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1.
Medicine (Baltimore) ; 99(39): e21941, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32991402

RESUMO

INTRODUCTION: Diffuse pulmonary lymphangiomatosis (DPL) is a rare condition. Most patients with DPL present dyspnea, cough, expectoration, and hemoptysis. There are few reports of DPL accompanied by thrombocytopenia, whose cause remains unknown. PATIENT CONCERNS: An 18-year-old male patient presented with recurrent cough, expectoration, and dyspnea for 5 years, and thrombocytopenia was observed during a 2-month follow-up. DIAGNOSIS: Chest computed tomography showed diffuse patchy shadows in both lungs, and pleural and pericardial effusions. Immunohistochemical lung tissue staining showed lymphatic and vascular endothelial cells positive for D2-40, CD31 and CD34. Routine blood test revealed platelets at 62 × 10 cells/L during follow-up. Bone marrow biopsy was normal. Ultrasound revealed no hepatosplenomegaly. Finally, the patient was diagnosed with DPL accompanied by thrombocytopenia. INTERVENTIONS: He was treated by subtotal pericardial resection, thoracocentesis, and anti-infective therapy. Oral prednisone was administered for 2 months. OUTCOMES: The symptoms of cough and shortness of breath were improved, but thrombocytopenia persisted. We investigated the cause of thrombocytopenia. Whole-exome sequencing identified a mutation in exon 3 of the TNFRSF13B gene in this patient. CONCLUSION: DPL may present with thrombocytopenia and DIC. Patients with thrombocytopenia but not DIC and splenomegaly should be screened for gene mutations.


Assuntos
Pneumopatias/congênito , Linfangiectasia/congênito , Trombocitopenia/complicações , Adolescente , Criança , Humanos , Pneumopatias/complicações , Pneumopatias/diagnóstico por imagem , Pneumopatias/genética , Pneumopatias/patologia , Linfangiectasia/complicações , Linfangiectasia/diagnóstico por imagem , Linfangiectasia/genética , Linfangiectasia/patologia , Masculino , Mutação de Sentido Incorreto , Trombocitopenia/diagnóstico , Tomografia Computadorizada por Raios X , Proteína Transmembrana Ativadora e Interagente do CAML , Sequenciamento Completo do Exoma
2.
Adv Exp Med Biol ; 1255: 63-72, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949390

RESUMO

This chapter overviews roles of DNA methylation in inflammatory cell biology with the focuses on lymphocytes and macrophages/monocytes in lung diseases, although the molecular mechanisms by which target genes are methylated and regulated in lung diseases remain unclear. Most of epigenetic studies on DNA methylation of target genes in lung diseases mainly demonstrated the correlation of DNA methylation of target genes with the levels of other corresponding factors, with the specificity of clinical phenomes, and with the severity of lung diseases. There is an urgent need to identify and validate the specificity and regulatory mechanisms of inflammatory cell epigenetics in depth. The epigenetic heterogeneity among different subsets of T cells and among promoters or non-promoters of target genes should be furthermore clarified in acute or chronic lung diseases and cancers. The hyper/hypo-methylation and modifications of chromosol and extrachromosomal DNA may result in alternations in proteins within inflammatory cells, which can be identified as disease-specific biomarkers and therapeutic targets.


Assuntos
Metilação de DNA , Inflamação/genética , Pneumopatias/genética , Pneumopatias/patologia , Epigênese Genética , Epigenômica , Humanos
3.
Am J Physiol Cell Physiol ; 319(2): C316-C320, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32639871

RESUMO

Pulmonary surfactant is a heterogeneous active surface complex made up of lipids and proteins. The major glycoprotein in surfactant is surfactant protein A (SP-A), which is released into the alveolar lumen from cytoplasmic lamellar bodies in type II alveolar epithelial cells. SP-A is involved in phospholipid absorption. SP-A together with other surfactant proteins and phospholipids prevent alveolar collapse during respiration by decreasing the surface tension of the air-liquid interface. Additionally, SP-A interacts with pathogens to prevent their propagation and regulate host immune responses. Studies in human and animal models have shown that deficiencies or mutations in surfactant components result in various lung or kidney pathologies, suggesting a role for SP-A in the development of lung and kidney diseases. In this mini-review, we discuss the current understanding of SP-A functions, recent findings of its dysfunction in specific lung and kidney pathologies, and how SP-A has been used as a biomarker to detect the outcome of lung diseases.


Assuntos
Nefropatias/genética , Pneumopatias/genética , Alvéolos Pulmonares/metabolismo , Proteína A Associada a Surfactante Pulmonar/genética , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Citoplasma/genética , Citoplasma/metabolismo , Progressão da Doença , Humanos , Rim/metabolismo , Rim/patologia , Nefropatias/patologia , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/patologia , Alvéolos Pulmonares/patologia , Surfactantes Pulmonares/metabolismo
4.
Cancer Cytopathol ; 128(8): 553-562, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32320527

RESUMO

BACKGROUND: Approximately one third of needle biopsies that are performed to rule out malignancy of indeterminate pulmonary nodules detected radiologically during lung cancer screening are negative, thus exposing cancer-free patients to risks of pneumothorax, bleeding, and infection. A noninvasive confirmatory tool (eg, liquid biopsy) is urgently needed in the lung cancer diagnosis setting to stratify patients who should receive biopsy versus those who should be monitored. METHODS: A novel antigen-independent, 4-color fluorescence in situ hybridization (FISH)-based method was developed to detect circulating tumor cells (CTCs) with abnormalities in gene copy numbers in mononuclear cell-enriched peripheral blood samples from patients with (n = 107) and without (n = 100) lung cancer. RESULTS: Identification of CTCs using FISH probes at 10q22.3/CEP10 and 3p22.1/3q29 detected lung cancer cases with 94.2% accuracy, 89% sensitivity, and 100% specificity compared with biopsy. CONCLUSION: The high accuracy of this liquid biopsy method suggests that it may be used as a noninvasive decision tool to reduce the frequency of unnecessary needle biopsy in patients with benign pulmonary lesions.


Assuntos
Pneumopatias/diagnóstico , Neoplasias Pulmonares/diagnóstico , Células Neoplásicas Circulantes , Tomografia Computadorizada por Raios X/métodos , Células A549 , Idoso , Aneuploidia , Diagnóstico Diferencial , Feminino , Humanos , Hibridização in Situ Fluorescente/métodos , Biópsia Líquida , Pneumopatias/diagnóstico por imagem , Pneumopatias/genética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Sensibilidade e Especificidade
5.
Exp Hematol ; 84: 1-6.e1, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32243995

RESUMO

Sickle cell disease (SCD) is a monogenic disorder estimated to affect more than three million people worldwide. Acute systemic painful vaso-occlusive episode (VOE) is the primary reason for emergency medical care among SCD patients. VOE may also progress to acute chest syndrome (ACS), a type of acute lung injury and one of the primary reasons for mortality among SCD patients. Recently, P-selectin monoclonal antibodies were found to attenuate VOE in SCD patients and lung vaso-occlusion in transgenic humanized SCD mice, highlighting the therapeutic benefit of P-selectin inhibition in SCD. Here, we use quantitative fluorescence intravital lung microscopy (qFILM) to illustrate that tandem P-selectin-glycoprotein ligand-immunoglobulin (TSGL-Ig) fusion molecule containing four P-selectin binding sites, significantly attenuated intravenous (IV) oxyhemoglobin triggered lung vaso-occlusion in SCD mice. These findings highlight the therapeutic potential of TSGL-Ig in preventing VOE and ACS in SCD.


Assuntos
Anemia Falciforme/tratamento farmacológico , Imunoglobulinas/farmacologia , Pneumopatias/tratamento farmacológico , Selectina-P/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Doenças Vasculares/tratamento farmacológico , Anemia Falciforme/genética , Anemia Falciforme/metabolismo , Anemia Falciforme/patologia , Animais , Feminino , Humanos , Imunoglobulinas/genética , Pneumopatias/genética , Pneumopatias/metabolismo , Pneumopatias/patologia , Masculino , Camundongos , Selectina-P/genética , Ratos , Proteínas Recombinantes de Fusão/genética , Doenças Vasculares/genética , Doenças Vasculares/metabolismo
6.
Pediatr Pulmonol ; 55(6): 1481-1486, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32293809

RESUMO

OBJECTIVE: Combined methylmalonic acidemia and homocysteinemia is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism, which consists of five subtypes including cblC, cblD, cblF, cblJ, and cblX deficiencies. The purpose of this study is to summarize new clinical features mainly diffuse alveolar hemorrhage (DAH) in cblC deficiency. METHODS: We made a retrospective analysis of four pediatric patients diagnosed with DAH and pulmonary microangiopathy due to cblC deficiency between January 2017 and December 2018 in Beijing Children's Hospital. RESULTS: This study describes four patients with their ages ranging from 4 years 2 months to 7 years 6 months with cblC deficiency who developed late-onset diffuse lung disease (DLD). Of these, the first three patients presented predominantly with DAH, and the last patient with pulmonary microangiopathy confirmed by thoracoscopic lung biopsy. All patients were accompanied by pulmonary arterial hypertension (PAH), two accompanied by respiratory failure, and two accompanied by moderate megaloblastic anemia. Diffuse ground-glass opacification and poorly defined ground-glass centrilobular nodules were seen on high-resolution computed tomography in one patient and three patients, respectively. All patients were suspected of having idiopathic pulmonary hemosiderosis or interstitial lung disease at other hospitals. All of them received treatment with corticosteroid before admission, but the symptoms did not improve. Moreover, all patients carried compound heterozygous mutations (c.80A>G, c.609G>A) in MMACHC and improved significantly after being treated for cblC deficiency and PAH. CONCLUSIONS: CblC deficiency should be considered in the differential diagnosis of DAH especially with PAH, and pulmonary microangiopathy be the main reason of DLD in these patients.


Assuntos
Hemorragia/diagnóstico , Hemossiderose/diagnóstico , Pneumopatias/diagnóstico , Deficiência de Vitamina B 12/diagnóstico , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Hemorragia/etiologia , Hemorragia/genética , Hemossiderose/etiologia , Hemossiderose/genética , Humanos , Pneumopatias/etiologia , Pneumopatias/genética , Masculino , Mutação , Oxirredutases/genética , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/genética
7.
Am J Physiol Lung Cell Mol Physiol ; 318(5): L845-L851, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32191117

RESUMO

Premature infants are often exposed to positive pressure ventilation and supplemental oxygen, which leads to the development of chronic lung disease (CLD). There are currently no standard serum biomarkers used for prediction or early detection of patients who go on to develop CLD. MicroRNAs (miRNAs) are a novel class of naturally occurring, short, noncoding substances that regulate gene expression at the posttranscriptional level and cause translational inhibition and/or mRNA degradation and present in body fluids packaged in extracellular vesicles (EVs), rendering them remarkably stable. Our aim was to evaluate miRNAs identified in serum EVs of premature infants as potential biomarkers for CLD. Serum EVs were extracted from premature infants at birth and on the 28th day of life (DOL). Using a human miRNA array, we identified 62 miRNAs that were universally expressed in CLD patients and non-CLD patients. Of the 62 miRNAs, 59 miRNAs and 44 miRNAs were differentially expressed on DOL0 and DOL28 in CLD and non-CLD patients, respectively. Of these miRNAs, serum EV miR-21 was upregulated in CLD patients on DOL28 compared with levels at birth and downregulated in non-CLD patients on DOL28 compared with levels at birth. In neonatal mice exposed to hyperoxia for 7days, as a model of CLD, five miRNAs (miR-34a, miR-21, miR-712, miR-682, and miR-221) were upregulated, and 7 miRNAs (miR-542-5p, miR-449a, miR-322, miR-190b, miR-153, miR-335-3p, miR-377) were downregulated. MiR-21 was detected as a common miRNA that changed in CLD patients and in the hyperoxia exposed mice. We conclude that EV miR-21 may be a biomarker of CLD.


Assuntos
Hiperóxia/diagnóstico , Hiperóxia/genética , Pneumopatias/diagnóstico , Pneumopatias/genética , MicroRNAs/genética , Animais , Animais Recém-Nascidos , Antagomirs/genética , Antagomirs/metabolismo , Biomarcadores/metabolismo , Doença Crônica , Modelos Animais de Doenças , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Hiperóxia/sangue , Hiperóxia/fisiopatologia , Recém-Nascido , Recém-Nascido Prematuro , Pneumopatias/sangue , Pneumopatias/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/sangue , MicroRNAs/classificação , Análise de Sequência com Séries de Oligonucleotídeos , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Prognóstico
8.
Sci Rep ; 10(1): 3178, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081976

RESUMO

Pulmonary disease (PD) due to nontuberculous mycobacteria (NTM) is increasing globally, but specific biomarkers for NTM-PD have not been established. As circulating miRNAs are promising biomarkers for various diseases, we investigated whether miRNAs have potential as NTM-PD biomarkers. Sera from 12 NTM-PD patients due to Mycobacterium avium, M. intracellulare, M. abscessus, or M. massiliense and three healthy controls were initially evaluated via small RNA sequencing. Multiple miRNAs showed significant differences in expression in patients compared to in healthy controls, with some expression differences unique to PD caused by a specific mycobacterial species. Notably, 14 miRNAs exhibited significant expression differences in PD associated with all four mycobacteria. Validation by quantitative reverse-transcription-PCR in an additional 40 patients with NTM-PD and 40 healthy controls confirmed that four differentially expressed miRNAs (hsa-miR-484, hsa-miR-584-5p, hsa-miR-625-3p, and hsa-miR-4732-5p) showed significantly higher serum expressions in NTM-PD patients than in controls. Receiver operating characteristic curve analysis of these four miRNAs supported the discriminative potential for NTM-PD and their combination provided an improved diagnostic value for NTM-PD. Furthermore, bioinformatics analysis revealed their 125 target genes, which were mostly associated with immune responses. Collectively, this study identified four miRNAs as potential biomarkers for NTM-PD and provided insight into NTM-PD pathophysiology.


Assuntos
Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Pneumopatias/genética , MicroRNAs/genética , Infecções por Mycobacterium não Tuberculosas/genética , Área Sob a Curva , Estudos de Casos e Controles , Análise por Conglomerados , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Pneumopatias/sangue , Pneumopatias/complicações , Masculino , MicroRNAs/sangue , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/sangue , Infecções por Mycobacterium não Tuberculosas/complicações , Curva ROC , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
9.
Anim Genet ; 51(3): 382-390, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32069517

RESUMO

The pulmonary hypoplasia and anasarca syndrome (PHA) is a congenital lethal disorder, which until now has been reported in cattle and sheep. PHA is characterized by extensive subcutaneous fetal edema combined with hypoplasia or aplasia of the lungs and dysplasia of the lymphatic system. PHA is assumed to be of genetic etiology. This study presents the occurrence of PHA in two different cattle breeds and their genetic causation. Two PHA cases from one sire were observed in Slovenian Cika cattle. Under the assumption of monogenic inheritance, genome-wide homozygosity mapping scaled down the critical regions to 3% of the bovine genome including a 43.6 Mb-sized segment on chromosome 6. Whole-genome sequencing of one case, variant filtering against controls and genotyping of a larger cohort of Cika cattle led to the detection of a likely pathogenic protein-changing variant perfectly associated with the disease: a missense variant on chromosome 6 in ADAMTS3 (NM_001192797.1: c.1222C>T), which affects an evolutionary conserved residue (NP_001179726.1: p.(His408Tyr)). A single PHA case was found in Danish Holstein cattle and was whole-genome sequenced along with its parents. However, as there was no plausible private protein-changing variant, mining for structural variation revealed a likely pathogenic trisomy of the entire chromosome 20. The identified ADAMTS3 associated missense variant and the trisomy 20 are two different genetic causes, which shows a compelling genetic heterogeneity for bovine PHA.


Assuntos
Anormalidades Múltiplas/veterinária , Doenças dos Bovinos/genética , Bovinos , Edema/veterinária , Genoma , Pneumopatias/veterinária , Pulmão/anormalidades , Anormalidades Múltiplas/genética , Animais , Mapeamento Cromossômico/veterinária , Edema/genética , Pneumopatias/genética , Mutação de Sentido Incorreto
10.
Clin Immunol ; 212: 108248, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31382036
11.
Am J Physiol Cell Physiol ; 318(1): C1-C28, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483703

RESUMO

Although a majority of the mammalian genome is transcribed to RNA, mounting evidence indicates that only a minor proportion of these transcriptional products are actually translated into proteins. Since the discovery of the first non-coding RNA (ncRNA) in the 1980s, the field has gone on to recognize ncRNAs as important molecular regulators of RNA activity and protein function, knowledge of which has stimulated the expansion of a scientific field that quests to understand the role of ncRNAs in cellular physiology, tissue homeostasis, and human disease. Although our knowledge of these molecules has significantly improved over the years, we have limited understanding of their precise functions, protein interacting partners, and tissue-specific activities. Adding to this complexity, it remains unknown exactly how many ncRNAs there are in existence. The increased use of high-throughput transcriptomics techniques has rapidly expanded the list of ncRNAs, which now includes classical ncRNAs (e.g., ribosomal RNAs and transfer RNAs), microRNAs, and long ncRNAs. In addition, splicing by-products of protein-coding genes and ncRNAs, so-called circular RNAs, are now being investigated. Because there is substantial heterogeneity in the functions of ncRNAs, we have summarized the present state of knowledge regarding the functions of ncRNAs in heart, lungs, and skeletal muscle. This review highlights the pathophysiologic relevance of these ncRNAs in the context of human cardiovascular, pulmonary, and muscle diseases.


Assuntos
Doenças Cardiovasculares/genética , Pneumopatias/genética , Doenças Musculares/genética , RNA não Traduzido/genética , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Pneumopatias/diagnóstico , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Valor Preditivo dos Testes , RNA não Traduzido/metabolismo , Transdução de Sinais
13.
Dev Growth Differ ; 62(1): 67-79, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31613406

RESUMO

The respiratory system has ideal tissue structure and cell types for efficient gas exchange to intake oxygen and release carbon dioxide. This complex system develops through orchestrated intercellular signaling among various cell types, such as club, ciliated, basal, neuroendocrine, AT1, AT2, endothelial, and smooth muscle cells. Notch signaling is a highly conserved cell-cell signaling pathway ideally suited for very short-range cellular communication because Notch signals are transmitted by direct contact with an adjacent cell. Enthusiastic efforts by Notch researchers over the last two decades have led to the identification of critical roles of this signaling pathway during development, homeostasis, and regeneration of the respiratory system. The dysregulation of Notch signaling results in a wide range of respiratory diseases such as pulmonary artery hypertension (PAH), chronic obstructive pulmonary disease (COPD), interstitial pulmonary fibrosis (IPF), and lung cancer. Thus, a deep understanding of the biological functions of Notch signaling will help identify novel treatment targets in various respiratory diseases.


Assuntos
Homeostase , Pneumopatias , Pulmão/fisiologia , Receptores Notch , Regeneração , Transdução de Sinais , Traqueia/fisiologia , Doenças da Traqueia , Animais , Humanos , Pneumopatias/genética , Pneumopatias/metabolismo , Pneumopatias/patologia , Receptores Notch/genética , Receptores Notch/metabolismo , Doenças da Traqueia/genética , Doenças da Traqueia/metabolismo , Doenças da Traqueia/patologia
14.
Thorax ; 75(1): 92-95, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31666386

RESUMO

COPA (coatomer subunit α) syndrome is a newly recognised cause of interstitial lung disease in children and adults, frequently associated with arthritis and renal dysfunction. We report a 11-year-old girl with disease limited to major pulmonary haemosiderosis manifesting at the age of 2 years, due to a heterozygous p.(Arg233His) mutation in COPA Her interferon (IFN) signature was elevated (10.312 and 12.429, healthy <2.466), as was the level of serum IFNα (211 fg/mL, healthy <10 fg/mL). STAT1 phosphorylation in T lymphocytes and monocytes was increased as compared with healthy controls. Based on these results she was treated with the JAK1/2 inhibitor ruxolitinib, which resulted in reduction in IFN signalling and appeared to be associated with partial though incomplete decrease in the severity of her pulmonary disease. Patients with alveolar haemorrhage of unknown origin should be considered for COPA screening. Functional tests can help to personalise patient therapy.


Assuntos
Hemorragia/tratamento farmacológico , Hemossiderose/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Pirazóis/uso terapêutico , Criança , Feminino , Hemossiderose/genética , Humanos , Pneumopatias/genética
15.
Genes (Basel) ; 10(11)2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683933

RESUMO

Exercise-induced pulmonary haemorrhage (EIPH) occurs in horses performing high-intensity athletic activity. The application of physics principles to derive a 'physical model', which is coherent with existing physiology and cell biology data, shows that critical parameters for capillary rupture are cell-cell adhesion and cell stiffness (cytoskeleton organisation). Specifically, length of fracture in the capillary is a ratio between the energy involved in cell-cell adhesion and the stiffness of cells suggesting that if the adhesion diminishes and/or that the stiffness of cells increases EIPH is more likely to occur. To identify genes associated with relevant cellular or physiological phenotypes, the physical model was used in a post-genome-wide association study (GWAS) to define gene sets associated with the model parameters. The primary study was a GWAS of EIPH where the phenotype was based on weekly tracheal wash samples collected over a two-year period from 72 horses in a flat race training yard. The EIPH phenotype was determined from cytological analysis of the tracheal wash samples, by scoring for the presence of red blood cells and haemosiderophages. Genotyping was performed using the Illumina Equine SNP50 BeadChip and analysed using linear regression in PLINK. Genes within significant genome regions were selected for sets based on their GeneOntology biological process, and analysed using fastBAT. The gene set analysis showed that genes associated with cell stiffness (cytoskeleton organisation) and blood flow have the most significant impact on EIPH risk.


Assuntos
Loci Gênicos , Hemorragia/genética , Doenças dos Cavalos/genética , Pneumopatias/genética , Esforço Físico , Animais , Citoesqueleto/genética , Feminino , Estudo de Associação Genômica Ampla/veterinária , Hemorragia/etiologia , Hemorragia/patologia , Hemorragia/veterinária , Doenças dos Cavalos/etiologia , Doenças dos Cavalos/patologia , Cavalos , Pneumopatias/etiologia , Pneumopatias/patologia , Pneumopatias/veterinária , Masculino , Microvasos/patologia , Fenótipo
16.
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
17.
BMJ Case Rep ; 12(9)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31494588

RESUMO

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition which classically manifests with skin lesions such as fibrofolliculomas, pulmonary cysts that predispose to spontaneous pneumothorax and an increased risk of developing renal cell carcinoma. We describe the case of a patient who presented with a spontaneous pneumothorax on a background of multiple lung cysts, in the absence of cutaneous fibrofolliculomas and renal tumours. A germline mutation in the folliculin FLCN gene was subsequently identified, confirming BHD syndrome. Our case highlights the importance of considering a broad differential diagnosis for the cause of a spontaneous pneumothorax in the presence of unexplained cystic lung disease and emphasises the value of maintaining a high index of clinical suspicion for inherited causes of pneumothoraces.


Assuntos
Apicectomia , Síndrome de Birt-Hogg-Dubé/diagnóstico , Drenagem , Neoplasias Renais/genética , Pneumopatias/genética , Pneumotórax/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/terapia , Dispneia , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Pneumotórax/genética , Pneumotórax/terapia , Cirurgia Torácica Vídeoassistida , Resultado do Tratamento
18.
Am J Respir Cell Mol Biol ; 61(2): 150-161, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31368812

RESUMO

Defining responses of the structural and immune cells in biologic systems is critically important to understanding disease states and responses to injury. This requires accurate and sensitive methods to define cell types in organ systems. The principal method to delineate the cell populations involved in these processes is flow cytometry. Although researchers increasingly use flow cytometry, technical challenges can affect its accuracy and reproducibility, thus significantly limiting scientific advancements. This challenge is particularly critical to lung immunology, as the lung is readily accessible and therefore used in preclinical and clinical studies to define potential therapeutics. Given the importance of flow cytometry in pulmonary research, the American Thoracic Society convened a working group to highlight issues and technical challenges to the performance of high-quality pulmonary flow cytometry, with a goal of improving its quality and reproducibility.


Assuntos
Citometria de Fluxo/métodos , Citometria de Fluxo/normas , Pneumopatias/diagnóstico , Pneumopatias/genética , Pulmão/citologia , Animais , Apoptose , Separação Celular , Congressos como Assunto , Humanos , Pulmão/imunologia , Pulmão/patologia , Células Mieloides/citologia , Fenótipo , Guias de Prática Clínica como Assunto , Reprodutibilidade dos Testes , Sociedades Médicas , Estados Unidos
19.
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
20.
Chest ; 156(5): 991-1000, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31255581

RESUMO

Chronic inflammatory diseases of the lung are often life-threatening and are a leading cause of morbidity in our communities. MicroRNAs (miRs) are now recognized to play critical roles in a wide range of cellular functions, including the regulation of immunologic processes, which are often dysregulated in chronic respiratory diseases. These small noncoding RNA molecules regulate networks of genes by inhibiting translation through the targeting of one or multiple messenger RNA transcripts. This review highlights discoveries that identify important roles for miRs in the regulation of specific pathogenic features of a range of diseases. Furthermore, experimental evidence suggests that pharmacologic inhibition of miR function or delivery of mimics may have therapeutic potential. The review also therefore discusses the potential utility and limitations of therapeutically targeting these molecules and their downstream pathways.


Assuntos
Predisposição Genética para Doença , Pneumopatias/genética , Pulmão/metabolismo , MicroRNAs/genética , Animais , Progressão da Doença , Humanos , Pneumopatias/metabolismo , MicroRNAs/metabolismo , Transdução de Sinais
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