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1.
Immunology ; 159(2): 167-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31646612

RESUMO

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doenças do Sistema Endócrino/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/efeitos adversos , Pneumopatias/induzido quimicamente , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/terapia , Doenças do Sistema Endócrino/imunologia , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/terapia , Gastroenteropatias/imunologia , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/terapia , Neoplasias/imunologia , Neoplasias/metabolismo , Fatores de Risco , Evasão Tumoral/efeitos dos fármacos
2.
Clin Nucl Med ; 45(1): e15-e19, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31524673

RESUMO

Bilateral lung parenchymal involvement is seen in infective as well as noninfective conditions, appearing as focal or diffuse lung disease. PET/CT with FDG helps in characterization (increased glucose utilization is seen by both inflammatory and neoplastic cells). In this article, we describe the spectrum of patterns of FDG uptake and associated CT changes involving bilateral lung parenchyma. Benign conditions described are aspiration pneumonia; pulmonary toxicity by bleomycin; infections, namely, sarcoidosis, miliary pulmonary tuberculosis, and pulmonary nocardiosis; and inflammatory conditions such as pulmonary Langerhans cell histiocytosis and pulmonary alveolar proteinosis. Neoplastic conditions described are bilateral pulmonary metastases and lymphangitic carcinomatosis.


Assuntos
Fluordesoxiglucose F18/metabolismo , Pneumopatias/metabolismo , Pneumopatias/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Transporte Biológico , Feminino , Humanos , Pneumopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade
3.
Nat Commun ; 10(1): 4906, 2019 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-31659165

RESUMO

The delivery of biologic cargoes to airway epithelial cells is challenging due to the formidable barriers imposed by its specialized and differentiated cells. Among cargoes, recombinant proteins offer therapeutic promise but the lack of effective delivery methods limits their development. Here, we achieve protein and SpCas9 or AsCas12a ribonucleoprotein (RNP) delivery to cultured human well-differentiated airway epithelial cells and mouse lungs with engineered amphiphilic peptides. These shuttle peptides, non-covalently combined with GFP protein or CRISPR-associated nuclease (Cas) RNP, allow rapid entry into cultured human ciliated and non-ciliated epithelial cells and mouse airway epithelia. Instillation of shuttle peptides combined with SpCas9 or AsCas12a RNP achieves editing of loxP sites in airway epithelia of ROSAmT/mG mice. We observe no evidence of short-term toxicity with a widespread distribution restricted to the respiratory tract. This peptide-based technology advances potential therapeutic avenues for protein and Cas RNP delivery to refractory airway epithelial cells.


Assuntos
Proteínas de Bactérias/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Endonucleases/metabolismo , Células Epiteliais/metabolismo , Pneumopatias/terapia , Pulmão/metabolismo , Peptídeos/genética , Animais , Proteínas de Bactérias/genética , Brônquios/citologia , Brônquios/metabolismo , Endonucleases/genética , Terapia Genética , Humanos , Pneumopatias/genética , Pneumopatias/metabolismo , Camundongos , Peptídeos/administração & dosagem , Peptídeos/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Suínos
4.
Int J Mol Sci ; 20(16)2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412612

RESUMO

INTRODUCTION: MiRNAs have been shown to play a crucial role among lung cancer, pulmonary fibrosis, tuberculosis (TBC) infection, and bronchial hypersensitivity, thus including chronic obstructive pulmonary disease (COPD) and asthma. The oncogenic effect of several miRNAs has been recently ruled out. In order to act on miRNAs turnover, antagomiRs have been developed. MATERIALS AND METHODS: The systematic review was conducted under the PRISMA guidelines (registration number is: CRD42019134173). The PubMed database was searched between 1 January 2000 and 30 April 2019 under the following search strategy: (((antagomiR) OR (mirna antagonists) OR (mirna antagonist)) AND ((lung[MeSH Terms]) OR ("lung diseases"[MeSH Terms]))). We included original articles, published in English, whereas exclusion criteria included reviews, meta-analyses, single case reports, and studies published in a language other than English. RESULTS AND CONCLUSIONS: A total of 68 articles matching the inclusion criteria were retrieved. Overall, the use of antagomiR was seen to be efficient in downregulating the specific miRNA they are conceived for. The usefulness of antagomiRs was demonstrated in humans, animal models, and cell lines. To our best knowledge, this is the first article to encompass evidence regarding miRNAs and their respective antagomiRs in the lung, in order to provide readers a comprehensive review upon major lung disorders.


Assuntos
Antagomirs/genética , Regulação da Expressão Gênica , Pneumopatias/genética , Interferência de RNA , Animais , Antagomirs/administração & dosagem , Biomarcadores , Linhagem Celular , Células Cultivadas , Humanos , Pneumopatias/diagnóstico , Pneumopatias/metabolismo , Pneumopatias/terapia , MicroRNAs/genética , Modelos Animais
5.
Molecules ; 24(16)2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31426440

RESUMO

Matrix metalloproteinases (MMPs) are a family of zinc- and calcium-dependent endopeptidases which are secreted or anchored in the cell membrane and are capable of degrading the multiple components of the extracellular matrix (ECM). MMPs are frequently overexpressed or highly activated in numerous human diseases. Owing to the important role of MMPs in human diseases, many MMP inhibitors (MMPIs) have been developed as novel therapeutics, and some of them have entered clinical trials. However, so far, only one MMPI (doxycycline) has been approved by the FDA. Therefore, the evaluation of the activity of a specific subset of MMPs in human diseases using clinically relevant imaging techniques would be a powerful tool for the early diagnosis and assessment of the efficacy of therapy. In recent years, numerous MMPIs labeled imaging agents have emerged. This article begins by providing an overview of the MMP subfamily and its structure and function. The latest advances in the design of subtype selective MMPIs and their biological evaluation are then summarized. Subsequently, the potential use of MMPI-labeled diagnostic agents in clinical imaging techniques are discussed, including positron emission tomography (PET), single-photon emission computed tomography (SPECT) and optical imaging (OI). Finally, this article concludes with future perspectives and clinical utility.


Assuntos
Aterosclerose/diagnóstico por imagem , Doenças Cardiovasculares/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Inibidores de Metaloproteinases de Matriz/farmacocinética , Metaloproteinases da Matriz/química , Sondas Moleculares/farmacocinética , Neoplasias/diagnóstico por imagem , Osteoartrite/diagnóstico por imagem , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Domínio Catalítico/genética , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/diagnóstico por imagem , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Humanos , Pneumopatias/metabolismo , Pneumopatias/patologia , Inibidores de Metaloproteinases de Matriz/síntese química , Metaloproteinases da Matriz/genética , Metaloproteinases da Matriz/metabolismo , Imagem Molecular/métodos , Sondas Moleculares/síntese química , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Osteoartrite/metabolismo , Osteoartrite/patologia , Tomografia por Emissão de Pósitrons/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
6.
Med Sci Monit ; 25: 5229-5236, 2019 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-31302663

RESUMO

BACKGROUND Increased risk of acute exacerbation of chronic obstructive pulmonary disease (COPD) has been reported in patients who are overweight and obese. However, the effects of body fat in patients with normal or low body mass index (BMI) and COPD remain unknown. This study aimed to examine the association between acute exacerbations of COPD and the lean-to-fat (LTF) ratio in patients with a normal or low BMI. MATERIAL AND METHODS Patients with COPD (n=68) underwent assessment of body composition, in whom 43 cases had a normal BMI (18.5 to 25 kg/m²) and 14 cases were underweight (<18.5 kg/m²). Patients with COPD were treated according to current clinical guidelines and underwent regular follow-up for one year. Acute exacerbations of COPD were recorded. RESULTS BMI, the fat-free mass index (FFMI), skeletal muscle mass index (SMMI), and LTF ratio had no significant effect of the risk of acute exacerbations of COPD in the whole study cohort, but a low LTF ratio was significantly associated with reduced risk of acute exacerbations of COPD in the subgroup with a BMI<25 kg/m² (OR=4.528; P<0.05). The Fat Mass Index (FMI) had a protective effect in the whole cohort (OR=0.292; P=0.024) and in the subgroup with BMI <25 kg/m² (OR=0.253, P=0.049). The cumulative incidence of acute exacerbations of COPD was significantly increased in the patients with a high LTF ratio in the whole cohort (P=0.047) and in the subgroup with BMI <25 kg/m² (P=0.014). CONCLUSIONS In patients with BMI <25 kg/m², the LTF ratio was positively correlated with the risk of occurrence of acute exacerbations of COPD.


Assuntos
Tecido Adiposo/metabolismo , Composição Corporal/fisiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , China , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso , Pacientes , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fatores de Risco , Perda de Peso
7.
Life Sci ; 233: 116671, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31336122

RESUMO

Toll-like receptors (TLRs) comprise a clan of proteins involved in identification and triggering a suitable response against pathogenic attacks. As lung is steadily exposed to multiple infectious agents, antigens and host-derived danger signals, the inhabiting stromal and myeloid cells of the lung express an aggregate of TLRs which perceive the endogenously derived damage-associated molecular patterns (DAMPs) along with pathogen associated molecular patterns (PAMPs) and trigger the TLR-associated signalling events involved in host defence. Thus, they form an imperative component of host defence activation in case of microbial infections as well as non-infectious pulmonary disorders such as interstitial lung disease, acute lung injury and airways disease, such as COPD and asthma. They also play an equally important role in lung cancer. Targeting the TLR signalling network would pave ways to the design of more reliable and effective vaccines against infectious agents and control deadly infections, desensitize allergens and reduce inflammation. Moreover, TLR agonists may act as adjuvants by increasing the efficiency of cancer vaccines, thereby contributing their role in treatment of lung cancer too. Overall, TLRs present a compelling and expeditiously bolstered area of research and addressing their signalling events would be of significant use in pulmonary diseases.


Assuntos
Pneumopatias/fisiopatologia , Receptores Toll-Like/metabolismo , Animais , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Transdução de Sinais
8.
Eur Respir Rev ; 28(152)2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31243097

RESUMO

This review presents and discusses a new frontier for fast, risk-free and potentially inexpensive diagnostics of respiratory diseases by detecting volatile organic compounds (VOCs) present in exhaled breath. One part of the review is a didactic presentation of the overlaying concept and the chemistry of exhaled breath. The other part discusses diverse sensors that have been developed and used for the detection of respiratory diseases (e.g. chronic obstructive pulmonary disease, asthma, lung cancer, pulmonary arterial hypertension, tuberculosis, cystic fibrosis, obstructive sleep apnoea syndrome and pneumoconiosis) by analysis of VOCs in exhaled breath. The strengths and pitfalls are discussed and criticised, particularly in the perspective in disseminating information regarding these advances. Ideas regarding the improvement of sensors, sensor arrays, sensing devices and the further planning of workflow are also discussed.


Assuntos
Testes Respiratórios/instrumentação , Expiração , Pneumopatias/diagnóstico , Pulmão/metabolismo , Transdutores , Compostos Orgânicos Voláteis/metabolismo , Biomarcadores/metabolismo , Desenho de Equipamento , Humanos , Pulmão/fisiopatologia , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes
9.
Mediators Inflamm ; 2019: 4742634, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31236064

RESUMO

Chlamydia pneumoniae (Cpn) infection causes multiple acute and chronic human diseases. The role of DCs in host defense against Cpn infection has been well documented. The same is true for invariant natural killer T (iNKT) cells and NK cells, but the interaction among cells is largely unknown. In this study, we investigated the influence and mechanism of iNKT cell on the differentiation and function of NK cell in Cpn lung infection and the role played by DCs in this process. We found that expansion of IFN-γ-producing NK cells quickly happened after the infection, but this response was altered in iNKT knockout (KO) mice. The expression of activation markers and the production of IFN-γ by different NK subsets were significantly lower in KO mice than wild-type (WT) mice. Using in vitro DC-NK coculture and in vivo adoptive transfer approaches, we further examined the role of DCs in iNKT-mediated modulation of NK cell function. We found that NK cells expressed lower levels of activation markers and produced less IFN-γ when they were cocultured with DCs from KO mice than WT mice. More importantly, we found that the adoptive transfer of DCs from the KO mice induced less NK cell activation and IFN-γ production. The results provided evidence on the modulating effect of iNKT cell on NK cell function, particularly the critical role of DCs in this modulation process. The finding suggests the complexity of cellular interactions in Cpn lung infection, which should be considered in designing preventive and therapeutic approaches for diseases and infections.


Assuntos
Infecções por Chlamydophila/imunologia , Chlamydophila pneumoniae/patogenicidade , Células Dendríticas/metabolismo , Células Matadoras Naturais/metabolismo , Pneumopatias/imunologia , Pneumopatias/microbiologia , Animais , Feminino , Interferon gama/metabolismo , Pneumopatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
10.
Virchows Arch ; 475(3): 335-340, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31254069

RESUMO

Pulmonary dirofilariasis is an infection caused by Dirofilaria immitis, which is an endemic parasite in Japan. We experienced 13 surgical cases of pulmonary dirofilariasis in our hospital. Of the 13 patients, 61.5% were men. The responsible lesions were located in the right lung in all cases, and 76.9% of them were in the lower lobe. Histologically, 12 cases showed necrotic nodules with peripheral granuloma with worms inside the pulmonary artery. One case did not show a necrotic nodule but showed only thickening and hyalinization of the pulmonary artery wall with a degenerated worm inside. Eosinophils were found histologically in all cases. Thirteen cases of dirofilariasis in one institution seem to be the largest number in Japan, based on previous reports. One reason for this increased prevalence may be the hot and humid climate of our prefecture considering the ecology of the mosquito as a vector. Elastic staining and eosinophils in peripheral granulomatous areas can contribute to the diagnosis when the worms are degenerated.


Assuntos
Dirofilariose/diagnóstico , Dirofilariose/patologia , Pneumopatias/metabolismo , Adulto , Idoso , Animais , Diagnóstico Diferencial , Dirofilaria immitis/patogenicidade , Dirofilariose/etiologia , Eosinófilos/patologia , Feminino , Cardiopatias/patologia , Humanos , Japão , Pulmão/patologia , Pneumopatias/etiologia , Pneumopatias Parasitárias/patologia , Masculino , Pessoa de Meia-Idade
11.
Adv Protein Chem Struct Biol ; 116: 311-345, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31036295

RESUMO

Aquaporins (AQPs) are a family of membrane water channel proteins that osmotically modulate water fluid homeostasis in several tissues; some of them also transport small solutes such as glycerol. At the cellular level, the AQPs regulate not only cell migration and transepithelial fluid transport across membranes, but also common events that are crucial for the inflammatory response. Emerging data reveal a new function of AQPs in the inflammatory process, as demonstrated by their dysregulation in a wide range of inflammatory diseases including edematous states, cancer, obesity, wound healing and several autoimmune diseases. This chapter summarizes the discoveries made so far about the structure and functions of the AQPs and provides updated information on the underlying mechanisms of AQPs in several human inflammatory diseases. The discovery of new functions for AQPs opens new vistas offering promise for the discovery of mechanisms and therapeutic opportunities in inflammatory disorders.


Assuntos
Aquaporinas/metabolismo , Inflamação/metabolismo , Água/metabolismo , Animais , Aquaporinas/análise , Aquaporinas/imunologia , Autoimunidade , Doenças do Sistema Digestório/imunologia , Doenças do Sistema Digestório/metabolismo , Humanos , Inflamação/imunologia , Nefropatias/imunologia , Nefropatias/metabolismo , Pneumopatias/imunologia , Pneumopatias/metabolismo , Modelos Moleculares
12.
Cell Commun Signal ; 17(1): 35, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992007

RESUMO

Forkhead box M1 (FOXM1), a transcriptional regulator of G1/S and G2/M transition and M phase progression in the cell cycle, plays a principal role in many physiological and pathological processes. A growing number of studies have focused on the relationship between abnormal FOXM1 expression and pulmonary diseases, such as lung cancer, chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), pulmonary fibrosis, and pulmonary arterial hypertension (PAH). These studies indicate that the FOXM1 regulatory network is a major predictor of poor outcomes, especially in lung cancer, and provide novel insight into various pulmonary diseases. For the first time, this review summarizes the mechanistic relationship between FOXM1 dysregulation and pulmonary diseases, the benefits of targeting abnormal FOXM1 expression, and the questions that remain to be addressed in the future.


Assuntos
Proteína Forkhead Box M1/metabolismo , Pneumopatias/metabolismo , Animais , Proteína Forkhead Box M1/genética , Regulação da Expressão Gênica , Humanos , Pneumopatias/genética , Modelos Animais
14.
Int J Mol Sci ; 20(7)2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30965568

RESUMO

Emerging evidence suggests that platelets, cytoplasmic fragments derived from megakaryocytes, can no longer be considered just as mediators in hemostasis and coagulation processes, but as key modulators of immunity. Platelets have received increasing attention as the emergence of new methodologies has allowed the characterization of their components and functions in the immune continuum. Platelet activation in infectious and allergic lung diseases has been well documented and associated with bacterial infections reproduced in several animal models of pulmonary bacterial infections. Direct interactions between platelets and bacteria have been associated with increased pulmonary platelet accumulation, whereas bacterial-derived toxins have also been reported to modulate platelet function. Recently, platelets have been found extravascular in the lungs of patients with asthma, and in animal models of allergic lung inflammation. Their ability to interact with immune and endothelial cells and secrete immune mediators makes them one attractive target for biomarker identification that will help characterize their contribution to lung diseases. Here, we present an original review of the last advances in the platelet field with a focus on the contribution of platelets to respiratory infections and allergic-mediated diseases.


Assuntos
Plaquetas/fisiologia , Doenças Transmissíveis/imunologia , Doenças Transmissíveis/metabolismo , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Animais , Plaquetas/metabolismo , Humanos
16.
BMJ Case Rep ; 12(3)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30904891

RESUMO

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterised by calcific deposits in lung parenchyma. PAM being a progressive disease with dissociation between severity of clinical symptoms and radiological picture, it is often detected incidentally. Mutations in the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells are considered to be involved in the pathogenesis of PAM. The majority of the patients are diagnosed usually between the ages of 20 and 40 years, although paediatric PAM has also been reported. Diagnosis is confirmed by combination of radiological features, bronchial lavage and histopathological testing. At present, lung transplant is the only definitive treatment available. Though rare, the prevalence of PAM is worldwide. Till June 2018, 86 cases have been reported from India and 1042 cases have been reported worldwide. We report three cases from India, including a student, cement factory worker and a tailor, which will highlight the varied clinical and radiological presentations of this rare disease along with the response to treatment.


Assuntos
Alendronato/administração & dosagem , Broncodilatadores/administração & dosagem , Calcinose/diagnóstico por imagem , Doenças Genéticas Inatas/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Adulto , Alendronato/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Broncodilatadores/uso terapêutico , Calcinose/metabolismo , Tosse/etiologia , Dispneia/etiologia , Doenças Genéticas Inatas/metabolismo , Hemoptise/etiologia , Humanos , Índia , Pneumopatias/metabolismo , Masculino , Inaladores Dosimetrados , Radiografia , Tomografia Computadorizada por Raios X , Adulto Jovem
17.
Oxid Med Cell Longev ; 2019: 7090534, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30728889

RESUMO

Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidant response element- (ARE-) driven cytoprotective protein expression. The activation of Nrf2 signaling plays an essential role in preventing cells and tissues from injury induced by oxidative stress. Under the unstressed conditions, natural inhibitor of Nrf2, Kelch-like ECH-associated protein 1 (Keap1), traps Nrf2 in the cytoplasm and promotes the degradation of Nrf2 by the 26S proteasome. Nevertheless, stresses including highly oxidative microenvironments, impair the ability of Keap1 to target Nrf2 for ubiquitination and degradation, and induce newly synthesized Nrf2 to translocate to the nucleus to bind with ARE. Due to constant exposure to external environments, including diverse pollutants and other oxidants, the redox balance maintained by Nrf2 is fairly important to the airways. To date, researchers have discovered that Nrf2 deletion results in high susceptibility and severity of insults in various models of respiratory diseases, including bronchopulmonary dysplasia (BPD), respiratory infections, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and lung cancer. Conversely, Nrf2 activation confers protective effects on these lung disorders. In the present review, we summarize Nrf2 involvement in the pathogenesis of the above respiratory diseases that have been identified by experimental models and human studies and describe the protective effects of Nrf2 inducers on these diseases.


Assuntos
Pneumopatias/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Elementos de Resposta Antioxidante , Humanos , Pneumopatias/genética , Pneumopatias/patologia , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/fisiologia
18.
Birth Defects Res ; 111(5): 237-247, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30719872

RESUMO

BACKGROUND: The mutant chondrodysplasia (cho) is a cartilage-targeting disorder in C57BL mice that results in dwarfing and other malformations stemming from this collagenopathy. Clarke Fraser made the discovery of the mutation accidentally in the early 1960s during the thalidomide tragedy. METHODS: For this review we identified key research on cho as since its discovery. Relevant data were compiled to make a comprehensive review that details discoveries associated with the cho mutation, that describes the associated phenotypes and molecular mechanisms, and that provides a discussion surrounding its current clinical relevance. RESULTS: Mechanistically, cho acts by hindering chondrogenesis and endochondral bone formation. The phenotype results from a 1-nt deletion in the gene encoding the alpha 1 chain of type XI collagen. For more than half a century, researchers have studied the pathogenesis of the cho mutation in relation to a variety of mouse models of human birth defects and disease. These studies have resulted in several discoveries linking cho with such human disorders as dwarfism, tracheal stenosis, cleft palate, pulmonary hypoplasia, and osteoarthritis (OA). CONCLUSION: The study of cho has led to numerous advances in understanding human birth defects, congenital disorders, and adult human disease. The most recent studies have suggested a role for the TGF-Beta, HtrA1, Ddr2, and Mmp-13 pathway in the degradation of articular cartilage and the development of OA in cho/+ mice. We have shown that the anti-hypertension drug Losartan is a TGF-Beta blocker that could be used to treat OA in Stickler syndrome, and thereby rescue the WT phenotype.


Assuntos
Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Osteocondrodisplasias/fisiopatologia , Anormalidades Múltiplas/metabolismo , Animais , Cartilagem Articular , Colágeno Tipo XI/genética , Colágeno Tipo XI/metabolismo , Modelos Animais de Doenças , Pulmão/anormalidades , Pulmão/metabolismo , Pneumopatias/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Anormalidades Musculoesqueléticas/metabolismo , Mutação , Osteoartrite , Fenótipo
19.
Clin Lab ; 65(1)2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30775896

RESUMO

BACKGROUND: Previous studies have found that vascular endothelial growth factor (VEGF) is associated with lung cancer, yet little is known about vascular endothelial growth factor-D (VEGF-D) in bronchoalveolar lavage fluid (BALF) of lung cancer patients. In this study, we aim to investigate the expression and evaluation of VEGF-D in BALF for lung cancer diagnosis. METHODS: BALF samples were acquired from 81 patients: 40 with benign diseases and 41 with lung cancer. The expression of VEGF-D in BALF was measured using sandwich enzyme-linked immune sorbent assays (ELISA), and the evaluation of VEGF-D in BALF for lung cancer diagnosis was also investigated. RESULTS: In the BALF samples, the levels of VEGF-D in the lung cancer group were higher than in the benign disease group; however, there was no statistical significance between the two groups (p > 0.05). In the pathological classification of lung cancer, the levels of VEGF-D in the BALF differed significantly between the lung squamous carcinoma group and the benign disease group (p < 0.05). The diagnostic accuracies of VEGF-D in BALF for discrimination between patients with squamous cell carcinoma and benign disease were reasonable based on receiver operating characteristic (ROC curve) analysis, with a corresponding sensitivity of 64.7% and specificity of 60%, respectively. CONCLUSIONS: This study demonstrated that the detection of VEGF-D levels in BALF is a valuable diagnostic tool for lung squamous carcinoma.


Assuntos
Biomarcadores Tumorais/análise , Líquido da Lavagem Broncoalveolar/química , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fator D de Crescimento do Endotélio Vascular/análise , Carcinoma de Células Escamosas/diagnóstico , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Pneumopatias/diagnóstico , Pneumopatias/metabolismo , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Curva ROC , Carcinoma de Pequenas Células do Pulmão/diagnóstico
20.
Am J Physiol Lung Cell Mol Physiol ; 316(5): L826-L842, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30785345

RESUMO

Cellular senescence results in cell cycle arrest with secretion of cytokines, chemokines, growth factors, and remodeling proteins (senescence-associated secretory phenotype; SASP) that have autocrine and paracrine effects on the tissue microenvironment. SASP can promote remodeling, inflammation, infectious susceptibility, angiogenesis, and proliferation, while hindering tissue repair and regeneration. While the role of senescence and the contributions of senescent cells are increasingly recognized in the context of aging and a variety of disease states, relatively less is known regarding the portfolio and influences of senescent cells in normal lung growth and aging per se or in the induction or progression of lung diseases across the age spectrum such as bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis. In this review, we introduce concepts of cellular senescence, the mechanisms involved in the induction of senescence, and the SASP portfolio that are relevant to lung cells, presenting the potential contribution of senescent cells and SASP to inflammation, hypercontractility, and remodeling/fibrosis: aspects critical to a range of lung diseases. The potential to blunt lung disease by targeting senescent cells using a novel class of drugs (senolytics) is discussed. Potential areas for future research on cellular senescence in the lung are identified.


Assuntos
Envelhecimento/metabolismo , Citocinas/metabolismo , Pneumopatias/metabolismo , Pulmão/metabolismo , Envelhecimento/patologia , Animais , Senescência Celular , Humanos , Inflamação/metabolismo , Inflamação/patologia , Pulmão/patologia , Pneumopatias/patologia
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