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1.
Toxicol Lett ; 337: 57-67, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232776

RESUMO

In this study, a ricin toxin (RT)-induced pulmonary intoxication model was established in mice by intratracheal-delivered RT at a dose of 2× LD50. Based on this model, the histopathological evaluation of the lungs at 24 h and 48 h post-exposure was executed, and the genome-wide transcriptome of the lungs at 4, 12, 24 and 48 h post-exposure was analyzed. Histopathological analysis showed that a large number of neutrophils infiltrated the lungs at 24 h post-exposure, and slight pulmonary edema and perivascular-peribronchiolar edema appeared in the lungs at 48 h. Transcriptome analysis showed that the expression of a large number of genes related to leukocyte migration and chemotaxis consistently increased in the lungs upon exposure to RT, and the expression of genes that participate in acute phase immune and/or inflammatory response, also increased within 12 h of exposure to RT, which could be confirmed by the measurement of cytokines, such as IL-1ß, TNF-α and IL-6, in bronchoalveolar lavage fluid. While the expression of genes related to cellular components of the extracellular matrix and cell membrane integrity consistently decreased in the lungs, and the expression of genes related to antioxidant activity also decreased within the first 12 h. There are 17 differentially expressed genes (DEGs) that participate in ribotoxic stress response, endoplasmic reticulum stress response or immune response in the lungs at 4 h post-exposure. The expression of these DEGs was upregulated, and the number of these DEGs accounted for about 59 % of all DEGs at 4 h. The 17 DEGs may play an important role in the occurrence and development of inflammation. Notably, Atf3, Egr1, Gdf15 and Osm, which are poorly studied, may be important targets for the subsequent research of RT-induced pulmonary intoxication. This study provides new information and insights for RT-induced pulmonary intoxication, and it can provide a reference for the subsequent study of the toxicological mechanism and therapeutic approaches for RT-induced pulmonary intoxication.


Assuntos
Armas Biológicas , Perfilação da Expressão Gênica , Pneumopatias/induzido quimicamente , Ricina/administração & dosagem , Ricina/toxicidade , Reação de Fase Aguda/induzido quimicamente , Reação de Fase Aguda/patologia , Animais , Líquido da Lavagem Broncoalveolar , Citocinas/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/genética , Feminino , Expressão Gênica/efeitos dos fármacos , Estudo de Associação Genômica Ampla , Inflamação/induzido quimicamente , Inflamação/patologia , Intubação Intratraqueal , Pulmão/patologia , Pneumopatias/genética , Pneumopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL
2.
BMC Infect Dis ; 20(1): 892, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243155

RESUMO

BACKGROUND: A pneumatocele is a transient thin-walled lesion and rare complication in adult pneumonia. A variety of infectious pathogens have been reported in children with pneumatoceles. We report the first case of adult pneumonia with pneumatocele formation that is likely caused by Streptococcus pyogenes and coinfection with influenza A virus. CASE PRESENTATION: A 64-year-old Japanese man presented with a one-week history of fever, sore throat, and arthralgia. He was referred to our university hospital for respiratory distress. He required mechanical ventilation in the intensive care unit (ICU). Bacterial culture detected S. pyogenes in the bronchoscopic aspirates, which was not detected in blood. Although a rapid influenza antigen test was negative, an influenza A polymerase chain reaction (PCR) test was positive. Therefore, he was diagnosed with coinfection of influenza A and group A streptococcus (GAS) pneumonia complicated by probable streptococcal toxic shock syndrome. A chest radiograph on admission showed diffuse patchy opacification and consolidation in the bilateral lung fields. Multiple thin-walled cysts appeared in both middle lung fields on computed tomography (CT). On the following day, the bilateral cysts had turned into a mass-like opacity. The patient died despite intensive care. An autopsy was performed. The pathology investigation revealed multiple hematomas formed by bleeding in pneumatoceles. CONCLUSIONS: There have been no previous reports of a pneumatocele complicated by S. pyogenes in an adult patient coinfected with influenza A. Further molecular investigation revealed that the S. pyogenes isolate had the sequence type of emm3.


Assuntos
Coinfecção , Influenza Humana/complicações , Influenza Humana/patologia , Pneumopatias/etiologia , Pneumonia/complicações , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/patologia , Coinfecção/complicações , Coinfecção/patologia , Cistos/diagnóstico por imagem , Evolução Fatal , Humanos , Vírus da Influenza A , Influenza Humana/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico por imagem , Pneumonia/microbiologia , Pneumonia/patologia , Choque Séptico/diagnóstico , Infecções Estreptocócicas/diagnóstico por imagem , Infecções Estreptocócicas/microbiologia , Streptococcus pyogenes , Tomografia Computadorizada por Raios X
3.
Stem Cell Reports ; 15(5): 1015-1025, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33065046

RESUMO

Despite the central importance of the respiratory system, the exact mechanisms governing lung repair after severe injury remain unclear. The notion that alveolar type 2 cells (AT2s) self-renew and differentiate into alveolar type 1 cells (AT1s) does not fully encompass scenarios where these progenitors are severely affected by disease, e.g., H1N1 influenza or SARS-CoV-2 (COVID-19). Intrapulmonary p63+ progenitor cells, a rare cell type in mice but potentially encompassing more numerous classic basal cells in humans, are activated in such severe injury settings, proliferating and migrating into the injured alveolar parenchyma, providing a short-term "emergency" benefit. While the fate of these cells is controversial, most studies indicate that they represent a maladaptive repair pathway with a fate restriction toward airway cell types, rarely differentiating into AT2 or AT1 cells. Here, we discuss the role of intrapulmonary basal-like p63+ cells in alveolar regeneration and suggest a unified model to guide future studies.


Assuntos
Pulmão/fisiologia , Regeneração , Células-Tronco/metabolismo , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , /virologia , Diferenciação Celular , Humanos , Pulmão/metabolismo , Pneumopatias/patologia , Pneumopatias/terapia , Pneumopatias/virologia , Transplante de Células-Tronco , Células-Tronco/citologia
5.
BMJ Case Rep ; 13(10)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33122234

RESUMO

A 60-year-old man presented with sudden onset right-sided chest pain and gradually worsening shortness of breath on exertion. Eleven days earlier, he had an admission with COVID-19 pneumonitis requiring 8 days of continuous positive airway pressure. He was tachypnoeic with a respiratory rate of 24 breaths/min, oxygen saturations on room air of 91%. Examination revealed reduced air entry and a resonant percussion note over the right hemithorax. Chest radiograph suggested a complex right pneumothorax; however, a CT chest was notable for widespread right-sided bullous lung disease. After a day of observation on a COVID-19 ward (and a repeat radiograph with a stable appearance), he was discharged with a 2-week follow-up with the respiratory team, safety netting advice and ambulatory oxygen. This case suggests that bullous lung disease may be a complication of severe COVID-19 pneumonitis.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/terapia , Pneumopatias/patologia , Pneumonia Viral/complicações , Pneumonia Viral/terapia , Pneumotórax/diagnóstico por imagem , Pneumotórax/etiologia , Síndrome Respiratória Aguda Grave/complicações , Dor no Peito/diagnóstico , Dor no Peito/etiologia , Técnicas de Laboratório Clínico/métodos , Pressão Positiva Contínua nas Vias Aéreas/métodos , Infecções por Coronavirus/diagnóstico , Diagnóstico Diferencial , Dispneia/diagnóstico , Dispneia/etiologia , Serviço Hospitalar de Emergência , Humanos , Pneumopatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumotórax/terapia , Radiografia Torácica/métodos , Medição de Risco , Síndrome Respiratória Aguda Grave/diagnóstico , Síndrome Respiratória Aguda Grave/terapia , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
6.
Nat Commun ; 11(1): 5165, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057007

RESUMO

Angiotensin-converting enzyme 2 (ACE2) has been identified as the host entry receptor for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for the COVID-19 pandemic. ACE2 is a regulatory enzyme of the renin-angiotensin system and has protective functions in many cardiovascular, pulmonary and metabolic diseases. This review summarizes available murine models with systemic or organ-specific deletion of ACE2, or with overexpression of murine or human ACE2. The purpose of this review is to provide researchers with the genetic tools available for further understanding of ACE2 biology and for the investigation of ACE2 in the pathogenesis and treatment of COVID-19.


Assuntos
Doenças Cardiovasculares/patologia , Modelos Animais de Doenças , Pneumopatias/patologia , Peptidil Dipeptidase A/metabolismo , Animais , Betacoronavirus/fisiologia , Doenças Cardiovasculares/metabolismo , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Humanos , Pneumopatias/metabolismo , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Camundongos , Camundongos Mutantes , Pandemias , Peptidil Dipeptidase A/genética , Pneumonia Viral/metabolismo , Pneumonia Viral/patologia , Pneumonia Viral/virologia
7.
PLoS One ; 15(10): e0240333, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33057360

RESUMO

CRISPR/Cas9-mediated gene editing often generates founder generation (F0) mice that exhibit somatic mosaicism in the targeted gene(s). It has been known that Fibroblast growth factor 10 (Fgf10)-null mice exhibit limbless and lungless phenotypes, while intermediate limb phenotypes (variable defective limbs) are observed in the Fgf10-CRISPR F0 mice. However, how the lung phenotype in the Fgf10-mosaic mutants is related to the limb phenotype and genotype has not been investigated. In this study, we examined variable lung phenotypes in the Fgf10-targeted F0 mice to determine if the lung phenotype was correlated with percentage of functional Fgf10 genotypes. Firstly, according to a previous report, Fgf10-CRISPR F0 embryos on embryonic day 16.5 (E16.5) were classified into three types: type I, no limb; type II, limb defect; and type III, normal limbs. Cartilage and bone staining showed that limb truncations were observed in the girdle, (type I), stylopodial, or zeugopodial region (type II). Deep sequencing of the Fgf10-mutant genomes revealed that the mean proportion of codons that encode putative functional FGF10 was 8.3 ± 6.2% in type I, 25.3 ± 2.7% in type II, and 54.3 ± 9.5% in type III (mean ± standard error of the mean) mutants at E16.5. Histological studies showed that almost all lung lobes were absent in type I embryos. The accessory lung lobe was often absent in type II embryos with other lobes dysplastic. All lung lobes formed in type III embryos. The number of terminal tubules was significantly lower in type I and II embryos, but unchanged in type III embryos. To identify alveolar type 2 epithelial (AECII) cells, known to be reduced in the Fgf10-heterozygous mutant, immunostaining using anti-surfactant protein C (SPC) antibody was performed: In the E18.5 lungs, the number of AECII was correlated to the percentage of functional Fgf10 genotypes. These data suggest the Fgf10 gene dose-related loss of the accessory lobe and decrease in the number of alveolar type 2 epithelial cells in mouse lung. Since dysfunction of AECII cells has been implicated in the pathogenesis of parenchymal lung diseases, the Fgf10-CRISPR F0 mouse would present an ideal experimental system to explore it.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Fator 10 de Crescimento de Fibroblastos/genética , Edição de Genes/métodos , Pulmão/metabolismo , Células Epiteliais Alveolares/citologia , Células Epiteliais Alveolares/metabolismo , Animais , Modelos Animais de Doenças , Embrião de Mamíferos/metabolismo , Dosagem de Genes , Genótipo , Pulmão/citologia , Pulmão/patologia , Pneumopatias/metabolismo , Pneumopatias/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Camundongos Transgênicos
8.
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
9.
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
10.
Toxicology ; 445: 152598, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32976959

RESUMO

Human exposure to carbon nanotubes (CNT) has been associated with the development of pulmonary sarcoid-like granulomatous disease. Our previous studies demonstrated that multi-walled carbon nanotubes (MWCNT) induced chronic pulmonary granulomatous inflammation in mice. Granuloma formation was accompanied by decreased peroxisome proliferator-activated receptor gamma (PPARγ) and disrupted intracellular lipid homeostasis in alveolar macrophages. Others have shown that PPARγ activation increases mitochondrial fatty acid oxidation (FAO) to reduce free fatty acid accumulation. Hence, we hypothesized that the disrupted lipid metabolism suppresses mitochondrial FAO. To test our hypothesis, C57BL/6 J mice were instilled by an oropharyngeal route with 100 µg MWCNT freshly suspended in 35 % Infasurf. Control sham mice received vehicle alone. Sixty days following instillation, mitochondrial FAO was measured in permeabilized bronchoalveolar lavage (BAL) cells. MWCNT instillation reduced the mitochondrial oxygen consumption rate of BAL cells in the presence of palmitoyl-carnitine as mitochondrial fuel. MWCNT also reduced mRNA expression of mitochondrial genes regulating FAO, carnitine palmitoyl transferase-1 (CPT1), carnitine palmitoyl transferase-2 (CPT2), hydroxyacyl-CoA dehydrogenase subunit beta (HADHB), and PPARγ coactivator 1 alpha (PPARGC1A). Importantly, both oxidative stress and apoptosis in alveolar macrophages and lung tissues of MWCNT-instilled mice were increased. Because macrophage PPARγ expression has been reported to be controlled by miR-27b which is known to induce oxidative stress and apoptosis, we measured the expression of miR-27b. Results indicated elevated levels in alveolar macrophages from MWCNT-instilled mice compared to controls. Given that inhibition of FAO and apoptosis are linked to M1 and M2 macrophage activation, respectively, the expression of both M1 and M2 key indicator genes were measured. Interestingly, results showed that both M1 and M2 phenotypes of alveolar macrophages were activated in MWCNT-instilled mice. In conclusion, alveolar macrophages of MWCNT-instilled mice had increased miR-27b expression, which may reduce the expression of PPARγ resulting in attenuation of FAO. This reduction in FAO may lead to activation of M1 macrophages. The upregulation of miR-27b may also induce apoptosis, which in turn can cause M2 activation of alveolar macrophages. These observations indicate a possible role of miR-27b in impaired mitochondrial function in the chronic activation of alveolar macrophages by MWCNT and the development of chronic pulmonary granulomatous inflammation.


Assuntos
Doença Granulomatosa Crônica/induzido quimicamente , Pneumopatias/induzido quimicamente , Macrófagos Alveolares/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Nanotubos de Carbono/toxicidade , Animais , Doença Granulomatosa Crônica/metabolismo , Doença Granulomatosa Crônica/patologia , Pneumopatias/metabolismo , Pneumopatias/patologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia
11.
BMC Pulm Med ; 20(1): 246, 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32938454

RESUMO

BACKGROUND: Myospherulosis develops as the result of a reaction between exogenous lipids and red blood cells (RBC) of the patient, being the latter injured when perceived as a foreign body by the immune system, triggering an intense inflammatory response. CASE PRESENTATION: A 63-year-old man with a history of dyslipidemia, Barret's esophagus, and coronary disease, who was taken to thoracoscopy and left inferior lobectomy due to the presence of a pulmonary mass. A primary pulmonary adenocarcinoma was diagnosed. On follow up a PET-CT was performed, in which a metabolically active lesion was described adjacent to the prior lobectomy, suggesting a local relapse. EBUS-TBNA was then performed, obtaining a sample from which histopathological pattern compatible with myospherulosis was obtained. CONCLUSIONS: Although it is a rare entity, myospherulosis has a well-defined morphological pattern. By not recognizing myospherulosis as a benign lesion, a patient's risk of invasive cancer can be overestimated. It is a phenomenon found with increasing frequency and has been reported in different tissues, however, this is the first report in the literature of myospherulosis of the lung. Greater awareness is required regarding the existence of this phenomenon.


Assuntos
Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Eritrócitos , Granuloma/patologia , Lipídeos , Pneumopatias/patologia , Brônquios , Humanos , Masculino , Pessoa de Meia-Idade
12.
Sci Rep ; 10(1): 15811, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978505

RESUMO

Hemorrhagic shock results in systemic injury to the endothelium contributing to post-shock morbidity and mortality. The mechanism involves syndecan-1, the backbone of the endothelial glycocalyx. We have shown in a rodent model that lung syndecan-1 mRNA is reduced following hemorrhage, whereas the molecular mechanism underlying the mRNA reduction is not clear. In this study, we present evidence that miR-19b targets syndecan-1 mRNA to downregulate its expression. Our results demonstrate that miR-19b was increased in hemorrhagic shock patients and in-vitro specifically bound to syndecan-1 mRNA and caused its degradation. Further, hypoxia/reoxygenation (H/R), our in vitro hemorrhage model, increased miR-19b expression in human lung microvascular endothelial cells, leading to a decrease in syndecan-1 mRNA and protein. H/R insult and miR-19b mimic overexpression comparably exaggerated permeability and enhanced endothelial barrier breakdown. The detrimental role of miR-19b in inducing endothelial dysfunction was confirmed in vivo. Lungs from mice undergoing hemorrhagic shock exhibited a significant increase in miR-19b and a concomitant decrease in syndecan-1 mRNA. Pretreatment with miR-19b oligo inhibitor significantly decreased lung injury, inflammation, and permeability and improved hemodynamics. These findings suggest that inhibition of miR-19b may be a putative therapeutic avenue for mitigating post shock pulmonary endothelial dysfunction in hemorrhage shock.


Assuntos
Modelos Animais de Doenças , Endotélio Vascular/patologia , Pneumopatias/patologia , MicroRNAs/genética , Choque Hemorrágico/complicações , Sindecana-1/metabolismo , Animais , Estudos de Casos e Controles , Endotélio Vascular/metabolismo , Humanos , Pneumopatias/etiologia , Pneumopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sindecana-1/genética
13.
PLoS One ; 15(9): e0238066, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32916689

RESUMO

Oxidative stress (OS) plays a marked role in aging and results from a variety of stressors, making it a powerful measure of health and a way to examine costs associated with life history investments within and across species. However, few urinary OS markers have been examined under field conditions, particularly in primates, and their utility to non-invasively monitor the costs of acute stressors versus the long-term damage associated with aging is poorly understood. In this study, we examined variation in 5 urinary markers of oxidative damage and protection under 5 validation paradigms for 37 wild, chimpanzees living in the Kibale National Park, Uganda. We used 924 urine samples to examine responses to acute immune challenge (respiratory illness or severe wounding), as well as mixed-longitudinal and intra-individual variation with age. DNA damage (8-OHdG) correlated positively with all other markers of damage (F-isoprostanes, MDA-TBARS, and neopterin) but did not correlate with protection (total antioxidant capacity). Within individuals, all markers of damage responded to at least one if not both types of acute infection. While OS is expected to increase with age, this was not generally true in chimpanzees. However, significant changes in oxidative damage were detected within past-prime individuals and those close to death. Our results indicate that OS can be measured using field-collected urine and integrates short- and long-term aspects of health. They further suggest that more data are needed from long-lived, wild animals to illuminate if common age-related increases in inflammation and OS damage are typical or recently aberrant in humans.


Assuntos
Envelhecimento , Biomarcadores/urina , Estresse Oxidativo , 8-Hidroxi-2'-Desoxiguanosina/urina , Animais , Animais Selvagens , Antioxidantes/química , Antioxidantes/metabolismo , Isoprostanos/urina , Pneumopatias/patologia , Pneumopatias/urina , Neopterina/urina , Pan troglodytes , Ferimentos e Lesões/patologia , Ferimentos e Lesões/urina
14.
Sci Rep ; 10(1): 15640, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973236

RESUMO

Lung disease is common in patients with rheumatoid arthritis (RA). The onset of lung involvement in RA is not well known. The objective is to describe the features and evolution of lung involvement in early RA, its relationship with disease activity parameters, smoking and treatments. Consecutive patients with early RA without respiratory symptoms were included and tracked for 5 years. Lung assessment included clinical, radiological and pulmonary function tests at diagnosis and during follow-up. Peripheral blood parameters (erythrocyte sedimentation rate, C reactive protein, rheumatoid factor and anti-citrullinated peptide autoantibodies) and scales of articular involvement, such as DAS28-CRP, were evaluated. 40 patients were included and 32 completed the 5-year follow up. 13 patients presented lung involvement in the initial 5 years after RA diagnosis, 3 of them interstitial lung disease. Significant decrease of diffusion lung transfer capacity of carbon monoxide over time was observed in six patients, 2 of them developed interstitial lung disease. DLCO decrease was correlated with higher values of CRP and ESR at diagnosis. Methotrexate was not associated with DLCO deterioration or lung disease development. Subclinical progressive lung disease correlates with RA activity parameters. Smoking status and methotrexate were not associated with development or progression of lung disease.


Assuntos
Artrite Reumatoide/complicações , Pneumopatias/complicações , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
15.
Adv Exp Med Biol ; 1265: 57-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32761570

RESUMO

Lung diseases affect millions of individuals all over the world. Various environmental factors, such as toxins, chemical pollutants, detergents, viruses, bacteria, microbial dysbiosis, and allergens, contribute to the development of respiratory disorders. Exposure to these factors activates stress responses in host cells and disrupt lung homeostasis, therefore leading to dysfunctional epithelial barriers. Despite significant advances in therapeutic treatments for lung diseases in the last two decades, novel interventional targets are imperative, considering the side effects and limited efficacy in patients treated with currently available drugs. Nutrients, such as amino acids (e.g., arginine, glutamine, glycine, proline, taurine, and tryptophan), peptides, and bioactive molecules, have attracted more and more attention due to their abilities to reduce oxidative stress, inhibit apoptosis, and regulate immune responses, thereby improving epithelial barriers. In this review, we summarize recent advances in amino acid metabolism in the lungs, as well as multifaceted functions of amino acids in attenuating inflammatory lung diseases based on data from studies with both human patients and animal models. The underlying mechanisms for the effects of physiological amino acids are likely complex and involve cell signaling, gene expression, and anti-oxidative reactions. The beneficial effects of amino acids are expected to improve the respiratory health and well-being of humans and other animals. Because viruses (e.g., coronavirus) and environmental pollutants (e.g., PM2.5 particles) induce severe damage to the lungs, it is important to determine whether dietary supplementation or intravenous administration of individual functional amino acids (e.g., arginine-HCl, citrulline, N-acetylcysteine, glutamine, glycine, proline and tryptophan) or their combinations to affected subjects may alleviate injury and dysfunction in this vital organ.


Assuntos
Aminoácidos/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Pneumopatias/metabolismo , Pneumopatias/patologia , Animais , Humanos , Pneumopatias/fisiopatologia
16.
Am J Respir Cell Mol Biol ; 63(6): 794-805, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32853043

RESUMO

Electronic-cigarette (e-cig) vaping is a serious concern, as many pregnant women who vape consider it safe. However, little is known about the harmful effects of prenatal e-cig exposure on adult offspring, especially on extracellular-matrix (ECM) deposition and myogenesis in the lungs of offspring. We evaluated the biochemical and molecular implications of maternal exposure during pregnancy to e-cig aerosols on the adult offspring of both sexes, with a particular focus on pulmonary ECM remodeling and myogenesis. Pregnant CD-1 mice were exposed to e-cig aerosols with or without nicotine, throughout gestation, and lungs were collected from adult male and female offspring. Compared with the air-exposed control group, female mice exposed to e-cig aerosols, with or without nicotine, demonstrated increased lung protein abundance of LEF-1 (lymphoid enhancer-binding factor 1), fibronectin, and E-cadherin, whereas altered E-cadherin and PPARγ (peroxisome proliferator-activated receptor γ) levels were observed only in males exposed to e-cig aerosols with nicotine. Moreover, lipogenic and myogenic mRNAs were dysregulated in adult offspring in a sex-dependent manner. PAI-1 (plasminogen activator inhibitor-1), one of the ECM regulators, was significantly increased in females exposed prenatally to e-cig aerosols with nicotine and in males exposed to e-cig aerosols compared with control animals exposed to air. MMP9 (matrix metalloproteinase 9), a downstream target of PAI-1, was downregulated in both sexes exposed to e-cig aerosols with nicotine. No differences in lung histology were observed among any of the treatment groups. Overall, adult mice exposed prenatally to e-cig aerosols could be predisposed to developing pulmonary disease later in life. Thus, these findings suggest that vaping during pregnancy is unsafe and increases the propensity for later-life interstitial lung diseases.


Assuntos
Aerossóis/farmacologia , Sistemas Eletrônicos de Liberação de Nicotina , Efeitos Tardios da Exposição Pré-Natal/patologia , Fatores Sexuais , Animais , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Camundongos , Nicotina/farmacologia , Gravidez
17.
Am J Physiol Cell Physiol ; 319(4): C675-C693, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783658

RESUMO

The ability to replace defective cells in an airway with cells that can engraft, integrate, and restore a functional epithelium could potentially cure a number of lung diseases. Progress toward the development of strategies to regenerate the adult lung by either in vivo or ex vivo targeting of endogenous stem cells or pluripotent stem cell derivatives is limited by our fundamental lack of understanding of the mechanisms controlling human lung development, the precise identity and function of human lung stem and progenitor cell types, and the genetic and epigenetic control of human lung fate. In this review, we intend to discuss the known stem/progenitor cell populations, their relative differences between rodents and humans, their roles in chronic lung disease, and their therapeutic prospects. Additionally, we highlight the recent breakthroughs that have increased our understanding of these cell types. These advancements include novel lineage-traced animal models and single-cell RNA sequencing of human airway cells, which have provided critical information on the stem cell subtypes, transition states, identifying cell markers, and intricate pathways that commit a stem cell to differentiate or to maintain plasticity. As our capacity to model the human lung evolves, so will our understanding of lung regeneration and our ability to target endogenous stem cells as a therapeutic approach for lung disease.


Assuntos
Pneumopatias/terapia , Pulmão/crescimento & desenvolvimento , Células-Tronco Pluripotentes/transplante , Regeneração/genética , Diferenciação Celular/genética , Epitélio/crescimento & desenvolvimento , Humanos , Pulmão/patologia , Pneumopatias/genética , Pneumopatias/patologia
18.
PLoS One ; 15(8): e0237613, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790786

RESUMO

BACKGROUND: Nordihydroguaiaretic acid (NDGA) is a plant extract that has been shown to act as a free radical scavenger and pluripotent inhibitor of pro-inflammatory cytokines, two major cellular processes involved in the pathophysiology of sepsis. We investigated whether NDGA would improve markers of organ injury as well as survival in a rodent model of sepsis. METHODS: Abdominal sepsis was induced by cecal ligation and double puncture (CLP) in male Sprague-Dawley rats. NDGA was administered either at the time of injury (pre-) or 6 hours later (post-treatment). A sham surgery group and a vehicle only group were also followed as controls. Blood and lung tissue were collected 24 h after CLP. Lung tissue was used for histopathologic analysis and to measure pulmonary edema. Arterial oxygenation was measured directly to generate PaO2/FiO2, and markers of renal injury (blood urea nitrogen), liver injury (alanine aminotransferase), and tissue hypoxia (lactate) were measured. In a separate set of animals consisting of the same treatment groups, animals were followed for up to 36 hours for survival. RESULTS: NDGA pre-treatment resulted in improved oxygenation, less lung edema, lower lactate, lower BUN, and reduced histologic lung injury. NDGA post-treatment resulted in less lung edema, lower lactate, lower BUN, and less histologic lung injury, but did not significantly change oxygenation. None of the NDGA treatment groups statistically affected ALT or creatinine. NDGA pre-treatment showed improved survival compared with control CLP animals at 36 hours, while post-treatment did not. CONCLUSIONS: NDGA represents a novel pleiotropic anti-inflammatory agent with potential clinical utility for modulation of organ injury secondary to sepsis.


Assuntos
Antioxidantes/farmacologia , Ceco/cirurgia , Ligadura/efeitos adversos , Pneumopatias/tratamento farmacológico , Masoprocol/farmacologia , Punções/efeitos adversos , Sepse/cirurgia , Animais , Pneumopatias/etiologia , Pneumopatias/patologia , Masculino , Ratos , Ratos Sprague-Dawley
19.
Sci Rep ; 10(1): 9795, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32747665

RESUMO

Exercise-induced pulmonary hemorrhage (EIPH) is a common condition in sport horses with negative impact on performance. Cytology of bronchoalveolar lavage fluid by use of a scoring system is considered the most sensitive diagnostic method. Macrophages are classified depending on the degree of cytoplasmic hemosiderin content. The current gold standard is manual grading, which is however monotonous and time-consuming. We evaluated state-of-the-art deep learning-based methods for single cell macrophage classification and compared them against the performance of nine cytology experts and evaluated inter- and intra-observer variability. Additionally, we evaluated object detection methods on a novel data set of 17 completely annotated cytology whole slide images (WSI) containing 78,047 hemosiderophages. Our deep learning-based approach reached a concordance of 0.85, partially exceeding human expert concordance (0.68 to 0.86, mean of 0.73, SD of 0.04). Intra-observer variability was high (0.68 to 0.88) and inter-observer concordance was moderate (Fleiss' kappa = 0.67). Our object detection approach has a mean average precision of 0.66 over the five classes from the whole slide gigapixel image and a computation time of below two minutes. To mitigate the high inter- and intra-rater variability, we propose our automated object detection pipeline, enabling accurate, reproducible and quick EIPH scoring in WSI.


Assuntos
Técnicas Citológicas , Aprendizado Profundo , Hemorragia/patologia , Pneumopatias/patologia , Animais , Cavalos , Análise de Célula Única
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