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1.
Medicine (Baltimore) ; 98(29): e16419, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335692

RESUMO

Squawks are lung adventitious sounds with a mix of both musical and nonmusical components heard during the inspiratory phase. Small series have described squawks in interstitial lung diseases. Hypersensitivity pneumonitis and other diseases involving small airways can result in squawks, but new interstitial lung diseases (ILDs) involving peripheral airways are being described. A retrospective analysis was performed on 1000 consecutive patients from a database of ILD of a tertiary referral center. Squawks were recorded in 49 cases (4.9%), hypersensitivity pneumonitis (23 cases), connective tissue disease (7), microaspiration (4), pleuroparenchymal fibroelastosis (4), fibrosing cryptogenic organizing pneumonia (, 3), familial ILD (2), sarcoidosis (2), idiopathic pulmonary fibrosis (IPF; 1), bronchiolitis (2), and nonspecific interstitial pneumonia (1). One patient had a final diagnosis of IPF. There was a significant association between mosaic pattern and squawks: 20 cases with squawks (40.8%) had mosaic pattern compared with 140 (14.7%) cases without squawks (x = 23.6, P < .001).Findings indicative of fibrosis were described on high-resolution chest tomography (HRCT) in 715 cases (71.5%). Squawks were more common in patients with findings indicative of fibrosis on HRCT: 45 of 715 (6.3%) compared with 4 of 285 (1.4%) of those without findings indicative of fibrosis (x = 10.46, P = .001).In conclusion, squawks are an uncommon finding on physical examination in patients with ILD, but when present suggest fibrosing ILD associated with bronchiolar involvement. However, squawks are rare in IPF.


Assuntos
Doenças Pulmonares Intersticiais , Fibrose Pulmonar , Sons Respiratórios , Auscultação/métodos , Bronquíolos/patologia , Bronquíolos/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/fisiopatologia , Sons Respiratórios/diagnóstico , Sons Respiratórios/fisiopatologia , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos
2.
Environ Pollut ; 253: 864-871, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349195

RESUMO

It is estimated that 10% of the worldwide population lives in the vicinity of an active volcano. However, volcanogenic air pollution studies are still outnumbered when compared with anthropogenic air pollution studies, representing an unknown risk to human populations inhabiting volcanic areas worldwide. This study was carried out in the Azorean archipelago of Portugal, in areas with active non-eruptive volcanism. The hydrothermal emissions within the volcanic complex of Furnas (São Miguel Island) are responsible for the emission of nearly 1000 tons of CO2 per day, along with H2S, the radioactive gas - radon, among others. Besides the gaseous emissions, metals (e.g., Hg, Cd, Al, Ni) and particulate matter are also released into the environment. We test the hypothesis that chronic exposure to volcanogenic air pollution alters the histomorphology of the bronchioles and terminal bronchioles, using the house mouse, Mus musculus, as bioindicator species. Mus musculus were live-captured at three different locations: two villages with active volcanism and a village without any type of volcanic activity (reference site). The histomorphology of the bronchioles (diameter, epithelium thickness, smooth muscle layer thickness, submucosa thickness and the histological evaluation of the peribronchiolar inflammation) and of the terminal bronchioles (epithelium thickness and classification) were evaluated. Mice chronically exposed to volcanogenic air pollution presented bronchioles with increased epithelial thickness, increased smooth muscle layer, increased submucosa thickness and increased peribronchiolar inflammation. Similarly, terminal bronchioles presented structural alterations consistent with bronchodysplasia. For the first time we demonstrate that chronic exposure to non-eruptive volcanically active environments causes inflammation and histomorphological alterations in mice lower airways consistent with asthma and chronic bronchitis. These results reveal that chronic exposure to non-eruptive volcanic activity represents a risk factor that can affect the health of the respiratory system of humans inhabiting hydrothermal areas.


Assuntos
Poluentes Atmosféricos/toxicidade , Poluição do Ar/análise , Testes de Toxicidade Crônica , Erupções Vulcânicas , Poluentes Atmosféricos/análise , Animais , Asma , Bronquíolos/patologia , Gases , Humanos , Inflamação , Metais , Camundongos , Material Particulado , Portugal
3.
Int J Mol Sci ; 20(11)2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31141956

RESUMO

Small airways were historically considered to be almost irrelevant in the development and control of pulmonary chronic diseases but, as a matter of fact, in the past few years we have learned that they are not so "silent". Asthma is still a worldwide health issue due to the great share of patients being far from optimal management. Several studies have shown that the deeper lung inflammation plays a critical role in asthma pathogenesis, mostly in these not well-controlled subjects. Therefore, assessing the degree of small airways inflammation and impairment appears to be a pivotal step in the asthmatic patient's management. It is now possible to evaluate them through direct and indirect measurements, even if some obstacles still affect their clinical application. The success of any treatment obviously depends on several factors but reaching the deeper lung has become a priority and, for inhaled drugs, this is strictly connected to the molecule's size. The aim of the present review is to summarize the recent evidence concerning the small airway involvement in asthma, its physiopathological characteristics and how it can be evaluated in order to undertake a personalized pharmacological treatment and achieve a better disease control.


Assuntos
Antiasmáticos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Bronquíolos/patologia , Administração por Inalação , Antiasmáticos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Asma/diagnóstico , Humanos
4.
J Pediatr Surg ; 54(5): 937-944, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30792093

RESUMO

PURPOSE: Tracheal occlusion (TO) reverses pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH), but its mechanism of action remains poorly understood. Wnt signaling plays a critical role in lung development, but few studies exist. The purpose of our study was to a) confirm that our CDH rabbit model produced PH which was reversed by TO and b) determine the effects of CDH +/- TO on Wnt signaling. METHODS: CDH was created in fetal rabbits at 23 days, TO at 28 days, and lung collection at 31 days. Lung body weight ratio (LBWR) and mean terminal bronchiole density (MTBD) were determined. mRNA and miRNA expression was determined in the left lower lobe using RT-qPCR. RESULTS: Fifteen CDH, 15 CDH + TO, 6 sham CDH, and 15 controls survived and were included in the study. LBWR was low in CDH, while CDH + TO was similar to controls (p = 0.003). MTBD was higher in CDH fetuses and restored to control levels in CDH + TO (p < 0.001). Reference genes TOP1, SDHA, and ACTB were consistently expressed within and between treatment groups. miR-33 and MKI67 were increased, and Lgl1 was decreased in CDH + TO. CONCLUSION: TO reversed pulmonary hypoplasia and stimulated early Wnt signaling in CDH fetal rabbits. TYPE OF STUDY: Basic science, prospective. LEVEL OF EVIDENCE: II.


Assuntos
Obstrução das Vias Respiratórias/metabolismo , Bronquíolos/patologia , Modelos Animais de Doenças , Hérnias Diafragmáticas Congênitas/metabolismo , Pulmão/patologia , Via de Sinalização Wnt , Obstrução das Vias Respiratórias/complicações , Animais , DNA Topoisomerases Tipo I/genética , Complexo II de Transporte de Elétrons/genética , Feto , Expressão Gênica , Glicoproteínas/genética , Hérnias Diafragmáticas Congênitas/complicações , Pulmão/embriologia , MicroRNAs/genética , Tamanho do Órgão , Cuidado Pré-Natal , Estudos Prospectivos , Coelhos , Traqueia
5.
Pathol Int ; 68(7): 425-430, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29696743

RESUMO

Both glandular papilloma (GP) and sclerosing pneumocytoma (SP) are rare tumors in the lung. We herein report an extremely rare case of coexistence of these two uncommon tumors. The patient was a 40-year-old Japanese woman with no chief complaint. A solitary nodule of the lung was detected using chest computed tomography. The transbronchial biopsy revealed that the tumor histologically corresponded to GP. The patient subsequently underwent partial resection of the right upper lobe. Histological examination of the resected specimens further revealed that the mass contained two different and independent elements and displayed typically histological features of GP and SP. Molecular analysis further revealed the presence of BRAF V600E and AKT1 E17K mutations in GP, whereas only AKT1 mutation was detected in SP. To our knowledge, this is the first case of coexistence of GP and SP in the bronchiole harboring common AKT1 mutation and different BRAF V600E mutational status.


Assuntos
Bronquíolos/patologia , Neoplasias Pulmonares/patologia , Neoplasias Primárias Múltiplas/patologia , Papiloma/patologia , Hemangioma Esclerosante Pulmonar/patologia , Adulto , Feminino , Humanos
6.
J Virol ; 92(11)2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29593031

RESUMO

Lower respiratory tract infection with respiratory syncytial virus (RSV) produces profound inflammation. Despite an understanding of the role of adaptive immunity in RSV infection, the identity of the major sentinel cells initially triggering inflammation is controversial. Here we evaluate the role of nonciliated secretoglobin (Scgb1a1)-expressing bronchiolar epithelial cells in RSV infection. Mice expressing a tamoxifen (TMX)-inducible Cre recombinase-estrogen receptor fusion protein (CreERTM) knocked into the Scgb1a1 locus were crossed with mice that harbor a RelA conditional allele (RelAfl ), with loxP sites flanking exons 5 to 8 of the Rel homology domain. The Scgb1a1CreERTM/+ × RelAfl/fl mouse is a RelA conditional knockout (RelACKO) of a nonciliated epithelial cell population enriched in the small bronchioles. TMX-treated RelACKO mice have reduced pulmonary neutrophilic infiltration and impaired expression and secretion of NF-κB-dependent cytokines in response to RSV. In addition, RelACKO mice had reduced expression levels of interferon (IFN) regulatory factor 1/7 (IRF1/7) and retinoic acid-inducible gene I (RIG-I), components of the mucosal IFN positive-feedback loop. We demonstrate that RSV replication induces RelA to complex with bromodomain-containing protein 4 (BRD4), a cofactor required for RNA polymerase II (Pol II) phosphorylation, activating the atypical histone acetyltransferase (HAT) activity of BRD4 required for phospho-Ser2 Pol II formation, histone H3K122 acetylation, and cytokine secretion in vitro and in vivo TMX-treated RelACKO mice have less weight loss and reduced airway obstruction/hyperreactivity yet similar levels of IFN-γ production despite higher levels of virus production. These data indicate that the nonciliated Scgb1a1-expressing epithelium is a major innate sensor for restricting RSV infection by mediating neutrophilic inflammation and chemokine and mucosal IFN production via the RelA-BRD4 pathway.IMPORTANCE RSV infection is the most common cause of infant hospitalizations in the United States, resulting in 2.1 million children annually requiring medical attention. RSV primarily infects nasal epithelial cells, spreading distally to produce severe lower respiratory tract infections. Our study examines the role of a nonciliated respiratory epithelial cell population in RSV infection. We genetically engineered a mouse that can be selectively depleted of the NF-κB/RelA transcription factor in this subset of epithelial cells. These mice show an impaired activation of the bromodomain-containing protein 4 (BRD4) coactivator, resulting in reduced cytokine expression and neutrophilic inflammation. During the course of RSV infection, epithelial RelA-depleted mice have reduced disease scores and airway hyperreactivity yet increased levels of virus replication. We conclude that RelA-BRD4 signaling in nonciliated bronchiolar epithelial cells mediates neutrophilic airway inflammation and disease severity. This complex is an attractive target to reduce the severity of infection.


Assuntos
Células Epiteliais Alveolares/metabolismo , Interferon gama/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Proteínas Nucleares/metabolismo , Infecções por Vírus Respiratório Sincicial/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/metabolismo , Uteroglobina/metabolismo , Células Epiteliais Alveolares/virologia , Animais , Bronquíolos/patologia , Bronquíolos/virologia , Linhagem Celular , Proteína DEAD-box 58/biossíntese , Feminino , Humanos , Inflamação/patologia , Inflamação/virologia , Fator Regulador 1 de Interferon/biossíntese , Fator Regulador 7 de Interferon/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Mucosa Respiratória/patologia , Mucosa Respiratória/virologia , Infecções por Vírus Respiratório Sincicial/patologia , Infecções por Vírus Respiratório Sincicial/virologia , Infecções Respiratórias/imunologia , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Tamoxifeno/farmacologia , Fator de Transcrição RelA/genética
7.
Curr Opin Allergy Clin Immunol ; 18(2): 87-95, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29394172

RESUMO

PURPOSE OF REVIEW: Exposure-related bronchiolitis is increasingly recognized as an important but challenging clinical diagnosis. Acute and chronic inhalational exposures are associated with variable clinical presentations and a spectrum of histopathologic abnormalities affecting the small airways. This review provides an overview of the histologic patterns and occupational settings for exposure-related bronchiolitis, along with recent advances in disease diagnosis and management. RECENT FINDINGS: The entire histopathologic spectrum of bronchiolitis (constrictive, obliterative, proliferative, lymphocytic, respiratory) has been reported in exposure-related bronchiolitis. Recent studies have shown that lung clearance index testing and impulse oscillometry are more sensitive than spirometry in detecting small airways abnormalities and may augment the diagnosis of occupational bronchiolitis. Prognosis in indolent occupational bronchiolitis appears more favorable than some other types of bronchiolitis but is variable depending on the extent of bronchiolar inflammation and the stage of disease at which exposure removal occurs. SUMMARY: No specific histopathologic pattern of bronchiolitis is pathognomonic for occupational bronchiolitis as one or more histologic patterns may be present. A high index of suspicion is needed for exposure and disease recognition. Recent advances that may aid in diagnosis include transbronchial cryobiopsy, lung clearance index testing, and impulse oscillometry, although further research is needed.


Assuntos
Bronquiolite/patologia , Exposição por Inalação/efeitos adversos , Doenças Profissionais/patologia , Exposição Ocupacional/efeitos adversos , Biópsia , Bronquíolos/patologia , Bronquiolite/diagnóstico , Bronquiolite/tratamento farmacológico , Bronquiolite/etiologia , Aditivos Alimentares/efeitos adversos , Indústria Alimentícia , Glucocorticoides/uso terapêutico , Humanos , Doenças Profissionais/diagnóstico , Doenças Profissionais/tratamento farmacológico , Doenças Profissionais/etiologia , Prognóstico , Vigilância em Saúde Pública/métodos , Testes de Função Respiratória
8.
Histopathology ; 73(1): 29-37, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29464753

RESUMO

AIMS: To confirm whether or not grade 4 asbestosis progresses from the respiratory bronchiole to the peripheral lung. METHODS AND RESULTS: We examined retrospectively the autopsy or lobectomy specimens from 31 cases (29 males; mean age 64 years) satisfying the pathological criteria of grade 4 asbestosis. Asbestos bodies (ABs) were quantified in samples of dissolved lung and in tissue preparations on glass slides. Respiratory bronchiolar lesions were graded as 0, 1 and ≥2. Grade 4 asbestosis was subdivided into an atelectatic induration (AI) and usual interstitial pneumonia pattern (UIP pattern). Five, 10, and 16 cases had grades 0, 1 or ≥2 lesions, respectively, with mean respective numbers of ABs in dissolved lung of 117 000/g dry lung, 468 000/g and 968 000/g; and in specimens on glass slides of seven ABs/cm2 of tissue slice, 34 ABs /cm2 and 195 ABs /cm2 . The differences were significant. Fifteen and 16 cases showed AI and UIP patterns, respectively, with mean respective numbers of ABs in dissolved lung of 1 006 000/g dry lung and 354 000/g, and 186 and 56 ABs/cm2 on glass slides. The differences were significant. AI patterns originated in subpleural lobules or subpleural zonal areas and UIP patterns originated in subpleural, peripheral lobules. CONCLUSIONS: Grade 4 asbestosis does not start in the respiratory bronchiole. The presence of a grade 1 lesion is not required for the diagnosis of grade 4 asbestosis.


Assuntos
Asbestose/patologia , Bronquíolos/patologia , Idoso , Feminino , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Histol Histopathol ; 33(3): 317-326, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28952142

RESUMO

Lung adenocarcinomas (ADCs) have been roughly divided into two groups: the terminal respiratory unit (TRU) type and non-TRU type. These ADCs appear to develop through exclusive carcinogenetic pathways because of differences in their cellular morphologies and the profiles of protein expression and genetic alterations. The TRU type develops from atypical adenomatous hyperplasia as a precursor. On the other hand, the histogenesis of the non-TRU type has not yet been defined in detail. We herein investigated histopathological changes in the non-tumor lung tissues of patients with non-TRU-type ADCs in order to define their potential histogenesis. The non-TRU type preferentially occurs in patients with interstitial pneumonia, in whom tumors are located in honeycomb lesions and are associated with bronchiolar metaplasia (BM). Among patients without interstitial pneumonia, non-tumor lung tissues from non-TRU-type ADCs were often affected by multiple BM. In these cases, tumors often were associated with BM. Metaplastic cells adjacent to non-TRU-type ADCs ectopically expressed HNF-4α, a marker for non-TRU-type ADCs. These results suggest that the non-TRU type develops through distinct histogenesis, in which BM is implicated.


Assuntos
Adenocarcinoma/patologia , Bronquíolos/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma de Pulmão , Adulto , Idoso , Feminino , Humanos , Masculino , Metaplasia , Pessoa de Meia-Idade
10.
J Occup Environ Med ; 60(1): 90-96, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28953074

RESUMO

OBJECTIVE: We identified cases of constrictive bronchiolitis (CB), an inflammatory injury obliterating the small airways, in adults caused by inhalational exposure to determine an appropriate case definition. METHODS: We performed a systematic review with meta-analysis for these cases from 1990 to 2017. Publications were included if there was 1) inhalational exposure; 2) respiratory symptoms/signs; 3) pulmonary function test results; and 4) computerized tomographic chest imaging. Many had a lung biopsy. RESULTS: Two hundred seventy-four articles were retrieved; 22 manuscripts comprising 102 cases were included. Diagnostic criteria from cases associated with military deployment to southwest Asia were statistically different from criteria of other etiologies. CONCLUSION: In three cases, the scan was consistent with CB, the biopsy nondiagnostic, yet the diagnosis was made. CB associated with military deployment presented with diagnostic features statistically different from features in the other cases.


Assuntos
Bronquiolite Obliterante/diagnóstico , Bronquiolite Obliterante/fisiopatologia , Exposição por Inalação/efeitos adversos , Biópsia , Bronquíolos/patologia , Bronquiolite Obliterante/induzido quimicamente , Humanos , Testes de Função Respiratória , Tomografia Computadorizada por Raios X
11.
Am J Pathol ; 188(2): 417-431, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29169991

RESUMO

Subclinical primary Pneumocystis infection is the most common pulmonary infection in early infancy, making it important to determine whether it damages the lung. Pneumocystis peaks at 2 to 5 months of age, when respiratory morbidity coincidently increases. We have documented that Pneumocystis increases mucus production in infant lungs, and animal models reveal lung lesions that warrant characterization. Herein, immunocompetent rats infected at birth with Pneumocystis by cohabitation, to resemble community-acquired infection, underwent lung assessments at 45, 60, and 75 days of age. Lungs fixed by vascular perfusion to prevent collapse during necropsy were used for morphometry evaluations of mucus production, airway epithelial thickening, perivascular and peribronchiolar inflammation, and structural airway remodeling. Changes in these histologic features indicate lung disease. Selected immune markers were assessed in parallel using fresh-frozen lung tissue from sibling rats of the same cages. Sequential activation of NF-κB and an increased Gata3/T-bet mRNA level ratio, consistent with a type 2 helper T-cell-type inflammatory response, and subacute fibrosis were recognized. Therefore, documenting subclinical Pneumocystis infection induces lung disease in the immunocompetent host. Taken together with the peak age of primary Pneumocystis infection, results warrant investigating the clinical impact of this often subclinical infection on the severity of respiratory diseases in early infancy. This model can also be used to assess the effects of airway insults, including coinfections by recognized respiratory pathogens.


Assuntos
Pneumonia por Pneumocystis/imunologia , Células Th2/imunologia , Animais , Bronquíolos/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/patologia , Feminino , Regulação da Expressão Gênica/fisiologia , Imunocompetência , Mediadores da Inflamação/metabolismo , Muco/metabolismo , NF-kappa B/metabolismo , Pneumonia por Pneumocystis/patologia , RNA Mensageiro/genética , Ratos Sprague-Dawley , Mucosa Respiratória/patologia , Transdução de Sinais/fisiologia
12.
PLoS Negl Trop Dis ; 11(12): e0006076, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29240753

RESUMO

BACKGROUND: Cases of acute respiratory tract infection caused by Pteropine orthoreovirus (PRV) of the genus Orthoreovirus (family: Reoviridae) have been reported in Southeast Asia, where it was isolated from humans and bats. It is possible that PRV-associated respiratory infections might be prevalent in Southeast Asia. The clinical course of PRV is not fully elucidated. METHODS: The virulence, pathology, and pathogenesis of two PRV strains, a human-borne PRV strain (isolated from a patient, who returned to Japan from Bali, Indonesia in 2007) and a bat-borne PRV (isolated from a bat [Eonycteris spelaea] in the Philippines in 2013) were investigated in BALB/c mice using virological, pathological, and immunological study methods. RESULTS: The intranasal inoculation of BALB/c mice with human-borne PRV caused respiratory infection. In addition, all mice with immunity induced by pre-inoculation with a non-lethal dose of PRV were completely protected against lethal PRV infection. Mice treated with antiserum with neutralizing antibody activity after inoculation with a lethal dose of PRV showed a reduced fatality rate. In this mouse model, bat-borne PRV caused respiratory infection similar to human-borne PRV. PRV caused lethal respiratory disease in an animal model of PRV infection, in which BALB/c mice were used. CONCLUSIONS: The BALB/c mouse model might help to accelerate research on the virulence of PRV and be useful for evaluating the efficacy of therapeutic agents and vaccines for the treatment and prevention of PRV infection. PRV was shown for the first time to be a causative virus of respiratory disease on the basis of Koch's postulations by the additional demonstration that PRV caused respiratory disease in mice through their intranasal inoculation with PRV.


Assuntos
Modelos Animais de Doenças , Orthoreovirus/patogenicidade , Infecções por Reoviridae/patologia , Infecções por Reoviridae/virologia , Virulência , Animais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Ásia Sudeste , Peso Corporal , Bronquíolos/patologia , Bronquíolos/virologia , Quirópteros/virologia , Feminino , Genoma Viral , Células HEK293 , Humanos , Indonésia , Japão , Pulmão/patologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Orthoreovirus/classificação , Orthoreovirus/genética , Orthoreovirus/isolamento & purificação , Filipinas , RNA Viral/análise , Infecções por Reoviridae/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/patologia , Infecções Respiratórias/virologia , Taxa de Sobrevida , Vacinas/farmacologia , Células Vero , Carga Viral , Ensaio de Placa Viral
13.
Toxicol Sci ; 159(2): 413-421, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28962520

RESUMO

Styrene is a mouse-specific lung carcinogen, and short-term mode of action studies have demonstrated that cytotoxicity and/or cell proliferation, and genomic changes are dependent on CYP2F2 metabolism. The current study examined histopathology, cell proliferation, and genomic changes in CD-1, C57BL/6 (WT), CYP2F2(-/-) (KO), and CYP2F2(-/-) (CYP2F1, 2B6, 2A13-transgene) (TG; humanized) mice following exposure for up to 104 weeks to 0- or 120-ppm styrene vapor. Five mice per treatment group were sacrificed at 1, 26, 52, and 78 weeks. Additional 50 mice per treatment group were followed until death or 104 weeks of exposure. Cytotoxicity was present in the terminal bronchioles of some CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Hyperplasia in the terminal bronchioles was present in CD-1 and WT mice exposed to styrene, but not in KO or TG mice. Increased cell proliferation, measured by KI-67 staining, occurred in CD-1 and WT mice exposed to styrene for 1 week, but not after 26, 52, or 78 weeks, nor in KO or TG mice. Styrene increased the incidence of bronchioloalveolar adenomas and carcinomas in CD-1 mice. No increase in lung tumors was found in WT despite clear evidence of lung toxicity, or, KO or TG mice. The absence of preneoplastic lesions and tumorigenicity in KO and TG mice indicates that mouse-specific CYP2F2 metabolism is responsible for both the short-term and chronic toxicity and tumorigenicity of styrene, and activation of styrene by CYP2F2 is a rodent MOA that is neither quantitatively or qualitatively relevant to humans.


Assuntos
Carcinógenos/toxicidade , Sistema Enzimático do Citocromo P-450/genética , Neoplasias Pulmonares/patologia , Pulmão/patologia , Estireno/toxicidade , Animais , Bronquíolos/efeitos dos fármacos , Bronquíolos/patologia , Carcinógenos/administração & dosagem , Humanos , Exposição por Inalação , Neoplasias Pulmonares/induzido quimicamente , Masculino , Camundongos , Camundongos Transgênicos , Estireno/administração & dosagem
14.
World J Gastroenterol ; 23(28): 5253-5256, 2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28811720

RESUMO

A 65-year-old man with cT1bN0M0 stage I middle thoracic esophageal cancer underwent subtotal esophagectomy and gastric tube reconstruction through the posterior mediastinal route after preoperative carbon-ion radiotherapy and chemotherapy in a clinical trial. Anastomotic leakage occurred, but it spontaneously improved. At six months after the operation, he was rehospitalized with a cough and dysphagia. An esophago-bronchiole fistula and stenosis of the gastric tube were observed. He first underwent stent placement in the gastric tube. Two weeks later, the syringeal epithelium was burned by argon plasma coagulation after stent removal. Endoscopic occlusion was then performed for the fistula with two guidewire-assisted silicone spigots. Two weeks later, he was discharged on an oral diet, and he has not developed recurrence of the fistula or cancer for three years. This is the first report of endoscopic occlusion with a guidewire-assisted silicone spigot through the esophagus.


Assuntos
Anastomose Cirúrgica/efeitos adversos , Fístula Anastomótica/terapia , Bronquíolos/patologia , Fístula Esofágica/terapia , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Idoso , Fístula Anastomótica/diagnóstico por imagem , Tosse/etiologia , Tosse/terapia , Fístula Esofágica/complicações , Fístula Esofágica/diagnóstico por imagem , Esofagoscópios , Esofagoscopia/instrumentação , Esofagoscopia/métodos , Esôfago/diagnóstico por imagem , Esôfago/cirurgia , Humanos , Masculino , Procedimentos Cirúrgicos Reconstrutivos/efeitos adversos , Silicones , Stents , Tomografia Computadorizada por Raios X
15.
Exp Toxicol Pathol ; 69(8): 637-642, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28602391

RESUMO

There are two types of bronchiolo-alveolar hyperplasia (hyperplasia) in rodent lungs. The first is "inflammatory hyperplasia" that retains its ability to revert to normal epithelia upon removal of the stimulating insult. The second is "latent tumorigenic hyperplasia", which is irreversible and causes independent preneoplastic lesions that can progress to bronchiolo-alveolar adenocarcinoma. Previously, lung samples with hyperplastic lesions were obtained from rats exposed to N-bis (2-hydroxypropyl) nitrosamine (DHPN) and fine particles (e.g. quartz), and 19 specific markers were examined immunohistochemically to identify latent tumorigenic hyperplasia. In the cytoplasm of the cells that make up the alveolar wall, we found that napsin A was weakly expressed in the inflammatory hyperplastic lesions, and was strongly expressed in the latent tumorigenic hyperplastic lesions induced by DHPN. To validate the possibility that napsin A may serve as a tumorigenic hyperplastic marker, additional experiments were performed with rats and mice. Latent tumorigenic hyperplasia induced by various carcinogens were positive for napsin A, similar to hyperplasia induced by DHPN. Thus, high expression of napsin A in alveolar walls may serve as a useful marker for detecting the tumorigenic potential of lung hyperplasia in rodents.


Assuntos
Adenocarcinoma Bronquioloalveolar/patologia , Ácido Aspártico Endopeptidases/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinogênese/patologia , Neoplasias Pulmonares/patologia , Adenocarcinoma Bronquioloalveolar/metabolismo , Animais , Bronquíolos/patologia , Carcinogênese/metabolismo , Carcinógenos/toxicidade , Feminino , Hiperplasia/patologia , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Alvéolos Pulmonares/patologia , Ratos Endogâmicos F344 , Reprodutibilidade dos Testes
16.
Am J Physiol Lung Cell Mol Physiol ; 313(1): L80-L91, 2017 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-28450285

RESUMO

Exposure to cadmium (Cd) has been associated with development of chronic obstructive lung disease (COPD). The mechanisms and signaling pathways whereby Cd causes pathological peribronchiolar fibrosis, airway remodeling, and subsequent airflow obstruction remain unclear. We aimed to evaluate whether low-dose Cd exposure induces vimentin phosphorylation and Yes-associated protein 1 (YAP1) activation leading to peribronchiolar fibrosis and subsequent airway remodeling. Our data demonstrate that Cd induces myofibroblast differentiation and extracellular matrix (ECM) deposition around small (<2 mm in diameter) airways. Upon Cd exposure, α-smooth muscle actin (α-SMA) expression and the production of ECM proteins, including fibronectin and collagen-1, are markedly induced in primary human lung fibroblasts. Cd induces Smad2/3 activation and the translocation of both Smad2/3 and Yes-associated protein 1 (YAP1) into the nucleus. In parallel, Cd induces AKT and cdc2 phosphorylation and downstream vimentin phosphorylation at Ser39 and Ser55, respectively. AKT and cdc2 inhibitors block Cd-induced vimentin fragmentation and secretion in association with inhibition of α-SMA expression, ECM deposition, and collagen secretion. Furthermore, vimentin silencing abrogates Cd-induced α-SMA expression and decreases ECM production. Vimentin-deficient mice are protected from Cd-induced peribronchiolar fibrosis and remodeling. These findings identify two specific sites on vimentin that are phosphorylated by Cd and highlight the functional significance of vimentin phosphorylation in YAP1/Smad3 signaling that mediates Cd-induced peribronchiolar fibrosis and airway remodeling.


Assuntos
Bronquíolos/patologia , Cádmio/efeitos adversos , Vimentina/metabolismo , Actinas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteína Quinase CDC2/metabolismo , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Colágeno/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrose , Inativação Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fosfoproteínas/metabolismo , Fosforilação/efeitos dos fármacos , Fosfosserina/metabolismo , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Smad/metabolismo , Fatores de Transcrição
17.
Exp Toxicol Pathol ; 69(5): 307-315, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28254108

RESUMO

3D constructs composed of primary normal differentiated human bronchiolar epithelial (NHBE) cells as mono- or co-culture in combination with normal human lung fibroblasts were exposed repeatedly at the air-liquid interface with non-lethal concentrations of mainstream cigarette smoke (4 cigarettes a day, 5days/week, 13 times repetition in total) to build up a permanent burden on the cells. Samples were taken after 4, 8 and 13 times of repeated smoke exposure and the cultures were analyzed by histopathological methods In comparison with the clean air exposure (process control) and incubator control cells the cigarette smoke exposed cultures showed a reduction of cilia bearing as well as mucus producing cells. In both mono- as well as co-cultures, hyperplasia was induced showing different histological cell types (undifferentiated secretory and squamous cell types). At the end of the exposure phase, we observed the development of non-hyperplastic areas strongly positive to CK13 antibody, commonly seen in squamous cells as a marker for non-cornified squamous epithelium, thus suggesting a transition of the normal bronchial epithelial cells towards metaplastic cells. The control cultures (clean air exposed and incubator cells) showed no comparable phenotypic changes. In conclusion, our in vitro model presents a valuable tool to study the induction of metaplastic alterations after exposure to airborne material.


Assuntos
Bronquíolos/efeitos dos fármacos , Técnicas de Cocultura/métodos , Metaplasia/induzido quimicamente , Fumaça/efeitos adversos , Tabaco/toxicidade , Bronquíolos/patologia , Células Cultivadas , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Fibroblastos/efeitos dos fármacos , Humanos , Fenótipo
18.
Am J Respir Cell Mol Biol ; 56(5): 648-656, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28187270

RESUMO

Klebsiella pneumoniae is a common cause of pneumonia. Previous studies have documented an important role for Toll-like receptors (TLRs) expressed by myeloid cells in the recognition of K. pneumoniae and the initiation of a protective immune response. Lung epithelial cells also express TLRs and can participate in innate immune defense. The aim of this study was to examine the role of the common TLR adaptor protein myeloid-differentiation factor (MyD) 88 in lung epithelium during host defense against K. pneumoniae-induced pneumonia. To this end, we first crossed mice expressing cre recombinase under the control of the surfactant protein C (SftpCcre) or the club cell 10 kD (CC10cre) promoter with reporter mice to show that SftpCcre mice mainly express cre in type II alveolar cells, whereas CC10cre mice express cre almost exclusively in bronchiolar epithelial cells. We then generated mice with cell-targeted deletion of MyD88 in type II alveolar (SftpCcre-MyD88-lox) and bronchiolar epithelial (CC10cre-MyD88-lox) cells, and infected them with K. pneumoniae via the airways. Bacterial growth and dissemination were not affected by the loss of MyD88 in SftpCcre-MyD88-lox or CC10cre-MyD88-lox mice compared with control littermates. Furthermore, inflammatory responses induced by K. pneumoniae in the lung were not dependent on MyD88 expression in type II alveolar or bronchiolar epithelial cells. These results indicate that MyD88 expression in two distinct lung epithelial cell types does not contribute to host defense during pneumonia caused by a common human gram-negative pathogen.


Assuntos
Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Infecções por Klebsiella/metabolismo , Klebsiella pneumoniae/fisiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Pneumonia Bacteriana/metabolismo , Animais , Bronquíolos/patologia , Células Epiteliais/patologia , Inflamação/patologia , Integrases/metabolismo , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/patologia , Camundongos , Viabilidade Microbiana , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/patologia , Proteína C Associada a Surfactante Pulmonar/metabolismo , Uteroglobina/metabolismo
19.
Am J Surg Pathol ; 41(2): 182-188, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28079597

RESUMO

The histologic changes occurring in severe/therapy-resistant asthma (SA) as defined by the European Respiratory Society/American Thoracic Society guidelines, particularly at the level of the distal airways are unknown. This study describes the clinical, radiologic, and histologic characteristics of 29 SA patients who underwent video-assisted thoracoscopic surgery lung biopsy. Pathologic observations were correlated with clinical features, especially the presence of autoimmune disease (AID) (15/29, 51.7%). Ten biopsies (10/29, 34.5%) showed only small airway manifestations of asthma, whereas in 19 (65.5%) asthmatic granulomatosis, manifested by asthmatic bronchiolitis supplemented by an alveolar septal mononuclear infiltrates with non-necrotizing granulomas, was present. SA patients without asthmatic granulomatosis showed more striking small airway injury, subbasement membrane thickening, and neutrophilic infiltrates. Cases with concurrent AID had a tendency to more parenchymal eosinophilic inflammation, more bronchiolocentric granulomas, and a suggestion of increased responsivity to nonsteroidal immunosuppressive therapy. Histologic examination of video-assisted thoracoscopic surgery lung biopsies in SA demonstrates diverse pathologies including cases associated with granulomatous inflammation in addition to eosinophilic infiltrates. This spectrum of histologies may link to a high incidence of AID.


Assuntos
Asma/patologia , Doenças Autoimunes/complicações , Bronquíolos/patologia , Granuloma/patologia , Adulto , Asma/complicações , Doenças Autoimunes/epidemiologia , Biópsia , Resistência a Medicamentos , Feminino , Granuloma/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Cirurgia Torácica Vídeoassistida
20.
Transplantation ; 101(2): 310-315, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27163544

RESUMO

BACKGROUND: Chronic lung allograft dysfunction (CLAD), presenting as bronchiolitis obliterans syndrome (BOS) or restrictive allograft syndrome (RAS) is the major limiting factor of long-term survival in lung transplantation. Its pathogenesis is still obscure. In BOS, persistent alloimmune injury and chronic airway inflammation are suggested. One of the main tasks of the lymphatic vessel (LV) system is the promotion of immune cell trafficking. The formation of new LVs has been shown to trigger chronic allograft rejection in kidney transplants. We therefore sought to address the role of lymphangiogenesis in CLAD. METHODS: Formalin-fixed paraffin-embedded tissue samples of 22 patients receiving a lung retransplantation due to BOS or RAS were collected. Lymphatic vessel density (LVD) was determined by immunohistochemical staining for podoplanin. Lung tissue obtained from 13 non-CLAD patients served as control. The impact of LVD on graft survival was assessed. RESULTS: Lymphatic vessel density in CLAD patients did not differ from those in control subjects (median number of LVs per bronchiole: 4.75 (BOS), 6.47 (RAS), 4.25 (control), P = 0.97). Moreover, the number of LVs was not associated with regions of cellular infiltrates (median number of LVs per bronchiole: with infiltrates, 5.00 (BOS), 9.00 (RAS), 4.00 (control), P = 0.62; without infiltrates, 4.5 (BOS), 0.00 (RAS), 4.56 (control), P = 0.74). Lymphatic vessel density did not impact the time to development of BOS or RAS in lung transplantation (low vs high LVD: 38.5 vs 86.0 months, P = 0.15 [BOS]; 60.5 vs 69.5 months, P = 0.80 [RAS]). CONCLUSIONS: Unlike chronic organ failure in kidney transplantation, lymphangiogenesis is not altered in CLAD patients. Our findings highlight unique immunological processes leading to BOS and RAS.


Assuntos
Bronquíolos/patologia , Bronquiolite Obliterante/patologia , Transplante de Pulmão/efeitos adversos , Linfangiogênese , Vasos Linfáticos/patologia , Adulto , Aloenxertos , Biomarcadores/análise , Bronquíolos/química , Bronquíolos/imunologia , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/imunologia , Bronquiolite Obliterante/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Vasos Linfáticos/química , Vasos Linfáticos/imunologia , Masculino , Glicoproteínas de Membrana/análise , Pessoa de Meia-Idade , Síndrome , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
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