These include interferon-gamma, interleukin-10, and monocyte chemoattractant protein. The histopathology, cytokine/chemokine expression, and response to corticosteroids in reovirus 1/L-induced ARDS are similar to what is observed in human patients, making this a clinically relevant model.


Asunto(s)
Glucocorticoides/farmacología , Metilprednisolona/farmacología , Orthoreovirus de los Mamíferos/inmunología , Infecciones por Reoviridae/inmunología , Síndrome de Dificultad Respiratoria/inmunología , Animales , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Histocitoquímica , Humanos , Hidroxiprolina/análisis , Ratones , Ratones Endogámicos CBA , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/patología , ARN/química , ARN/genética , Infecciones por Reoviridae/tratamiento farmacológico , Infecciones por Reoviridae/patología , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/patología , Organismos Libres de Patógenos Específicos
17.
Exp Mol Pathol ; 72(1): 24-36, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11784120

RESUMEN

Acute respiratory distress syndrome (ARDS) is a clinical syndrome that is characterized by diffuse alveolar damage usually secondary to an intense host inflammatory response of the lung to a pulmonary or extrapulmonary infectious or noninfectious insult. In this report we describe a unique animal model in which CBA/J mice infected with reovirus serotype 1, strain Lang develop ARDS. This model recapitulates the histopathological changes observed in human ARDS, which consists of the overlapping phases of exudation including the formation of hyaline membranes, regeneration, and healing via resolution and/or repair with fibrosis. While the consequences of a number of infectious and noninfectious insults in various animal systems have been developed as models of human ARDS, they are models of acute lung injury and are of short-term duration. Therefore, they do not recapitulate all of the clinical and pathological phases observed in human ARDS. Thus, study of the cellular and molecular factors involved in these distinct phases of the disease have been limited. Reovirus 1/L infection of CBA/J mice will allow investigations of the pathophysiology of ARDS as it progresses from the initial stages of edema and neutrophilia to fibrotic lesion development in late stages.


Asunto(s)
Modelos Animales de Enfermedad , Pulmón/patología , Orthoreovirus de los Mamíferos , Infecciones por Reoviridae , Síndrome de Dificultad Respiratoria , Enfermedad Aguda , Animales , Líquido del Lavado Bronquioalveolar , Permeabilidad Capilar , Colágeno/metabolismo , Femenino , Fibrosis/patología , Humanos , Pulmón/virología , Ratones , Ratones Endogámicos CBA , Orthoreovirus de los Mamíferos/fisiología , Infecciones por Reoviridae/patología , Infecciones por Reoviridae/fisiopatología , Infecciones por Reoviridae/virología , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/fisiopatología , Síndrome de Dificultad Respiratoria/virología , Infecciones del Sistema Respiratorio/patología , Infecciones del Sistema Respiratorio/fisiopatología , Infecciones del Sistema Respiratorio/virología
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