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1.
Chemosphere ; 262: 128330, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182093

RESUMO

Recently, there have been reports that many microplastics are found in the air, which has raised concerns about their toxicity. To date, however, only limited research has investigated the effects of micro(nano)plastics on human health, and even less the potential for inhalation toxicity. To fill this research gap, we investigated the potential inhalation toxicity of micro(nano)plastics using a modified OECD Guideline for Testing of Chemicals No. 412 '28-Day (subacute) inhalation toxicity study' using a whole-body inhalation system. Sprague-Dawley rats were exposed to three different exposure concentrations of polystyrene micro(nano)plastics (PSMPs), as well as control, for 14 days of inhalation exposure. After 14 days, alterations were observed on sevral endpoints in physiological, serum biochemical, hematological, and respiratory function markers measured on the samples exposed to PSMPs. However, no concentration-response relationships were observed, suggesting that these effects may not be definitively linked to exposure of PSMPs. On the other hand, the expression of inflammatory proteins (TGF-ß and TNF-α) increased in the lung tissue in an exposure concentration-dependent manner. The overall results indicate that 14-day inhalation exposure of PSMPs to rats has a more pronounced effect at the molecular level than at the organismal one. These results suggest that if the exposure sustained, alterations at the molecular level may lead to subsequent alterations at the higher levels, and consequently, the health risks of inhalation exposed micro(nano)plastics should not be neglected.


Assuntos
Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Microplásticos/toxicidade , Nanopartículas/toxicidade , Poliestirenos/toxicidade , Aerossóis , Animais , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Microplásticos/farmacocinética , Nanopartículas/metabolismo , Organização para a Cooperação e Desenvolvimento Econômico , Tamanho da Partícula , Poliestirenos/farmacocinética , Ratos , Ratos Sprague-Dawley , Testes de Função Respiratória , Propriedades de Superfície
2.
Gene ; 766: 145153, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32950633

RESUMO

AIM: Acute lung injury (ALI) is the mild form of acute respiratory distress syndrome (ARDS) which is a common lung disease with a high incidence and mortality rate. Recent studies manifested that some circular RNAs were associated with ALI. In this study, we aimed to uncover the effect of circular RNA circ_0054633 on ALI initiation and progression and proposed a new mechanism related to ALI. METHODS: The lipopolysaccharides (LPS)-induced acute lung injury model were build both in vivo of rat and in vitro of primary murine pulmonary microvascular endothelial cells (MPVECs). Hematoxylin and eosin (H&E) was employed to observe the tissue morphology and estimate the degree of lung damage. We used real-time quantitative polymerase chain reaction (RT-qPCR) to measure the expression level of circ_0054633. The expression levels of inflammatory cytokines IL-17A and tumor necrosis factor-α (TNF-α) were detected by ELISA. The effects of circ_0054633 on MPVECs proliferation and apoptosis were detected with the help of CCK-8 and apoptosis assay, separately. The expression level of NF-κB p65 protein was measured by Western blot. RESULTS: circ_0054633, IL-17A, TNF-α and NF-κB p65 were all overexpressed in LPS-treated rat and MPVECs, and LPS enhanced the proliferation and apoptosis of MPVECs. While circ_0054633 silencing reversed the above promotion effects of LPS on IL-17A, TNF-α expression and MPVECs proliferation and apoptosis. CONCLUSIONS: Quietness of circ_0054633 alleviated LPS-induced ALI via NF-κB signaling pathway, implicating circ_0054633 may be a potential biomarker for diagnose and therapy of ALI.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Proliferação de Células/fisiologia , Células Endoteliais/metabolismo , Inflamação/metabolismo , NF-kappa B/metabolismo , RNA Circular/metabolismo , Lesão Pulmonar Aguda/induzido quimicamente , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Inflamação/induzido quimicamente , Interleucina-17/metabolismo , Lipopolissacarídeos/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
3.
Sci Rep ; 10(1): 19395, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173052

RESUMO

An incomplete understanding of the molecular mechanisms behind impairment of lung pathobiology by COVID-19 complicates its clinical management. In this study, we analyzed the gene expression pattern of cells obtained from biopsies of COVID-19-affected patient and compared to the effects observed in typical SARS-CoV-2 and SARS-CoV-infected cell-lines. We then compared gene expression patterns of COVID-19-affected lung tissues and SARS-CoV-2-infected cell-lines and mapped those to known lung-related molecular networks, including hypoxia induced responses, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism; all of which are suspected to be downregulated following SARS-CoV-2 infection based on the observed symptomatic impairments. Network analyses suggest that SARS-CoV-2 infection might lead to acute lung injury in COVID-19 by affecting surfactant proteins and their regulators SPD, SPC, and TTF1 through NSP5 and NSP12; thrombosis regulators PLAT, and EGR1 by ORF8 and NSP12; and mitochondrial NDUFA10, NDUFAF5, and SAMM50 through NSP12. Furthermore, hypoxia response through HIF-1 signaling might also be targeted by SARS-CoV-2 proteins. Drug enrichment analysis of dysregulated genes has allowed us to propose novel therapies, including lung surfactants, respiratory stimulants, sargramostim, and oseltamivir. Our study presents a distinct mechanism of probable virus induced lung damage apart from cytokine storm.


Assuntos
Infecções por Coronavirus/genética , Infecções por Coronavirus/metabolismo , Perfilação da Expressão Gênica , Pulmão/metabolismo , Terapia de Alvo Molecular , Pneumonia Viral/genética , Pneumonia Viral/metabolismo , Surfactantes Pulmonares/metabolismo , Biologia de Sistemas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Epigênese Genética , Humanos , Pulmão/efeitos dos fármacos , Especificidade de Órgãos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/imunologia , Proteínas Virais/metabolismo
5.
PLoS One ; 15(10): e0239431, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33017424

RESUMO

BACKGROUND: The loss of muscle mass in primary multidrug-resistant tuberculosis (MDR-TB) has not been examined in previous studies. This study aimed to investigate that low pectoralis muscle index and characteristic CT features can help differentiate patients with primary MDR-TB from those with drug-sensitive tuberculosis (DS-TB). MATERIAL AND METHODS: From 2010 to 2016, we retrospectively enrolled 90 patients with primary MDR-TB and 90 age- and sex-matched patients with primary DS-TB. The pectoralis muscle mass was quantitatively measured on axial CT images using density histogram analysis. The pectoralis muscle index (PMI) was defined as the pectoralis muscle mass divided by body mass index. We compared the PMI and characteristic CT features of pulmonary tuberculosis between the two groups. RESULTS: Low PMI, segmental to lobar consolidation, cavity in consolidation, cavitary nodule or mass, and bilateral involvement were more frequently observed in patients with MDR-TB than in those with DS-TB. In stepwise multivariate logistic regression analysis, low PMI (odds ratio, 2.776; 95% confidence interval, 1.450-5.314; p = 0.002), segmental or lobar consolidation (odds ratio, 3.123; 95% confidence interval, 1.629-5.987; p = 0.001), and cavitary nodule or mass (odds ratio, 2.790; 95% confidence interval, 1.348-5.176; p = 0.002) were significant factors for MDR-TB. CONCLUSION: Low pectoralis muscle index, segmental to lobar consolidation and cavitary nodule or mass can help differentiate primary MDR-TB from DS-TB.


Assuntos
Pulmão/patologia , Músculos Peitorais/patologia , Tuberculose Resistente a Múltiplos Medicamentos/patologia , Antituberculosos/uso terapêutico , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Pulmão/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Músculos Peitorais/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico por imagem
6.
Int J Nanomedicine ; 15: 7481-7489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116483

RESUMO

Introduction: We aimed to investigate the effects of cerium oxide, applied before the sevoflurane anesthesia, on lung tissue in rats with lower extremity ischemia-reperfusion (IR). Materials and Methods: A total of 30 rats were randomly divided into five groups as; control (C), IR, cerium oxide-IR (CO-IR), IR-sevoflurane (IRS), and cerium oxide-IR-sevoflurane (CO-IRS). In the CO-IR group, 30 minutes after the injection of cerium oxide (0.5 mg/kg, intraperitoneal (i.p)), an atraumatic microvascular clamp was placed on the infrarenal abdominal aorta for 120 minutes. Then, the clamp was removed and reperfused for 120 minutes. Sevoflurane was applied in 100% oxygen at a rate of 2.3% at 4 L/min during IR. The blood samples were taken for biochemical analysis and the lung tissue samples were taken for histological analysis. Results: Neutrophil infiltration/aggregation was significantly higher in the IR group than in the C and CO-IRS groups. The alveolar wall thickness and total lung injury scores were significantly higher in the IR group than in the C, IRS, CO-IR and CO-IRS groups. Discussion: We determined that the administration of 0.5 mg/kg dose of cerium oxide with sevoflurane reduces the oxidative stress and corrects IR-related damage in lung tissue. Our results show that the administration of cerium oxide before IR and the administration of sevoflurane during IR have a protective effect in rats.


Assuntos
Cério/farmacologia , Lesão Pulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Sevoflurano/farmacologia , Animais , Extremidade Inferior/irrigação sanguínea , Pulmão/fisiopatologia , Lesão Pulmonar/fisiopatologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Traumatismo por Reperfusão/fisiopatologia
7.
Med Hypotheses ; 143: 110110, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017904

RESUMO

Current formulations and dose regimens of hydroxychloroquine (HCQ) put patients at risk of harm. An analysis of clinical trials registered on ClinicalTrials.gov revealed that this may continue as many studies combine HCQ with agents that prolong the QT interval. Further, almost all of the trials registered do not consider dosage adjustment in the elderly, a patient population most likely to require HCQ treatment. Here we describe an inhaled formulation of HCQ which has passed safety studies in clinical trials for the treatment of asthma and discuss how this approach may reduce side-effects and improve efficacy. As this simple formulation progressed to phase II studies, safety data can be used to immediately enable phase II trials in COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/administração & dosagem , Pulmão/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Administração por Inalação , Adolescente , Adulto , Idoso , Asma/tratamento farmacológico , Betacoronavirus , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Segurança do Paciente , Resultado do Tratamento , Adulto Jovem
8.
BMC Infect Dis ; 20(1): 765, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066761

RESUMO

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).


Assuntos
Inibidores da Colinesterase/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Brometo de Piridostigmina/uso terapêutico , Adulto , Betacoronavirus/patogenicidade , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Humanos , Inflamação , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/fisiopatologia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Respiração Artificial
9.
Artigo em Inglês | MEDLINE | ID: mdl-33093769

RESUMO

Background and Objectives: Sarcoidosis typically presents with peribronchovascular and perilymphatic nodules on high-resolution computed tomography (HRCT); a miliary pattern is reported but not well described. Design setting: We describe four patients with miliary sarcoidosis and results of a systematic review of all previously reported cases from 1985 onwards. Results: We identified only 27 cases of "miliary" sarcoidosis in the HRCT era. These patients were older (85.2% older than 40 years), had more co-morbidities (72.7%) and were symptomatic compared to "typical" sarcoidosis. Respiratory symptoms were present in 61.9% at diagnosis. Hypercalcemia was seen in 28.5%. On review of HRCT images, only 34.6% (9/26) had a "true miliary" pattern without fissural nodules. In our series, prominent perivascular granulomas were seen on histopathology in all. 44.4% (12/27) had tuberculosis preceding or concurrent to miliary sarcoidosis. Of the eight true associations, tuberculosis preceded sarcoidosis by 52 (median, IQR 36) weeks in six and occurred concurrently in another two. The diagnosis of tuberculosis was clinical in all with concurrent diagnosis of tuberculosis and sarcoidosis. Treatment with steroids had 100% response and 14.2% relapse. Conclusions: A true miliary pattern in the HRCT era is very rare in sarcoidosis and subtle perilymphatic pattern is nearly always seen; this should be labeled "pseudo-miliary". Prominent perivascular granulomas are associated with true miliary pattern. Miliary sarcoidosis patients are older and symptomatic, needing treatment at diagnosis. "Miliary" sarcoidosis may follow treatment for tuberculosis; concurrent cases possibly indicate the difficulty in differentiating both or a "tuberculo-sarcoid" presentation. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 53-65).


Assuntos
Pulmão/diagnóstico por imagem , Sarcoidose Pulmonar/diagnóstico , Tomografia Computadorizada por Raios X , Tuberculose Miliar/diagnóstico , Adulto , Idoso , Antituberculosos/uso terapêutico , Técnicas Bacteriológicas , Biópsia , Diagnóstico Diferencial , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recuperação de Função Fisiológica , Recidiva , Sarcoidose Pulmonar/tratamento farmacológico , Sarcoidose Pulmonar/fisiopatologia , Esteroides/uso terapêutico , Resultado do Tratamento , Tuberculose Miliar/tratamento farmacológico , Tuberculose Miliar/microbiologia , Tuberculose Miliar/fisiopatologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-33093772

RESUMO

Background: Forms of interstitial pneumonia secondary to exposure to an air-contaminant are varied and so far, insufficiently described. Objectives/Methods: We report here a case of a 57-year-old patient managed in our department for the exploration of MRC grade 2 dyspnoea and interstitial pneumonia. He mentioned multiple occupational and domestic exposures such as hens' excrements, asbestos and metal particles; he also had a previous history of smoking. Results: High-resolution computed tomography showed ground glass opacities predominating in posterior territories and surrounding cystic lesions or emphysematous destruction. The entire etiological assessment revealed only macrophagic alveolitis with giant multinucleated cells on the bronchoalveolar lavage. A surgical lung biopsy allowed us to refine the diagnosis with evidence of desquamative interstitial pneumonia and pulmonary granulomatosis. Finally, the analysis of the mineral particles in the biopsy revealed abnormally high rates of Zirconium and Aluminium. We were therefore able to conclude to a desquamative interstitial pneumonia associated with pulmonary granulomatosis linked to metal exposure (Aluminium and Zirconium). The clinical, functional and radiological evolution was favorable after a systemic corticosteroid treatment with progressive decay over one year. Conclusion: This presentation reports the first case to our knowledge of desquamative interstitial pneumonitis related to exposure to Zirconium and the third one in the context of Aluminium exposure. The detailed analysis of the mineral particles present on the surgical lung biopsy allows for the identification of the relevant particle to refine the etiological diagnosis, to guide the therapeutic management and to give access to recognition as an occupational disease. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (1): 79-84).


Assuntos
Alumínio/efeitos adversos , Granuloma do Sistema Respiratório/induzido quimicamente , Exposição por Inalação/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Pulmão/efeitos dos fármacos , Zircônio/efeitos adversos , Corticosteroides/administração & dosagem , Alumínio/análise , Biópsia , Granuloma do Sistema Respiratório/diagnóstico , Granuloma do Sistema Respiratório/tratamento farmacológico , Granuloma do Sistema Respiratório/metabolismo , Humanos , Pulmão/química , Pulmão/diagnóstico por imagem , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Zircônio/análise
11.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 136-147, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093777

RESUMO

Background: Interstitial lung disease (ILD) is a common complication of primary Sjögren's syndrome (pSS). Because there is a paucity of literature on the management of pSS-associated ILD (pSS-ILD), this retrospective cohort study assessed the efficacy of azathioprine and mycophenolate therapy in adult patients with pSS-ILD. Methods: A retrospective cohort study was performed using electronic health records to identify adults meeting the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria for pSS. The presence of pSS-ILD was confirmed by characteristic high-resolution computed tomography and/or histopathology findings. Sociodemographic, clinical, and pulmonary function test (PFT) data were abstracted for patients meeting the criteria and followed longitudinally from the date of their ILD diagnosis. PFT values were anchored on time of treatment start, and linear mixed-effects modeling was used to analyze changes in diffusion capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) before and after treatment initiation. Results: We identified 19 subjects who had pSS-ILD, of whom seven were treated with azathioprine and seven were treated with mycophenolate. Within the azathioprine treated group, FVC% slope change trended toward improvement from a rate of -9.8% per month pre-treatment to 2.1% per month post-treatment (p = 0.13). Within the mycophenolate treated group, FVC% slope change improved from a rate of 1.5% per month pre-treatment to 4.3% per month post-treatment (p = 0.02) and DLCO% slope changed from a rate of -3.8% to -1.3% per month (p = 0.01) after therapy start. Conclusions: Mycophenolate treatment was associated with significant improvement in PFTs of pSS-ILD patients over time, and azathioprine treatment followed a similar non-significanttrend. Additional prospective studies are needed to further evaluate these findings. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 136-147).


Assuntos
Azatioprina/uso terapêutico , Imunossupressores/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pulmão/efeitos dos fármacos , Ácido Micofenólico/uso terapêutico , Síndrome de Sjogren/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Azatioprina/efeitos adversos , Registros Eletrônicos de Saúde , Feminino , Humanos , Imunossupressores/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Fatores de Tempo , Resultado do Tratamento
12.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 148-157, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093778

RESUMO

Background: Patients with idiopathic pulmonary fibrosis (IPF) often do not tolerate pirfenidone in the recommended dose of 2400 mg/day. The proportion of patients requiring dose reduction and its impact on survival in the real-world remain unclear. Methods: Consecutive subjects with IPF were enrolled between March 2017 and June 2019. The maximum tolerated dose of pirfenidone (primary outcome) and adverse drug reactions (ADRs) were recorded. A post hoc logistic regression analysis was performed to evaluate the predictors of drug discontinuation due to ADRs. We also compared survival between the full-dose (2400 mg/day), reduced-dose (< 2400 mg/day), and the no-pirfenidone groups, with age and percentage of the predicted forced vital capacity (%pred FVC) as covariates. Results: Of the 128 subjects (mean age, 67.4 years; 77.3% men) included, 115 were initiated on pirfenidone. Forty-nine (42.6%) and 51 (44.3%) subjects tolerated the full dose and reduced doses, respectively. Ninety-six (83.5%) subjects developed at least one ADR; anorexia dyspepsia, and nausea being the most common. Twenty-two subjects discontinued the drug; 15 of them due to ADRs. Body mass index < 20 kg/m2 was the only predictor of drug discontinuation due to ADRs. Among subjects newly initiated on treatment during the study period (n = 80), survival was longer (hazard ratio [interquartile range], 0.19 [0.04-0.96]; p = 0.045) in the full-dose but not the reduced-dose group (p = 0.08) compared with the no-pirfenidone group, after adjusting for covariates. Conclusion: Pirfenidone was tolerated in the full dose in a minority of patients with IPF and appears to improve survival only with the full dose. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 148-157).


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/administração & dosagem , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Volume Expiratório Forçado , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiopatologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Estudos Prospectivos , Piridonas/efeitos adversos , Recuperação de Função Fisiológica , Resultado do Tratamento , Capacidade Vital
13.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 218-224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093786

RESUMO

Introduction: Pirfenidone has been shown to reduce the decline in forced vital capacity (FVC) compared to placebo in patients with idiopathic pulmonary fibrosis (IPF). Previous studies have suggested that patients with a more rapid decline in FVC during the period before starting pirfenidone experience the greatest benefit from treatment. The purpose of this retrospective observational study was to investigate the response to pirfenidone in IPF patients, comparing two groups stratified by the annual rate of decline in FVC % predicted prior to treatment. Methods: Using the rate of decline in FVC % predicted in the 12 months prior to pirfenidone, patients were stratified into slow (<5%) or rapid (≥5%) decliner groups. Comparisons in the lung function response to pirfenidone in these two groups were performed. Results: Pirfenidone resulted in no statistically significant reduction in the median annual rate of decline in FVC or FVC % predicted. In the rapid decliners, pirfenidone significantly reduced the median (IQR) annual rate of decline in FVC % predicted (-8.7 (-14.2 - -7.0) %/yr vs 2.0 (-7.1 - 6.0) %/yr; n=17; p<0.01). In the slow decliners, pirfenidone did not reduce the median (IQR) annual rate of decline in FVC % predicted (-1.3 (-3.2 - 1.3) %/yr vs -5.0 (-8.3 - -0.35) %/yr; n=17; p=0.028). Conclusions: We demonstrate the greater net effect of pirfenidone in IPF patients declining rapidly. We suggest that using an annual rate of decline in FVC of <5% and ≥5% may be useful in counselling patients with regard to pirfenidone treatment. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 218-224).


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Pulmão/efeitos dos fármacos , Piridonas/uso terapêutico , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Progressão da Doença , Inglaterra , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Pulmão/fisiopatologia , Masculino , Piridonas/efeitos adversos , Recuperação de Função Fisiológica , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
14.
Sarcoidosis Vasc Diffuse Lung Dis ; 37(2): 231-233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33093788

RESUMO

Background: A subgroup of patients with fibrotic ILD experience progression and several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. Objective: To describe a possible new phenotype of rapidly non IPF progressive fibrosing with an IPF-like outcome. Methods: Three previously fit and well patients who developed a rapidly progressive ILD and died within 6 to 7 months from the initial development of respiratory symptoms. Results: Unlike what is currently known, our patients developed a severe fibrosing ILD with an IPF-like outcome despite a) being younger than the average patient with IPF, b) having received a non-IPF MDT diagnosis, c) having a non-UIP pattern on HRCT. Moreover and similarly to IPF, they failed to respond to immunosuppressive treatment which is the preferred treatment option in these cases. Conclusion: We believe that patients who present with similar characteristics should be considered as likely to develop a phenotype of rapidly progressive ILD and be treated with antifibrotic medications instead of immunosuppressive ones according to the favourable treatment response to antifibrotic therapy observed in clinical trials of patients with progressive fibrosing ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 231-233).


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Pulmão/diagnóstico por imagem , Fibrose Pulmonar/diagnóstico , Tomografia Computadorizada por Raios X , Adulto , Antibacterianos/uso terapêutico , Progressão da Doença , Evolução Fatal , Volume Expiratório Forçado , Humanos , Imunossupressores/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Fatores de Tempo , Falha de Tratamento , Capacidade Vital
15.
Biomed Environ Sci ; 33(9): 647-659, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-33106210

RESUMO

Objective: This panel study aimed to determine the acute effects of exposure to fine particulate matter (PM 2.5) on schoolchildren's pulmonary function. Methods: We selected 51 schoolchildren aged 9-12 years attending a full-time boarding school in Beijing, China, measured the indoor and outdoor PM 2.5 concentrations for five consecutive days, calculated the PM 2.5 time-weighted individual exposure levels based on the school micro-environmental concentrations and the time activity pattern recorded by schoolchildren, measured schoolchildren's pulmonary function on the fifth day. The survey was performed three times from December 2018 to April 2019. We used a linear mixed-effects model to evaluate the associations between PM 2.5 and pulmonary function. Results: During the three surveys, the median PM 2.5 time-weighted individual exposure concentrations were 15.30 µg/m 3, 48.92 µg/m 3, and 42.89 µg/m 3, respectively. There was a significant difference between the three surveys in vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in one second (FEV 1) and forced expiratory volume in one second/forced vital capacity (FEV 1/FVC) ( P < 0.05). The relevance analysis found that PM 2.5 had lag effect on schoolchildren's pulmonary function, each 10 µg/m 3increase in PM 2.5could cause largest decreases in FEF 25%-75%, FEV 1/FVC, FEF 75%, and FEV 1 on lag 0-1 d (80.44 mL/s, 35.85%, 78.58 mL/s, and 61.34 mL, respectively), and largest decreases in FEF 25% on lag 1 d (83.68 mL/s), in VC on lag 4 d (32.34 mL), and in FVC on lag 0-4 d (37.76 mL). Gender subgroup analysis revealed that the increase in PM 2.5 caused a decrease in FEV 1/FVC and VC on the day of physical examination only in boys, and on lag days it caused changes in different pulmonary function indicators, both for boys and girls, but most of the pulmonary function indicators decreased more in boys than in girls. Conclusion: Our findings show that acute PM 2.5 exposure has significant effects on pulmonary function within 0-4 d, on both small airway indicators and large airway indicators. Boys' pulmonary function is more sensitive to PM 2.5 than girls.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Exposição Ambiental/efeitos adversos , Pulmão/fisiologia , Material Particulado/efeitos adversos , Capacidade Vital , Criança , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/efeitos dos fármacos , Masculino
16.
Proc Natl Acad Sci U S A ; 117(43): 26955-26965, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33037151

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread around the globe after its emergence in Wuhan in December 2019. With no specific therapeutic and prophylactic options available, the virus has infected millions of people of which more than half a million succumbed to the viral disease, COVID-19. The urgent need for an effective treatment together with a lack of small animal infection models has led to clinical trials using repurposed drugs without preclinical evidence of their in vivo efficacy. We established an infection model in Syrian hamsters to evaluate the efficacy of small molecules on both infection and transmission. Treatment of SARS-CoV-2-infected hamsters with a low dose of favipiravir or hydroxychloroquine with(out) azithromycin resulted in, respectively, a mild or no reduction in virus levels. However, high doses of favipiravir significantly reduced infectious virus titers in the lungs and markedly improved lung histopathology. Moreover, a high dose of favipiravir decreased virus transmission by direct contact, whereas hydroxychloroquine failed as prophylaxis. Pharmacokinetic modeling of hydroxychloroquine suggested that the total lung exposure to the drug did not cause the failure. Our data on hydroxychloroquine (together with previous reports in macaques and ferrets) thus provide no scientific basis for the use of this drug in COVID-19 patients. In contrast, the results with favipiravir demonstrate that an antiviral drug at nontoxic doses exhibits a marked protective effect against SARS-CoV-2 in a small animal model. Clinical studies are required to assess whether a similar antiviral effect is achievable in humans without toxic effects.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Hidroxicloroquina/uso terapêutico , Pirazinas/uso terapêutico , Amidas/farmacocinética , Animais , Chlorocebus aethiops , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cricetinae , Modelos Animais de Doenças , Transmissão de Doença Infecciosa/prevenção & controle , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Hidroxicloroquina/farmacocinética , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pirazinas/farmacocinética , Resultado do Tratamento , Células Vero , Carga Viral/efeitos dos fármacos
17.
Toxicol Lett ; 334: 4-13, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32949624

RESUMO

Radon exposure is the most frequent cause of lung cancer in non-smokers. The high linear energy transfer alpha-particles from radon decay cause the accumulation of multiple genetic changes and lead to cancer development. Epithelial-mesenchymal transition (EMT) plays an important role in oncogenesis. However, the mechanisms underlying chronic radon exposure-induced EMT attributed to carcinogenesis are not understood. This study aimed to explore the EMT and potential molecular mechanisms induced by repeated radon exposure. The EMT model of 16HBE and BEAS-2B cells was established with radon exposure (20000 Bq/m3, 20 min each time every 3 days). We found repeated radon exposure facilitated epithelial cell migration, proliferation, reduced cell adhesion and ability to undergo EMT through a decrease in epithelial markers and an increase in mesenchymal markers. Radon regulated the expression of matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 2 (TIMP2) to disrupt the balance of MMP2/TIMP2. In vivo, BALB/c mice were exposed to 105 Bq/m3 radon gas for cumulative doses of 60 and 120 Working Level Months (WLM). Radon inhalation caused lung damage and fibrosis in mice, which was aggravated with the increase of exposure dose. EMT-like transformation also occurred in lung tissues of radon-exposure mice. Moreover, radon radiation increased p-PI3K, p-AKT and p-mTOR in cells and mice. Radon reduced the GSK-3ß level and elevated the active ß-catenin in 16HBE cells. The m-TOR and AKT inhibitors attenuated radon exposure-induced EMT by regulation related biomarkers. These data demonstrated that radon exposure induced EMT through the PI3K/AKT/mTOR pathway in epithelial cells and lung tissue.


Assuntos
Poluentes Radioativos do Ar/toxicidade , Células Epiteliais/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Lesão Pulmonar/induzido quimicamente , Pulmão , Radônio/toxicidade , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta à Radiação , Humanos , Exposição por Inalação/efeitos adversos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos BALB C , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Produtos de Decaimento de Radônio/toxicidade , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
18.
Toxicol Lett ; 334: 60-65, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32961271

RESUMO

Iron oxides are Group 3 (not classifiable as to its carcinogenicity to humans) according to the International Agency for Research on Cancer (IARC). Occupational exposures during iron and steel founding and hematite underground mining as well as other iron predominant exposures such as welding are Group 1 (carcinogenic to humans). The objective of this study was to investigate the potential of iron as iron (III) oxide (Fe2O3) to initiate lung tumors in A/J mice, a lung tumor susceptible strain. Male A/J mice were exposed by oropharyngeal aspiration to suspensions of Fe2O3 (1 mg) or calcium chromate (CaCrO4; 100 µg; positive control) for 26 weeks (once per week). Shams were exposed to 50 µL phosphate buffered saline (PBS; vehicle). Mice were euthanized 70 weeks after the first exposure and lung nodules were enumerated. Both CaCrO4 and Fe2O3 significantly increased gross-observed lung tumor multiplicity in A/J mice (9.63 ± 0.55 and 3.35 ± 0.30, respectively) compared to sham (2.31 ± 0.19). Histopathological analysis showed that bronchiolo-alveolar adenomas (BAA) and carcinomas (BAC) were the primary lung tumor types in all groups and were increased in the exposed groups compared to sham. BAC were significantly increased (146 %) in the CaCrO4 group and neared significance in the Fe2O3 group (100 % increase; p = 0.085). BAA and other histopathological indices of toxicity followed the same pattern with exposed groups increased compared to sham control. In conclusion, evidence from this study, in combination with our previous studies, demonstrate that exposure to iron alone may be a potential risk factor for lung carcinogenesis.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Compostos de Cálcio/toxicidade , Carcinogênese/efeitos dos fármacos , Cromatos/toxicidade , Compostos Férricos/toxicidade , Neoplasias Pulmonares/induzido quimicamente , Animais , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Hiperplasia/induzido quimicamente , Hiperplasia/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Soldagem
19.
Ecotoxicol Environ Saf ; 205: 111283, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32977282

RESUMO

Fine particulate matter (PM2.5) airborne pollution increases the risk of chronic respiratory diseases, such as idiopathic pulmonary fibrosis (IPF), which is characterized by non-specific inflammation of the interstitial lung and extensive deposition of collagen fibers. Type 2 alveolar epithelial cells (AEC2s) are alveolar stem cells in the adult lung that contribute to the lung repair process through complex signaling. Our previous studies demonstrated that OGG1, a kind of DNA repair enzyme, have a critical role in protecting cells from oxidative damage and apoptosis induced by PM2.5, but the contribution of OGG1 in proliferation and self-renewal of AEC2s is not known. Here, we constructed OGG1-/-mice to test the effect and mechanism of OGG1 on PM2.5-induced pulmonary fibrosis and injury in vivo. We detected proliferation and self-renewal of OGG1 overexpression or OGG1 knockout AEC2s after PM2.5 injury by flow cytometry and clone formation. We observed that knockout of OGG1 aggravated pulmonary fibrosis, oxidative stress, and AEC2 cell death in PM2.5-injured mice. In addition, OGG1 is required for the proliferation and renewal of AEC2s after PM2.5 injury. Overexpression of OGG1 promotes the proliferation and self-renewal of AEC2s by inhibiting PM2.5-mediated oxidative stress and NF-κB signaling hyperactivation in vitro. Furthermore, NF-κB inhibitors promoted proliferation and self-renewal of OGG1-deficient AEC2s cells after PM2.5 injury, and attenuated PM2.5-induced pulmonary fibrosis and injury in mice. These data establish OGG1 as a regulator of NF-κB signal that serves to regulate AEC2 cell proliferation and self-renewal, and suggest a mechanism that inhibition of the NF-κB signaling pathway may represent a potential therapeutic strategy for IPF patients with low-expression of OGG1.


Assuntos
Poluentes Atmosféricos/toxicidade , Células Epiteliais Alveolares/efeitos dos fármacos , Autorrenovação Celular/genética , DNA Glicosilases/metabolismo , Material Particulado/toxicidade , Fibrose Pulmonar/induzido quimicamente , Células-Tronco/efeitos dos fármacos , Células Epiteliais Alveolares/metabolismo , Células Epiteliais Alveolares/patologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , DNA Glicosilases/genética , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologia , Transdução de Sinais , Células-Tronco/metabolismo , Células-Tronco/patologia
20.
Mol Pharmacol ; 98(5): 586-597, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32938721

RESUMO

This study investigated the roles of transient receptor potential (TRP) ankyrin-1 (TRPA1) and TRP vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) and cytotoxicity in human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) and chemical agonists of each channel. Functions of TRPA1 and TRPV3 in pulmonary epithelial cells remain largely undefined. This study shows that TRPA1 activity localizes to the plasma membrane and endoplasmic reticulum (ER) of cells, whereas TRPV3 resides primarily in the ER. Additionally, treatment of cells using moderately cytotoxic concentrations of pine WSPM, carvacrol, and other TRPA1 agonists caused ERS as a function of both TRPA1 and TRPV3 activities. Specifically, ERS and cytotoxicity were attenuated by TRPA1 inhibition, whereas inhibiting TRPV3 exacerbated ERS and cytotoxicity. Interestingly, after treatment with pine WSPM, TRPA1 transcription was suppressed, whereas TRPV3 was increased. TRPV3 overexpression in HBECs conferred resistance to ERS and an attenuation of ERS-associated cell cycle arrest caused by WSPM and multiple prototypical ERS-inducing agents. Alternatively, short hairpin RNA-mediated knockdown of TRPV3, like the TRPV3 antagonist, exacerbated ERS. This study reveals previously undocumented roles for TRPA1 in promoting pathologic ERS and cytotoxicity elicited by pneumotoxic WSPM and TRPA1 agonists, and a unique role for TRPV3 in fettering pathologic facets of the integrated ERS response. SIGNIFICANCE STATEMENT: These findings provide new insights into how wood smoke particulate matter and other transient receptor potential ankyrin-1 (TRPA1) and transient receptor potential vanilloid-3 (TRPV3) agonists can affect human bronchial epithelial cells and highlight novel physiological and pathophysiological roles for TRPA1 and TRPV3 in these cells.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Material Particulado/administração & dosagem , Fumaça/efeitos adversos , Canal de Cátion TRPA1/metabolismo , Canais de Cátion TRPV/metabolismo , Linhagem Celular , Cimenos/efeitos adversos , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Células Epiteliais/metabolismo , Células HEK293 , Humanos , Pulmão/metabolismo , Pinus/efeitos adversos , Canais de Receptores Transientes de Potencial/metabolismo , Madeira/efeitos adversos
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