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1.
PLoS One ; 16(12): e0261866, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34941964

RESUMO

OBJECTIVES: Recently, incidence of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD) is increasing worldwide. We aimed to identify factors associated with severity of Mycobacterium abscessus (Mab) pulmonary disease (Mab-PD). METHODS: All patients diagnosed as Mab-PD based on the official ATS/IDSA statement between 2017 January 1 and 2021 July 31 were included (n = 13). We reviewed medical records, bacteriological and laboratory data of the patients. Severity of lung lesions and esophageal diameters in chest CT were quantitatively evaluated. Gaffky score in the sputum was used as airway mycobacterial burden. We explored the factors associated with high CT score and high Gaffky score. RESULTS: Maximum diameter of esophagus (MDE) in severe disease (CT score≧10) was greater than that in milder disease (CT score<10) (18.0±7.9mm, 9.3±3.1mm, respectively, p = 0.01), and MDE was well correlated with CT score (R = 0.69, p = 0.007). MDE in high mycobacterial burden group (Gaffky score ≧5) tended to be greater than that in low mycobacterial burden group (Gaffky score <5) (16.1±6.8mm, 10.1±5.5mm, respectively, p = 0.12), and MDE was well correlated with Gaffky score (R = 0.68, p = 0.009). Lung lesions were bilateral and predominant in middle or lower lobes. CONCLUSIONS: Esophageal dilatation was correlated with severity of Mab-PD and airway mycobacterial burden. Gastroesophageal reflux might be associated with Mab disease progression.


Assuntos
Doenças do Esôfago , Esôfago/patologia , Pneumopatias , Infecções por Mycobacterium não Tuberculosas , Mycobacterium abscessus , Idoso , Dilatação Patológica , Doenças do Esôfago/etiologia , Doenças do Esôfago/microbiologia , Doenças do Esôfago/patologia , Feminino , Humanos , Pneumopatias/complicações , Pneumopatias/metabolismo , Pneumopatias/microbiologia , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/complicações , Infecções por Mycobacterium não Tuberculosas/patologia , Estudos Retrospectivos
2.
Cell Mol Life Sci ; 79(1): 67, 2021 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-34971429

RESUMO

Mutations in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein lead to persistent lung bacterial infections, mainly due to Pseudomonas aeruginosa, causing loss of respiratory function and finally death of people affected by CF. Unfortunately, even in the era of CFTR modulation therapies, management of pulmonary infections in CF remains highly challenging especially for patients with advanced stages of lung disease. Recently, we identified antimicrobial peptides (AMPs), namely Esc peptides, with potent antipseudomonal activity. In this study, by means of electrophysiological techniques and computational studies we discovered their ability to increase the CFTR-controlled ion currents, by direct interaction with the F508del-CFTR mutant. Remarkably, this property was not explored previously with any AMPs or peptides in general. More interestingly, in contrast with clinically used CFTR modulators, Esc peptides would give particular benefit to CF patients by combining their capability to eradicate lung infections and to act as promoters of airway wound repair with their ability to ameliorate the activity of the channel with conductance defects. Overall, our findings not only highlighted Esc peptides as the first characterized AMPs with a novel property, that is the potentiator activity of CFTR, but also paved the avenue to investigate the functions of AMPs and/or other peptide molecules, for a new up-and-coming pharmacological approach to address CF lung disease.


Assuntos
/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Pneumopatias/tratamento farmacológico , Infecções por Pseudomonas/tratamento farmacológico , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Bicarbonatos/metabolismo , Cloretos/metabolismo , Fibrose Cística/genética , Fibrose Cística/microbiologia , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Transporte de Íons/efeitos dos fármacos , Pneumopatias/microbiologia , Pneumopatias/patologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/patogenicidade , Ratos , Ratos Endogâmicos F344
3.
Cells ; 10(12)2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34944053

RESUMO

Mechanistic target of rapamycin complex 1 (mTORC1) has been linked to different diseases. The mTORC1 signaling pathway is suggested to play a role in the granuloma formation of sarcoidosis. Recent studies demonstrated conflicting data on mTORC1 activation in patients with sarcoidosis by measuring activation of its downstream target S6 kinase (S6K) with either 33% or 100% of patients. Therefore, the aim of our study was to reevaluate the percentage of S6K activation in sarcoidosis patients in a Dutch cohort. To investigate whether this activation is specific for sarcoid granulomas, we also included Dutch patients with other granulomatous diseases of the lung. The activation of the S6K signaling pathway was evaluated by immunohistochemical staining of its downstream effector phospho-S6 in tissue sections. Active S6K signaling was detected in 32 (43%) of the sarcoidosis patients. Twelve (31%) of the patients with another granulomatous disorder also showed activated S6K signaling, demonstrating that the mTORC1 pathway may be activated in a range for different granulomatous diseases (p = 0.628). Activation of S6K can only be found in a subgroup of patients with sarcoidosis, as well as in patients with other granulomatous pulmonary diseases, such as hypersensitivity pneumonitis or vasculitis. No association between different clinical phenotypes and S6K activation can be found in sarcoidosis.


Assuntos
Pneumopatias/enzimologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Proteínas Quinases S6 Ribossômicas/metabolismo , Alveolite Alérgica Extrínseca/complicações , Ativação Enzimática , Humanos , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/patologia , Linfangioleiomiomatose/complicações , Linfangioleiomiomatose/patologia , Países Baixos , Fosforilação , Sarcoidose/complicações , Sarcoidose/patologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Vasculite/complicações
5.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575864

RESUMO

The importance of a healthy microbiome cannot be overemphasized. Disturbances in its composition can lead to a variety of symptoms that can extend to other organs. Likewise, acute or chronic conditions in other organs can affect the composition and physiology of the gut microbiome. Here, we discuss interorgan communication along the gut-lung axis, as well as interactions between lung and coronary heart diseases and between cardiovascular disease and the gut microbiome. This triangle of organs, which also affects the clinical outcome of COVID-19 infections, is connected by means of numerous receptors and effectors, including immune cells and immune-modulating factors such as short chain fatty acids (SCFA) and trimethlamine-N-oxide (TMAO). The gut microbiome plays an important role in each of these, thus affecting the health of the lungs and the heart, and this interplay occurs in both directions. The gut microbiome can be influenced by the oral uptake of probiotics. With an improved understanding of the mechanisms responsible for interorgan communication, we can start to define what requirements an 'ideal' probiotic should have and its role in this triangle.


Assuntos
COVID-19 , Doença das Coronárias , Microbioma Gastrointestinal/efeitos dos fármacos , Pneumopatias , Probióticos/administração & dosagem , Animais , COVID-19/microbiologia , COVID-19/patologia , Doença das Coronárias/microbiologia , Doença das Coronárias/patologia , Humanos , Pneumopatias/microbiologia , Pneumopatias/patologia
6.
PLoS One ; 16(9): e0256756, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34492061

RESUMO

There have been no studies on the effects of polyhexamethylene guanidine phosphate (PHMG) after a long period of exposure in the rodent model. We aimed to evaluate long-term lung damage after PHMG exposure using conventional chest computed tomography (CT) and histopathologic analysis in a rat model. A PHMG solution was intratracheally administrated to 24 male rats. At 8, 26, and 52 weeks after PHMG instillation, conventional chest CT was performed in all rats and both lungs were extracted for histopathologic evaluation. At 52 weeks after PHMG instillation, four carcinomas had developed in three of the eight rats (37.5%). Bronchiolo-alveolar hyperplasia and adenoma were found in rats at 8, 26, and 52 weeks post-instillation. The number of bronchiolo-alveolar hyperplasia significantly increased over time (P-value for trend< 0.001). The severity of lung fibrosis and fibrosis scores significantly increased over time (P-values for trend = 0.002 and 0.023, respectively). Conventional chest CT analysis showed that bronchiectasis and linear density scores suggestive of fibrosis significantly increased over time (P-value for trend < 0.001). Our study revealed that one instillation of PHMG in a rat model resulted in lung carcinomas and progressive and irreversible fibrosis one year later based on conventional chest CT and histopathologic analysis. PHMG may be a lung carcinogen in the rat model.


Assuntos
Guanidinas/farmacologia , Pneumopatias/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/diagnóstico , Animais , Modelos Animais de Doenças , Guanidinas/toxicidade , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pneumopatias/induzido quimicamente , Pneumopatias/diagnóstico , Pneumopatias/patologia , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/diagnóstico por imagem , Ratos , Tórax/diagnóstico por imagem , Tórax/efeitos dos fármacos , Tórax/patologia , Tomografia Computadorizada por Raios X
7.
Pathol Oncol Res ; 27: 1609900, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34421396

RESUMO

Background: Autopsies on COVID-19 deceased patients have many limitations due to necessary epidemiologic and preventative measures. The ongoing pandemic has caused a significant strain on healthcare systems and is being extensively studied around the world. Clinical data does not always corelate with post-mortem findings. The goal of our study was to find pathognomonic factors associated with COVID-19 mortality in 100 post-mortem full body autopsies. Materials and Methods: Following necessary safety protocol, we performed 100 autopsies on patients who were diagnosed with COVID-19 related death. The macroscopic and microscopic pathologies were evaluated along with clinical and laboratory findings. Results: Extensive coagulopathic changes are seen throughout the bodies of diseased patients. Diffuse alveolar damage is pathognomonic of COVID-19 viral pneumonia, and is the leading cause of lethal outcome in younger patients. Extrapulmonary pathology is predominantly seen in the liver and spleen. Intravascular thrombosis is often widespread and signs of septic shock are often present. Conclusion: The described pathological manifestations of COVID-19 in deceased patients are an insight into the main mechanisms of SARS-CoV-2 associated lethal outcome. The disease bears no obvious bias in severity, but seems to be more severe in some patients, hinting at genetic or epigenetic factors at play.


Assuntos
COVID-19/patologia , Laboratórios/estatística & dados numéricos , Pneumopatias/patologia , Idoso , Idoso de 80 Anos ou mais , Autopsia , COVID-19/complicações , COVID-19/virologia , Estudos de Coortes , Feminino , Humanos , Pneumopatias/complicações , Pneumopatias/virologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2
8.
Life Sci ; 283: 119871, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34352260

RESUMO

Non-communicable, chronic respiratory diseases (CRDs) affect millions of individuals worldwide. The course of these CRDs (asthma, chronic obstructive pulmonary disease, and cystic fibrosis) are often punctuated by microbial infections that may result in hospitalization and are associated with increased risk of morbidity and mortality, as well as reduced quality of life. Interleukin-13 (IL-13) is a key protein that regulates airway inflammation and mucus hypersecretion. There has been much interest in IL-13 from the last two decades. This cytokine is believed to play a decisive role in the exacerbation of inflammation during the course of viral infections, especially, in those with pre-existing CRDs. Here, we discuss the common viral infections in CRDs, as well as the potential role that IL-13 plays in the virus-induced disease pathogenesis of CRDs. We also discuss, in detail, the immune-modulation potential of IL-13 that could be translated to in-depth studies to develop IL-13-based therapeutic entities.


Assuntos
Influenza Humana/imunologia , Interleucina-13/imunologia , Pneumopatias/imunologia , Doença Crônica , Humanos , Inflamação/imunologia , Inflamação/patologia , Influenza Humana/patologia , Pneumopatias/patologia , Muco/imunologia
9.
Eur J Med Genet ; 64(10): 104294, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34352414

RESUMO

Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.


Assuntos
Deficiências do Desenvolvimento/genética , Insuficiência de Crescimento/genética , Hepatopatias/genética , Pneumopatias/genética , Tirosina-tRNA Ligase/genética , Deficiências do Desenvolvimento/patologia , Insuficiência de Crescimento/patologia , Feminino , Humanos , Lactente , Hepatopatias/patologia , Mutação com Perda de Função , Pneumopatias/patologia
10.
PLoS One ; 16(8): e0255617, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34343220

RESUMO

BACKGROUND: Coal mine dust lung disease comprises a group of occupational lung diseases including coal workers pneumoconiosis. In many countries, there is a lack of robust prevalence estimates for these diseases. Our objective was to perform a systematic review and meta-analysis of published contemporary estimates on prevalence, mortality, and survival for coal mine dust lung disease worldwide. METHODS: Systematic searches of PubMed, EMBASE and Web of Science databases for English language peer-reviewed articles published from 1/1/2000 to 30/03/2021 that presented quantitative estimates of prevalence, mortality, or survival for coal mine dust lung disease. Review was conducted per PRISMA guidelines. Articles were screened independently by two authors. Studies were critically assessed using Joanna Briggs Institute tools. Pooled prevalence estimates were obtained using random effects meta-analysis models. Heterogeneity was measured using the I2 statistics and publication bias using Egger's tests. RESULTS: Overall 40 studies were included, (31 prevalence, 8 mortality, 1 survival). Of the prevalence estimates, fifteen (12 from the United States) were retained for the meta-analysis. The overall pooled prevalence estimate for coal workers pneumoconiosis among underground miners was 3.7% (95% CI 3.0-4.5%) with high heterogeneity between studies. The pooled estimate of coal workers pneumoconiosis prevalence in the United States was higher in the 2000s than in the 1990s, consistent with published reports of increasing prevalence following decades of declining trends. Sub-group analyses also indicated higher prevalence among underground miners, and in Central Appalachia. The mortality studies were suggestive of reduced pneumoconiosis mortality rates over time, relative to the general population. CONCLUSION: The ongoing prevalence of occupational lung diseases among contemporary coal miners highlights the importance of respiratory surveillance and preventive efforts through effective dust control measures. Limited prevalence studies from countries other than the United States limits our understanding of the current disease burden in other coal-producing countries.


Assuntos
Antracose/patologia , Minas de Carvão/métodos , Pneumopatias/epidemiologia , Pneumopatias/mortalidade , Doenças Profissionais/epidemiologia , Doenças Profissionais/mortalidade , Exposição Ocupacional/efeitos adversos , Antracose/etiologia , Humanos , Agências Internacionais , Pneumopatias/patologia , Doenças Profissionais/patologia , Prevalência
11.
Nat Commun ; 12(1): 4314, 2021 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-34262047

RESUMO

Patients with chronic lung disease (CLD) have an increased risk for severe coronavirus disease-19 (COVID-19) and poor outcomes. Here, we analyze the transcriptomes of 611,398 single cells isolated from healthy and CLD lungs to identify molecular characteristics of lung cells that may account for worse COVID-19 outcomes in patients with chronic lung diseases. We observe a similar cellular distribution and relative expression of SARS-CoV-2 entry factors in control and CLD lungs. CLD AT2 cells express higher levels of genes linked directly to the efficiency of viral replication and the innate immune response. Additionally, we identify basal differences in inflammatory gene expression programs that highlight how CLD alters the inflammatory microenvironment encountered upon viral exposure to the peripheral lung. Our study indicates that CLD is accompanied by changes in cell-type-specific gene expression programs that prime the lung epithelium for and influence the innate and adaptive immune responses to SARS-CoV-2 infection.


Assuntos
Pneumopatias/genética , SARS-CoV-2/fisiologia , Transcriptoma , Internalização do Vírus , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/genética , COVID-19/patologia , Doença Crônica , Humanos , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/patologia , Imunidade Inata/genética , Inflamação/genética , Pulmão/metabolismo , Pulmão/patologia , Pneumopatias/patologia , SARS-CoV-2/patogenicidade , Replicação Viral/genética
12.
J Forensic Sci ; 66(6): 2499-2503, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34272739

RESUMO

Sudden unexpected death due to pneumothoraces caused by spontaneous rupture of bilateral pulmonary bullae is rare. This article reports the case of a 16-year-old girl who experienced this rare phenomenon without any precipitating factors. The patient did not have a history of chest pains or smoking but experienced chest tightness in the early morning and collapsed and died 4 h later. Autopsy identified the cause of death to be bilateral pneumothoraces and massive bilateral pulmonary collapse (atelectasis) due to ruptured apical bullae of the bilateral lungs. No injuries or other significant pathological findings were identified. A low body mass index (16.5) may have been a risk factor for the spontaneous tension pneumothoraces. In some situations, genetic counseling and testing may be helpful in identifying a heritable process associated with spontaneous pneumothoraces.


Assuntos
Vesícula/patologia , Morte Súbita/etiologia , Pneumopatias/patologia , Pneumotórax/patologia , Ruptura Espontânea/patologia , Adolescente , Feminino , Humanos , Atelectasia Pulmonar/patologia
13.
PLoS One ; 16(7): e0246270, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34237078

RESUMO

During infectious disease, pathogen load drives inflammation and immune response that together contribute to tissue injury often resulting in organ dysfunction. Pulmonary failure in SARS-CoV2-infected hospitalized COVID-19 patients is one such prominent example. Intervention strategies require characterization of the host-pathogen interaction by accurately assessing all of the above-mentioned disease parameters. To study infection in intact mammals, mice are often used as essential genetic models. Due to humane concerns, there is a constant unmet demand to develop studies that reduce the number of mice utilized while generating objective data. Here, we describe an integrated method of evaluating lung inflammation in mice infected with Pseudomonas aeruginosa or murine gammaherpesvirus (MHV)-68. This method conserves animal resources while permitting evaluation of disease mechanisms in both infection settings. Lungs from a single euthanized mouse were used for two purposes-biological assays to determine inflammation and infection load, as well as histology to evaluate tissue architecture. For this concurrent assessment of multiple parameters from a single euthanized mouse, we limit in-situ formalin fixation to the right lung of the cadaver. The unfixed left lung is collected immediately and divided into several segments for biological assays including determination of pathogen titer, assessment of infection-driven cytokine levels and appearance of cell death markers. In situ fixed right lung was then processed for histological determination of tissue injury and confirmation of infection-driven cell death patterns. This method reduces overall animal use and minimizes inter-animal variability that results from sacrificing different animals for different types of assays. The technique can be applied to any lung disease study in mice or other mammals.


Assuntos
Infecções por Herpesviridae/patologia , Pneumopatias/patologia , Pulmão/patologia , Infecções por Pseudomonas/patologia , Animais , Gammaherpesvirinae , Camundongos , Pseudomonas aeruginosa
14.
Am J Respir Cell Mol Biol ; 65(5): 473-488, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34293272

RESUMO

Compromised alveolar development and pulmonary vascular remodeling are hallmarks of pediatric lung diseases such as bronchopulmonary dysplasia (BPD) and alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Although advances in surfactant therapy, corticosteroids, and antiinflammatory drugs have improved clinical management of preterm infants, those who suffer with severe vascular complications still lack viable treatment options. Paucity of the alveolar capillary network in ACDMPV causes respiratory distress and leads to mortality in a vast majority of infants with ACDMPV. The discovery of endothelial progenitor cells (EPCs) in 1997 brought forth the paradigm of postnatal vasculogenesis and hope for promoting vascularization in fragile patient populations, such as those with BPD and ACDMPV. The identification of diverse EPC populations, both hematopoietic and nonhematopoietic in origin, provided a need to identify progenitor cell-selective markers that are linked to progenitor properties needed to develop cell-based therapies. Focusing on the future potential of EPCs for regenerative medicine, this review will discuss various aspects of EPC biology, beginning with the identification of hematopoietic, nonhematopoietic, and tissue-resident EPC populations. We will review knowledge related to cell surface markers, signature gene expression, and key transcriptional regulators and will explore the translational potential of EPCs for cell-based therapy for BPD and ACDMPV. The ability to produce pulmonary EPCs from patient-derived induced pluripotent stem cells in vitro holds promise for restoring vascular growth and function in the lungs of patients with pediatric pulmonary disorders.


Assuntos
Displasia Broncopulmonar/patologia , Células Progenitoras Endoteliais/fisiologia , Pneumopatias/terapia , Síndrome da Persistência do Padrão de Circulação Fetal/patologia , Animais , Displasia Broncopulmonar/terapia , Diferenciação Celular , Células Progenitoras Endoteliais/citologia , Células Progenitoras Endoteliais/transplante , Regulação da Expressão Gênica , Humanos , Células-Tronco Pluripotentes Induzidas , Recém-Nascido Prematuro , Pulmão/irrigação sanguínea , Pulmão/embriologia , Pulmão/metabolismo , Pneumopatias/patologia , Síndrome da Persistência do Padrão de Circulação Fetal/terapia
15.
Cells ; 10(7)2021 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206722

RESUMO

The lungs are affected by illnesses including asthma, chronic obstructive pulmonary disease, and infections such as influenza and SARS-CoV-2. Physiologically relevant models for respiratory conditions will be essential for new drug development. The composition and structure of the lung extracellular matrix (ECM) plays a major role in the function of the lung tissue and cells. Lung-on-chip models have been developed to address some of the limitations of current two-dimensional in vitro models. In this review, we describe various ECM substitutes utilized for modeling the respiratory system. We explore the application of lung-on-chip models to the study of cigarette smoke and electronic cigarette vapor. We discuss the challenges and opportunities related to model characterization with an emphasis on in situ characterization methods, both established and emerging. We discuss how further advancements in the field, through the incorporation of interstitial cells and ECM, have the potential to provide an effective tool for interrogating lung biology and disease, especially the mechanisms that involve the interstitial elements.


Assuntos
Dispositivos Lab-On-A-Chip , Pneumopatias/patologia , Pulmão/fisiologia , Regeneração/fisiologia , Mucosa Respiratória/citologia , COVID-19/patologia , COVID-19/terapia , COVID-19/virologia , Células Cultivadas , Matriz Extracelular/fisiologia , Humanos , Pulmão/citologia , Pulmão/patologia , Pneumopatias/fisiopatologia , Pneumopatias/terapia , Modelos Biológicos , Mucosa Respiratória/patologia , Mucosa Respiratória/fisiologia , SARS-CoV-2/patogenicidade , Técnicas de Cultura de Tecidos/instrumentação , Técnicas de Cultura de Tecidos/métodos
16.
Eur J Med Genet ; 64(9): 104262, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34161863

RESUMO

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease and usually involves the skin, musculoskeletal system, and kidneys. More than 30 genes have been to monogenic lupus, so far. Monogenic lupus is often characterized by an early-onset, similar family history, and syndromic appearance. Herein we present a pediatric patient with DNASE1L3 deficiency, suffering from both urticarial skin lesions, recurrent hemoptysis, and renal involvement, eventually diagnosed as this rare monogenic lupus. The patient suffered from recurrent urticarial rash and hemoptysis since the age of 15 months of age. He had microscopic hematuria, mild proteinuria, hypocomplementemia, and positive antinuclear antibody, anti-dsDNA, and antineutrophil cytoplasmic antibodies. Renal biopsy yielded immunocomplex glomerulonephritis. Due to early-onset, similar sibling history and consanguineous parents, we suspected monogenic lupus and performed whole-exome sequencing, which further revealed a homozygous T97Ifs*2 mutation (NM_004944.4: c.290_291delCA/p.Thr97Ilefs*2) in DNASE1L3 gene. In conclusion, DNASE1L3 deficiency should be thought when juvenile SLE occurs with early disease-onset, pulmonary hemorrhage, glomerulonephritis, and recurrent urticarial rash along with ANCA positivity.


Assuntos
Endodesoxirribonucleases/genética , Exantema/genética , Glomerulonefrite/genética , Hemorragia/genética , Síndromes de Imunodeficiência/genética , Pneumopatias/genética , Criança , Endodesoxirribonucleases/deficiência , Exantema/patologia , Glomerulonefrite/patologia , Hemorragia/patologia , Humanos , Síndromes de Imunodeficiência/patologia , Pneumopatias/patologia , Masculino
18.
Front Immunol ; 12: 588753, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34149680

RESUMO

Objective: To identify the existence of a correlation among the various organs affected, focusing primarily on immuno-dermatological aspects, and to create a risk prediction model of organ-specific complications. Material and Methods: Fifty-two patients with stable scleroderma, followed between 2015 and 2019, were investigated through an extensive multidisciplinary evaluation in the last year. Results: Patients with lung involvement presented a worse degree of skin fibrosis than patients without it (p <0.001). No relationship was observed for the heart, kidney, and esophagus. Patients with pulmonary involvement had a lower pressure of the low esophagus sphincter and a higher Warrick score than patients without it (p <0.05). Age was significantly higher in patients with kidney involvement. Diffuse scleroderma patients had a worse pulmonary impairment than limited scleroderma patients (p <0.05). The manometric "sclerodermic" pattern was observed to be the most frequent (55.6%, p <0.05) in dcSSc patients while the sclerodermic and normal pattern were equally represented (41.2 and 32.4% respectively, p <0.05) in lcSSc patients. When compared to the negative serological groups, anti-Scl-70 positive patients presented a worse lung involvement while anti-centromere patients presented a better lung outcome (p <0.05). PM-Scl 100/75 positive patients presented mostly a pulmonary fibrotic pattern (p <0.05) and, also, heart complications were more likely associated with anti PM-Scl 100/75 positivity (p <0.05). The risk prediction model for organ-specific complications had an accuracy of 84.4% (95%CI 78, 89) in complication-site prediction, AUC of 0.871, 86% of sensitivity, and 83% of specificity, Cohen's Kappa (k) of 0.68. Conclusions: Out of all the organs studied, the skin is the one that correlates with the lung. Patients with a diffuse form of disease presented more frequently the anti Scl-70 antibody and had a worse lung and esophageal involvement (scleroderma pattern) than the negative group. Conversely, patients with limited disease presented all positive for the anti-centromere antibody with a better lung involvement than the negative group, without any difference among the esophageal manometric pattern. Anti PM-Scl 100/75 antibody patients were associated with pulmonary fibrosis and presented cardiac involvement. The model created has demonstrated excellent values of sensitivity, specificity, and accuracy, but further studies are needed for validation.


Assuntos
Pneumopatias/diagnóstico , Pulmão/patologia , Escleroderma Sistêmico/diagnóstico , Pele/patologia , Fatores Etários , Idoso , Feminino , Humanos , Modelos Logísticos , Pneumopatias/epidemiologia , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Prognóstico , Risco , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/patologia , Sensibilidade e Especificidade
19.
Life Sci ; 281: 119718, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34147483

RESUMO

AIMS: Hypoxia, a pathophysiological condition, is profound in several cardiopulmonary diseases (CPD). Every individual's lethality to a hypoxia state differs in terms of hypoxia exposure time, dosage units and dependent on the individual's genetic makeup. Most of the proposed markers for CPD were generally aim to distinguish disease samples from normal samples. Although, as per the 2018 GOLD guidelines, clinically useful biomarkers for several cardio pulmonary disease patients in stable condition have yet to be identified. We attempt to address these key issues through the identification of Dynamic Network Biomarkers (DNB) to detect hypoxia induced early warning signals of CPD before the catastrophic deterioration. MATERIALS AND METHODS: The human microvascular endothelial tissues microarray datasets (GSE11341) of lung and cardiac expose to hypoxia (1% O2) for 3, 24 and 48 h were retrieved from the public repository. The time dependent differentially expressed genes were subjected to tissue specificity and promoter analysis to filtrate the noise levels in the networks and to dissect the tissue specific hypoxia induced genes. These filtered out genes were used to construct the dynamic segmentation networks. The hypoxia induced dynamic differentially expressed genes were validated in the lung and heart tissues of male rats. These rats were exposed to hypobaric hypoxia (simulated altitude of 25,000 or PO2 - 282 mm of Hg) progressively for 3, 24 and 48 h. KEY FINDINGS: To identify the temporal key genes regulated in hypoxia, we ranked the dominant genes based on their consolidated topological features from tissue specific networks, time dependent networks and dynamic networks. Overall topological ranking described VEGFA as a single node dynamic hub and strongly communicated with tissue specific genes to carry forward their tissue specific information. We named this type of VEGFAcentric dynamic networks as "V-DNBs". As a proof of principle, our methodology helped us to identify the V-DNBs specific for lung and cardiac tissues namely V-DNBL and V-DNBC respectively. SIGNIFICANCE: Our experimental studies identified VEGFA, SLC2A3, ADM and ENO2 as the minimum and sufficient candidates of V-DNBL. The dynamic expression patterns could be readily exploited to capture the pre disease state of hypoxia induced pulmonary vascular remodelling. Whereas in V-DNBC the minimum and sufficient candidates are VEGFA, SCL2A3, ADM, NDRG1, ENO2 and BHLHE40. The time dependent single node expansion indicates V-DNBC could also be the pre disease state pathological hallmark for hypoxia-associated cardiovascular remodelling. The network cross-talk and expression pattern between V-DNBL and V-DNBC are completely distinct. On the other hand, the great clinical advantage of V-DNBs for pre disease predictions, a set of samples during the healthy condition should suffice. Future clinical studies might further shed light on the predictive power of V-DNBs as prognostic and diagnostic biomarkers for CPD.


Assuntos
Cardiopatias/metabolismo , Hipóxia/metabolismo , Pneumopatias/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Biomarcadores/metabolismo , Deterioração Clínica , Regulação da Expressão Gênica , Cardiopatias/etiologia , Cardiopatias/patologia , Humanos , Hipóxia/complicações , Hipóxia/genética , Pneumopatias/etiologia , Pneumopatias/patologia , Masculino , Ratos , Ratos Sprague-Dawley
20.
Clin Immunol ; 229: 108764, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34089860

RESUMO

C57BL/6 mice with pristane-induced lupus develop macrophage-dependent diffuse alveolar hemorrhage (DAH), which is blocked by treatment with liver X receptor (LXR) agonists and is exacerbated by low IL-10 levels. Serp-1, a myxomavirus-encoded serpin that impairs macrophage activation and plasminogen activation, blocks DAH caused by MHV68 infection. We investigated whether Serp-1 also could block DAH in pristane-induced lupus. Pristane-induced DAH was prevented by treatment with recombinant Serp-1 and macrophages from Serp1-treated mice exhibited an anti-inflammatory M2-like phenotype. Therapy activated LXR, promoting M2 polarization and expression of Kruppel-like factor-4 (KLH4), which upregulates IL-10. In contrast, deficiency of tissue plasminogen activator or plasminogen activator inhibitor had little effect on DAH. We conclude that Serp-1 blocks pristane-induced lung hemorrhage by enhancing LXR-regulated M2 macrophage polarization and KLH4-regulated IL-10 production. In view of the similarities between DAH in pristane-treated mice and SLE patients, Serp-1 may represent a potential new therapy for this severe complication of SLE.


Assuntos
Lúpus Eritematoso Sistêmico/terapia , Macrófagos/efeitos dos fármacos , Serpinas/farmacologia , Proteínas Virais/farmacologia , Animais , Coagulação Sanguínea , Feminino , Hemorragia/sangue , Hemorragia/patologia , Hemorragia/prevenção & controle , Interleucina-10/biossíntese , Receptores X do Fígado/metabolismo , Pneumopatias/sangue , Pneumopatias/patologia , Pneumopatias/prevenção & controle , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/classificação , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Myxoma virus/genética , Células RAW 264.7 , Serpinas/genética , Terpenos/toxicidade , Proteínas Virais/genética
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