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1.
Autoimmun Rev ; 19(2): 102451, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31838159

RESUMO

BACKGROUND AND OBJECTIVE: Recently the term "interstitial pneumonia with autoimmune features" (IPAF) has been proposed to identify patients with interstitial lung disease and autoimmune characteristics, not fulfilling the criteria for specific connective tissue diseases (CTD). Only few data are available about the clinical and serological features of IPAF patients, their survival and the possible evolution in a CTD. The aims of the study were to investigate the demographic and clinico-serologic features of patients with IPAF, their relationship to survival, and the possible evolution in a definite CTD. PATIENTS AND METHODS: Fifty-two patients were consecutively enrolled and prospectively followed for 45 ± 31.6 months. Data about disease onset, serological, clinical and therapeutic features, pulmonary function tests and high-resolution computed tomography were periodically repeated. The survival of patients with IPAF was compared with that of 104 patients with idiopathic pulmonary fibrosis (IPF). RESULTS: The clinical domain for IPAF was satisfied in 44 patients, serological domain in 49 and the morphological domain in 29 patients. During the follow-up, a definite CTD was diagnosed in 7 patients, in particular Sjogren's syndrome in 4 patients, rheumatoid arthritis in 2, and polymyositis in the last. The estimated 5-year survival of IPAF patients 69.5 ± 7.8%, significantly higher than survival observed in IPF patients, and the baseline value of FVC and DLCO were the only factors associated to death. CONCLUSIONS: IPAF seems to a distinct entity, with a low tendency to evolve in a definite CTD. Nevertheless, further studies are needed to better define the clinical evolution and the outcome of IPAF.


Assuntos
Doenças Autoimunes/complicações , Fibrose Pulmonar Idiopática/complicações , Doenças Pulmonares Intersticiais/complicações , Idoso , Doenças Autoimunes/patologia , Feminino , Seguimentos , Humanos , Fibrose Pulmonar Idiopática/patologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Estudos Prospectivos
2.
Int J Cancer ; 146(2): 388-399, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31241180

RESUMO

Patients with idiopathic pulmonary fibrosis (IPF) have higher risk of developing lung cancer, for example, squamous cell carcinoma (SCC), and show poor prognosis, while the molecular basis has not been fully investigated. Here we conducted DNA methylome analysis of lung SCC using 20 SCC samples with/without IPF, and noncancerous lung tissue samples from smokers/nonsmokers, using Infinium HumanMethylation 450K array. SCC was clustered into low- and high-methylation epigenotypes by hierarchical clustering analysis. Genes hypermethylated in SCC significantly included genes targeted by polycomb repressive complex in embryonic stem cells, and genes associated with Gene Ontology terms, for example, "transcription" and "cell adhesion," while genes hypermethylated specifically in high-methylation subgroup significantly included genes associated with "negative regulation of growth." Low-methylation subgroup significantly correlated with IPF (78%, vs. 17% in high-methylation subgroup, p = 0.04), and the correlation was validated by additional Infinium analysis of SCC samples (n = 44 in total), and data from The Cancer Genome Atlas (n = 390). The correlation between low-methylation subgroup and IPF was further validated by quantitative methylation analysis of marker genes commonly hypermethylated in SCC (HOXA2, HOXA9 and PCDHGB6), and markers specifically hypermethylated in high-methylation subgroup (DLEC1, CFTR, MT1M, CRIP3 and ALDH7A1) in 77 SCC cases using pyrosequencing (p = 0.003). Furthermore, low-methylation epigenotype significantly correlated with poorer prognosis among all SCC patients, or among patients without IPF. Multivariate analysis showed that low-methylation epigenotype is an independent predictor of poor prognosis. These may suggest that lung SCC could be stratified into molecular subtypes with distinct prognosis, and low-methylation lung SCC that significantly correlates with IPF shows unfavorable outcome.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/genética , Fibrose Pulmonar Idiopática/genética , Neoplasias Pulmonares/genética , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Metilação de DNA , Epigênese Genética , Feminino , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/patologia , Estimativa de Kaplan-Meier , Pulmão/patologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico
3.
Zhonghua Wai Ke Za Zhi ; 57(12): 956-960, 2019 Dec 01.
Artigo em Chinês | MEDLINE | ID: mdl-31826603

RESUMO

Lung cancer is the leading cause of death in malignant tumors. Surgery is one of the main treatments for early stage lung cancer. Idiopathic pulmonary fibrosis (IPF), one of the most common interstitial lung disease, is a chronic, progressive lung disease, characterized by insidious onset and progressive deterioration. It is reported that there are common pathways in idiopathic pulmonary fibrosis and lung cancer, and patients with IPF have a higher risk of lung cancer than the general population, whose prevalence was 3.34 times than that of the general population. The incidence of acute exacerbations of IPF and postoperative mortality was significantly higher in lung cancer patients complicated with IPF than those without IPF. The long-term outcomes of patients with IPF are dramatically worse than those without IPF. It was concluded that lobectomy has been still the standard surgical procedure for such patients, but sublobectomy should be taken as potential alternative choice for patients with high risk after preoperative evaluation. Moreover, further studies should be conducted on the prevention and treatment of acute exacerbation of IPF after surgery.


Assuntos
Fibrose Pulmonar Idiopática/cirurgia , Neoplasias Pulmonares/cirurgia , Pneumonectomia/métodos , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/mortalidade , Pulmão/cirurgia , Neoplasias Pulmonares/etiologia , Pneumonectomia/mortalidade
4.
Int J Mycobacteriol ; 8(3): 298-301, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31512609

RESUMO

We report a case of idiopathic pulmonary fibrosis (IPF) treated with pirfenidone who developed tuberculosis (TB) and later had exfoliative dermatitis secondary to an interaction between pirfenidone and rifampicin. This case report highlights the possible risk of developing TB in patients diagnosed with IPF and on antifibrotic therapy like pirfenidone. Furthermore, this case report documents a previously unreported adverse reaction due to the interaction of rifampicin with pirfenidone.


Assuntos
Eritema/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas/efeitos adversos , Rifampina/efeitos adversos , Tuberculose/tratamento farmacológico , Tuberculose/etiologia , Idoso , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antibióticos Antituberculose/efeitos adversos , Interações de Medicamentos , Humanos , Fibrose Pulmonar Idiopática/complicações , Índia , Masculino , Piridonas/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
5.
Medicina (Kaunas) ; 55(10)2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31547107

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a chronic, pulmonary-limited, interstitial lung disease with a poor prognosis. This condition is characterized by different clinical scenarios, ranging from the most typical slow and progressive deterioration of symptoms to a rapid and abrupt decline of lung function. Rapid worsening of clinical course is due to superimposed complications and comorbidities that can develop in IPF patients, with a higher incidence rate compared to the general population. These conditions may require a different management of the patient and a therapy adjustment, and thus it is fundamental to recognize them. High Resolution Computed Tomography (HRCT) is sensitive, but not specific, in detecting these complications, and can evaluate the presence of radiological variations when previous examinations are available; it recognizes ground glass opacities or consolidation that can be related to a large spectrum of comorbidities, such as infection, lung cancer, or acute exacerbation. To reach the final diagnosis, a multidisciplinary discussion is required, particularly when the clinical context is related to imaging findings.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/microbiologia , Fibrose Pulmonar Idiopática/patologia , Pulmão/patologia , Masculino , Tomografia Computadorizada por Raios X/métodos
6.
Respir Res ; 20(1): 182, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31409344

RESUMO

Previous studies have shown that the co-existence of bone marrow failure and pulmonary fibrosis in a single patient or in a family is suggestive of telomere related genes (TRG) germline mutations. This study presents the genetic background, clinical characteristics, and outcome of a group of five Greek patients co-affected with IPF and MDS. Four out of five patients developed an IPF acute exacerbation that was not reversible. We failed to detect any mutation in the TERT, TERC, DKC1, TINF2, RTEL1, PARN, NAF1, ACD, NHP2 and NOP10 genes in any patient. Moreover, telomere length was normal in the two patients tested. This could suggest that although the co-occurence of IPF and MDS are suggestive of TRG mutation in patients < 65 years old, in the elderly it may occur without germline mutations and could negatively affect prognosis. Physicians should be aware for possible IPF deterioration and therapeutic options for MDS should be wisely considered.


Assuntos
Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/diagnóstico , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/diagnóstico , Exacerbação dos Sintomas , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fibrose Pulmonar Idiopática/genética , Masculino , Síndromes Mielodisplásicas/genética
7.
BMC Pulm Med ; 19(1): 149, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412851

RESUMO

BACKGROUND: Lung cancer is a common comorbidity of idiopathic pulmonary fibrosis (IPF) and has poor outcomes. The incidence and clinical factors related to development of lung cancer in idiopathic pulmonary fibrosis (IPF) are unclear. The aim of this study was to elucidate the cumulative incidence, risk factors, and clinical characteristics of lung cancer in IPF. METHODS: In this retrospective study, we analyzed clinical data for 938 patients who were diagnosed with IPF without lung cancer between 1998 and 2013. Demographic, physiologic, radiographic, and histologic characteristics were reviewed. Cumulative incidence of lung cancer and survival were estimated by the Kaplan-Meier method. Risk factors of lung cancer development were determined by Cox proportional hazard analysis. RESULTS: Among 938 IPF patients without lung cancer at initial diagnosis, lung cancer developed in 135 (14.5%) during the follow-up period. The cumulative incidences of lung cancer were 1.1% at 1 year, 8.7% at 3, 15.9% at 5, and 31.1% at 10 years. Risk factors of lung cancer were male gender, current smoking at IPF diagnosis, and rapid annual decline of 10% or more in forced vital capacity (FVC). Patients who developed lung cancer were mostly elderly men with smoking history. Squamous cell carcinoma followed by adenocarcinoma was the most common histologic type. Lung cancer was frequently located in areas abutting or within fibrosis. Survival was significantly worse in patients with lung cancer compared to patients with IPF alone. CONCLUSION: Lung cancer frequently developed in patients with IPF and was common in current-smoking men with rapid decline of FVC.


Assuntos
Adenocarcinoma/mortalidade , Carcinoma de Células Escamosas/mortalidade , Fibrose Pulmonar Idiopática/complicações , Neoplasias Pulmonares/mortalidade , Adenocarcinoma/fisiopatologia , Idoso , Carcinoma de Células Escamosas/fisiopatologia , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Incidência , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Centros de Atenção Terciária , Tomografia Computadorizada por Raios X , Capacidade Vital
8.
BMC Pulm Med ; 19(1): 156, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31438923

RESUMO

BACKGROUND: Nintedanib is a tyrosine kinase inhibitor that efficiently slows the progression of idiopathic pulmonary fibrosis (IPF) and has an acceptable tolerability profile. In contrast, immune checkpoint inhibitors (ICIs) such as programmed death 1 and programmed death ligand 1 inhibitors have shown clinical activity and marked efficacy in the treatment of non-small cell lung cancer. However, it is unclear whether nintedanib reduces the risk of ICI-induced pneumonitis in IPF. CASE PRESENTATION: A 78-year-old man with squamous cell lung carcinoma in IPF underwent second-line treatment with pembrolizumab. He was diagnosed as having pembrolizumab-induced pneumonitis after two cycles. He was administered prednisolone (PSL) and then improved immediately. Thereafter, his lung cancer lesion enlarged despite treatment with TS-1. Atezolizumab was then administered as 4th-line chemotherapy, but he immediately developed atezolizumab-induced pneumonitis after 1 cycle. The re-escalated dosage of PSL improved the pneumonitis, and then nintedanib was started as additional therapy. Under careful observation with nintedanib, atezolizumab was re-administered on day 1 of an every-21-day cycle. After three cycles, it remained stable without exacerbation of drug-induced pneumonitis. CONCLUSION: This case indicates the possibility that the addition of nintedanib to ICI therapy might prevent drug-induced pneumonitis or acute exacerbation of IPF. However, whether anti-fibrotic agents such as nintedanib are actually effective in preventing ICI-induced pneumonitis in ILD remains unknown and additional research is greatly needed to identify effective therapies for ILD combined with lung cancer.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Indóis/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/complicações , Progressão da Doença , Humanos , Fibrose Pulmonar Idiopática/complicações , Neoplasias Pulmonares/complicações , Masculino , Pneumonia/induzido quimicamente , Retratamento , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Tomografia Computadorizada por Raios X
9.
Medicine (Baltimore) ; 98(33): e16869, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31415423

RESUMO

RATIONALE: Precise lung isolation technique with visual confirmation is essential for thoracic surgeries to create a safe and clear surgical field. However, in certain situations, such as when patients have massive pulmonary secretion or when the fiberoptic bronchoscopy (FOB) is not applicable, lung isolation has been performed blindly. PATIENT CONCERN: A 52-year-old woman, whose airway was unable to visualize with FOB due to massive pulmonary secretion, was presented for bilateral sequential lung transplantation. Extracorporeal membranous oxygenation, tracheostomy, and mechanical ventilation were applied to the patient for 39 days preoperatively as a bridge for lung transplantation. DIAGNOSIS: Patient was diagnosed with an idiopathic pulmonary fibrosis and obesity. INTERVENTION: Initially, height-based blind positioning with a conventional double-lumen endobronchial tube (DLT) failed to ventilate the patient properly, and the confirmation of DLT positioning with FOB was impossible due to massive pulmonary secretion. Therefore, a novel DLT (ANKOR DLT) that has one more cuff, located at a point between the distal opening of the tracheal lumen and the starting point of bronchial cuff, than conventional DLT was used for the lung isolation in the patient. OUTCOMES: After the completion of lung graft, FOB finding showed that the ANKOR DLT was optimally positioned at the tracheobronchial tree of the patient, and its depth was 2.5 cm shallower than that of the conventional tube. LESSONS: ANKOR DLT would be a feasible choice to achieve successful blind lung isolation when the use of FOB is impossible to achieve the optimal lung isolation.


Assuntos
Broncoscopia/instrumentação , Fibrose Pulmonar Idiopática/cirurgia , Intubação Intratraqueal/métodos , Ventilação Monopulmonar/métodos , Desenho de Equipamento , Feminino , Humanos , Fibrose Pulmonar Idiopática/complicações , Transplante de Pulmão/instrumentação , Transplante de Pulmão/métodos , Pessoa de Meia-Idade , Obesidade/complicações
10.
DNA Cell Biol ; 38(9): 933-944, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31361540

RESUMO

Interstitial lung disease (ILD) is the main reason of death in patients with systemic sclerosis (SSc). The potential microRNA (miRNA)-messenger RNA (mRNA) interaction networks of SSc-ILD from a systematic biological perspective are unclear. To characterize differentially expressed miRNAs (DE-miRNAs) and differentially expressed genes (DEGs) likely related to SSc-ILD, we downloaded the miRNA microarray dataset (GSE81923) and mRNA datasets (GSE76808 and GSE81292) from the Gene Expression Omnibus database. Comprehensive bioinformatic analyses were conducted to predict target genes for DE-miRNAs and generate an miRNA-hub gene network with SSc-ILD. In total, 26 DE-miRNAs were detected in SSc-ILD, among which 2 were upregulated and 24 were downregulated. Additionally, 178 common DEGs (55 upregulated and 123 downregulated) were identified. miRNAs were primarily enriched in pathways involving inflammation and regulation of fibroblasts. The hub genes identified were MMP7, IER2, HBEGF, CCL4, NFKBIA, JUNB, LIF, SERPINE1, FOSL1, and NAMPT. We discovered the miRNA-mediated regulatory network in SSc-ILD using an integrated bioinformatic analysis. The findings provide novel insight and expand our comprehension of the molecular mechanisms participating in the pathogenesis of SSc-ILD, along with identification of new potential diagnostic biomarkers.


Assuntos
Redes Reguladoras de Genes , Fibrose Pulmonar Idiopática/genética , MicroRNAs/genética , Escleroderma Sistêmico/genética , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/metabolismo , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/metabolismo
11.
Ther Adv Respir Dis ; 13: 1753466619847130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170875

RESUMO

BACKGROUND: Some patients with idiopathic pulmonary fibrosis (IPF) develop acute exacerbation (AE-IPF) leading to severe acute respiratory failure (ARF); despite conventional supportive therapy, the mortality rate remains extremely high. The aim of this study was to assess how a treatment algorithm incorporating high-flow nasal cannula (HFNC) oxygen therapy affects the short-term mortality of patients with AE-IPF who develop ARF. METHOD AND DESIGN: A retrospective cohort analysis was conducted. PATIENTS AND INTERVENTIONS: The study consisted of 17 patients with AE-IPF admitted to a respiratory intensive care unit (RICU) for ARF managed using a treatment algorithm incorporating HFNC. The outcome measure was mortality rate during their stay in the RICU. RESULTS: Implementation of the treatment algorithm led to a successful outcome in nine patients and to a negative one in eight patients (47.1%) who died within 39 days of being admitted to the RICU. The survival rate was 70.6% (±0.1 %) at 15 days, 52.9% (±0.1%) at 30 days, 35.3% (±0.1%) at 90 days, and 15.6% (±9.73 %) at 365 days. Overall, 4 out of 10 patients who did not respond to conventional oxygen therapy showed a satisfactory response to HFNC. CONCLUSIONS: Short-term mortality fell to below 50% when a treatment algorithm incorporating HFNC was implemented in a group of patients with AE-IPF admitted to a RICU for ARF. Patients not responding to conventional oxygen therapy seemed to benefit from HFNC. The reviews of this paper are available via the supplementary material section.


Assuntos
Algoritmos , Fibrose Pulmonar Idiopática/terapia , Oxigenoterapia/métodos , Insuficiência Respiratória/terapia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Cânula , Estudos de Coortes , Feminino , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/mortalidade , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
12.
Biomed Res Int ; 2019: 1484736, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119153

RESUMO

Background and Objective: Progressive pulmonary fibrosis is the main cause of death in patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) and in those with idiopathic pulmonary fibrosis (IPF). Transforming growth factor-ß (TGF-ß) and NADPH oxidase- (NOX-) derived reactive oxygen species (ROS) are drivers of lung fibrosis. We aimed to determine the role of the epigenetic readers, bromodomain and extraterminal (BET) proteins in the regulation of redox balance in activated myofibroblasts. Methods: In TGF-ß-stimulated fibroblasts, we investigated the effect of the BET inhibitor JQ1 on the mRNA expression of the prooxidant gene NOX4 and the antioxidant gene superoxide dismutase (SOD2) by quantitative RT-PCR, the antioxidant transcription factor NF-E2-related factor 2 (Nrf2) activity by a reporter assay, and intracellular ROS levels by dichlorofluorescein staining. Myofibroblast activation was determined by α-smooth muscle actin immunocytochemistry. The role of specific BET protein isoforms in NOX4 gene regulation was studied by siRNA silencing and chromatin-immunoprecipitation. Results and Conclusions: Affymetrix gene array analysis revealed increased NOX4 and reduced SOD2 expression in SSc and IPF fibroblasts. SOD2 silencing in non-ILD control fibroblasts induced a profibrotic phenotype. TGF-ß increased NOX4 and inhibited SOD2 expression, while increasing ROS production and myofibroblast differentiation. JQ1 reversed the TGF-ß-mediated NOX4/SOD2 imbalance and Nrf2 inactivation and attenuated ROS production and myofibroblast differentiation. The BET proteins Brd3 and Brd4 were shown to bind to the NOX4 promoter and drive TGF-ß-induced NOX4 expression. Our data indicate a critical role of BET proteins in promoting redox imbalance and pulmonary myofibroblast activation and support BET bromodomain inhibitors as a potential therapy for fibrotic lung disease.


Assuntos
Fibrose Pulmonar Idiopática/genética , NADPH Oxidase 4/genética , Proteínas Nucleares/genética , Proteínas de Ligação a RNA/genética , Escleroderma Sistêmico/genética , Fatores de Transcrição/genética , Azepinas/farmacologia , Proteínas de Ciclo Celular , Desdiferenciação Celular/genética , Proliferação de Células/genética , Epigênese Genética , Regulação da Expressão Gênica/genética , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/patologia , Pulmão/metabolismo , Pulmão/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Fator 2 Relacionado a NF-E2/genética , Oxirredução , RNA Interferente Pequeno/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/patologia , Superóxido Dismutase/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologia , Triazóis/farmacologia
13.
Dis Model Mech ; 12(5)2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-31036697

RESUMO

Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome that predominantly affects male smokers or ex-smokers and it has a mortality rate of 55% and a median survival of 5 years. Pulmonary hypertension (PH) is a frequently fatal complication of CPFE. Despite this dismal prognosis, no curative therapies exist for patients with CPFE outside of lung transplantation and no therapies are recommended to treat PH. This highlights the need to develop novel treatment approaches for CPFE. Studies from our group have demonstrated that both adenosine and its receptor ADORA2B are elevated in chronic lung diseases. Activation of ADORA2B leads to elevated levels of hyaluronan synthases (HAS) and increased hyaluronan, a glycosaminoglycan that contributes to chronic lung injury. We hypothesize that ADORA2B and hyaluronan contribute to CPFE. Using isolated CPFE lung tissue, we characterized expression levels of ADORA2B and HAS. Next, using a unique mouse model of experimental lung injury that replicates features of CPFE, namely airspace enlargement, PH and fibrotic deposition, we investigated whether 4MU, a HAS inhibitor, was able to inhibit features of CPFE. Increased protein levels of ADORA2B and HAS3 were detected in CPFE and in our experimental model of CPFE. Treatment with 4MU was able to attenuate PH and fibrosis but not airspace enlargement. This was accompanied by a reduction of HAS3-positive macrophages. We have generated pre-clinical data demonstrating the capacity of 4MU, an FDA-approved drug, to attenuate features of CPFE in an experimental model of chronic lung injury.This article has an associated First Person interview with the first author of the paper.


Assuntos
Adenosina/efeitos adversos , Ácido Hialurônico/efeitos adversos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/patologia , Enfisema Pulmonar/complicações , Enfisema Pulmonar/patologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Adenosina Desaminase/metabolismo , Animais , Linhagem Celular , Doença Crônica , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Humanos , Hialuronan Sintases/metabolismo , Lesão Pulmonar/complicações , Lesão Pulmonar/patologia , Macrófagos/metabolismo , Camundongos , Receptor A2B de Adenosina/metabolismo
14.
BMC Pulm Med ; 19(1): 84, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053121

RESUMO

BACKGROUND AND OBJECTIVE: Gastroesophageal reflux disease (GORD) is highly prevalent in idiopathic pulmonary fibrosis (IPF) and may play a role in its pathogenesis. Recent IPF treatment guidelines suggest that all patients with IPF be considered for antacid therapy. However, emerging evidence suggests that antacid therapy does not improve IPF patient outcomes and may increase the risk of pulmonary infection. METHODS: Using prospectively collected data from the Australian IPF Registry including use of antacid therapy, GORD diagnosis and GORD symptoms, the relationship of these GORD variables to survival and disease progression was assessed. The severity of GORD symptoms using the frequency scale for symptoms of GORD (FSSG) and its relationships to outcomes was also assessed for the first time in an IPF cohort. RESULTS: Five hundred eighty-seven (86%) of the 684 patients in the Australian IPF Registry were eligible for inclusion. Patients were mostly male (69%), aged 71.0 ± 8.5 years with moderate disease (FVC 81.7 ± 21.5%; DLco 48.5 ± 16.4%). Most patients were taking antacids (n = 384; 65%), though fewer had a diagnosis of GORD (n = 243, 41.4%) and typical GORD symptoms were even less common (n = 171, 29.1%). The mean FSSG score was 8.39 ± 7.45 with 43% (n = 251) having a score > 8. Overall, there was no difference in survival or disease progression, regardless of antacid treatment, GORD diagnosis or GORD symptoms. CONCLUSIONS: Neither the use of antacid therapy nor the presence of GORD symptoms affects longer term outcomes in IPF patients. This contributes to the increasing evidence that antacid therapy may not be beneficial in IPF patients and that GORD directed therapy should be considered on an individual basis to treat the symptoms of reflux.


Assuntos
Antiácidos/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Idoso , Austrália , Progressão da Doença , Feminino , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/fisiopatologia , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/fisiopatologia , Estimativa de Kaplan-Meier , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sistema de Registros , Índice de Gravidade de Doença , Resultado do Tratamento , Capacidade Vital
15.
Chest ; 155(4): e91-e96, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30955586

RESUMO

A nonsmoker man in his 40s underwent bilateral lung transplantation with a referral diagnosis of genetic-related idiopathic pulmonary fibrosis (IPF). The patient had no medical history in childhood and early adulthood, nor was there a family history of IPF. His nonsmoker father presented with lung cancer at 59 years of age. The patient was a professional brass instrument player; he had started playing at 9 years of age, and he was recently playing 3 to 4 h per day. He had a 7-year clinical history of chronic cough and shortness of breath. Bilateral fine crackles were present at clinical examination. There was no digital clubbing. Data had been collected since 2015: no clinical or immunologic signs of connective tissue disease were evident, including autoantibodies for myositis or anti-synthetase syndrome. Chest radiograph showed diffuse interstitial lung disease. Results of pulmonary function tests yielded a restrictive pattern with decreased FVC and decreased total lung capacity (69% and 47% of predicted, respectively). The FEV1/FVC ratio was 86%, and carbon monoxide transfer coefficient was 36% of predicted. BAL cellular analysis consisted of macrophages (66%), lymphocytes (19%; CD4+/CD8+ ratio, 0.16), neutrophils (10%), and eosinophils (5%).


Assuntos
Alveolite Alérgica Extrínseca/diagnóstico , DNA/genética , Fibrose Pulmonar Idiopática/diagnóstico , Pulmão/diagnóstico por imagem , Mutação , não Fumantes , Proteína C Associada a Surfactante Pulmonar/genética , Adulto , Alveolite Alérgica Extrínseca/etiologia , Biópsia , Análise Mutacional de DNA , Diagnóstico Diferencial , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/genética , Masculino , Proteína C Associada a Surfactante Pulmonar/metabolismo , Radiografia Torácica , Testes de Função Respiratória , Tomografia Computadorizada por Raios X
16.
Medicina (Kaunas) ; 55(3)2019 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-30884853

RESUMO

Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia. Idiopathic pulmonary fibrosis is often seen in elderly men who smoke. A diagnosis of IPF is based on a combination of a detailed clinical history, specific physical examination, laboratory findings, pulmonary function tests, high-resolution computed tomography (HRCT) of the chest, and histopathology. Idiopathic pulmonary fibrosis has a heterogeneous clinical course, from an asymptomatic stable state to progressive respiratory failure or acute exacerbation (AE). Acute exacerbation of IPF has several important differential diagnoses, such as heart failure and volume overload. The International Working Group project proposed new criteria for defining AE of IPF in 2016, which divides it into triggered and idiopathic AE. On the basis of these criteria, physicians can detect AE of IPF more easily. The recent international IPF guidelines emphasized the utility of chest HRCT. In addition, two antifibrotic agents have become available. We should focus on both the management and prevention of AE. The diagnostic process, laboratory findings, typical chest imaging, management, and prognosis of AE are comprehensively reviewed in this article.


Assuntos
Dispneia/diagnóstico por imagem , Dispneia/prevenção & controle , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/patologia , Esteroides/administração & dosagem , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Idoso , Biomarcadores , Diagnóstico Diferencial , Progressão da Doença , Dispneia/tratamento farmacológico , Dispneia/etiologia , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/tratamento farmacológico , Masculino , Prognóstico , Pulsoterapia , Fatores de Risco
17.
PLoS One ; 14(3): e0214441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30921412

RESUMO

BACKGROUND AND OBJECTIVE: The idiopathic interstitial pneumonias (IIPs) are diffuse parenchymal lung disorders that are associated with substantial morbidity and mortality. Early diagnosis and disease stratification of IIP patients are important because these are related with the treatment and prognosis. Idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) are two major distinctive pathologic patterns of pulmonary fibrosis. We researched the application of the fluid-structure interaction (FSI) to the respiratory system and compared the pulmonary acinus mechanics and functions in healthy and IIP models. METHODS: The human pulmonary alveolus is idealized by a three-dimensional honeycomb-like geometry, and a fluid-structure interaction analysis is performed to study the normal and diseased breathing mechanics. The computational domain consists of two generations of alveolar ducts within the pulmonary acinus, with alveolar geometries approximated as closely packed 14-sided polygons. FINDINGS: In a normal breathing cycle, the flow rate of the healthy model is significantly larger than that of the NSIP and IPF models. Similar trends are observed for the volume change and the maximum pressure drop. The flow rate and the volume change of the NSIP are almost the same as those of IPF. The maximum pressure drop of NSIP is 5.5% larger than that of IPF. There is a 47% decrease in the pulmonary acinus compliance for the NSIP and IPF compared with that of the healthy model. The acinus resistances of NSIP and IPF are higher than those of the healthy lung by 6.4~11.2%. In particular, the pulmonary acinus resistance of the NSIP lung is higher than that of the IPF lung by 4.5%. CONCLUSIONS: Our study demonstrates the differences of air flow and lung function in the pulmonary acinus between the healthy and the IIP models. These changes in the lung are important considerations for early diagnosis and disease stratification in patients. Patient-based geometry can to be included in the computational models in future studies.


Assuntos
Células Acinares/patologia , Ar , Pneumonias Intersticiais Idiopáticas/patologia , Pneumonias Intersticiais Idiopáticas/fisiopatologia , Pulmão/patologia , Pulmão/fisiopatologia , Modelos Biológicos , Pneumonias Intersticiais Idiopáticas/complicações , Fibrose Pulmonar Idiopática/complicações
19.
Int J Mol Sci ; 20(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909462

RESUMO

Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, and limited to the lungs. Despite the increasing research interest in the pathogenesis of IPF, unfavorable survival rates remain associated with this condition. Recently, novel therapeutic agents have been shown to control the progression of IPF. However, these drugs do not improve lung function and have not been tested prospectively in patients with IPF and coexisting lung cancer, which is a common comorbidity of IPF. Optimal management of patients with IPF and lung cancer requires understanding of pathogenic mechanisms and molecular pathways that are common to both diseases. This review article reflects the current state of knowledge regarding the pathogenesis of pulmonary fibrosis and summarizes the pathways that are common to IPF and lung cancer by focusing on the molecular mechanisms.


Assuntos
Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/metabolismo , Fibrose Pulmonar/complicações , Fibrose Pulmonar/etiologia , Animais , Biomarcadores , Comunicação Celular , Transformação Celular Neoplásica , Progressão da Doença , Transição Epitelial-Mesenquimal , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/etiologia , Fibrose Pulmonar Idiopática/patologia , Neoplasias Pulmonares/patologia , Fibrose Pulmonar/patologia , Transdução de Sinais
20.
Respir Investig ; 57(4): 300-311, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30853366

RESUMO

Idiopathic Pulmonary Fibrosis (IPF) is a most common progressive interstitial lung disease (ILD) of unknown etiology, although majority of patients are elderly male smokers. The main pathogenesis is aberrant recovery of epithelial injury and collagen deposition. Fibrotic nonspecific interstitial pneumonia, connective tissue disease (CTD) especially rheumatoid arthritis (RA) associated ILD, and chronic hypersensitivity pneumonia(CHP) are important differential diagnosis. Main symptoms are non-productive cough and progressive exertional dyspnea. Crucial physical findings are scalene muscle hypertrophy, bibasilar fine crackles, and finger clubbing. The serum markers such as lactate dehydrogenase (LDH) and Krebs von den Lungen-6 (KL-6) are sensitive for ILD detection and activity. Both pulmonary function test (PFT) and the 6-minute walk test (6MWT) are useful tool for evaluation of disease progression of IPF. Serial changes of forced vital capacity (FVC) and 6MWT distance predict mortality in IPF effectively. Recently published international IPF guidelines highlight the importance of chest high resolution computed tomography (HRCT) findings such as honeycombing, traction bronchiectasis (TBE), and sub-pleural reticular opacity. IPF is chronic and progressive; therefore, tracking disease behavior is crucial. Unifying clinical, physiological, and imaging information over time is useful. With regard to its management, two anti-fibrotic drugs such as pirfenidone and nintedanib have been available. These drugs can slow the decline of FVC and prevent acute exacerbation (AE). In this review, I outline the clinical characteristics of IPF, physiological, imaging, pathological findings and review diagnosis process and management.


Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Biomarcadores/sangue , Doença Crônica , Tosse/etiologia , Diagnóstico Diferencial , Progressão da Doença , Dispneia/etiologia , Humanos , Fibrose Pulmonar Idiopática/complicações , Fibrose Pulmonar Idiopática/patologia , Indóis/uso terapêutico , L-Lactato Desidrogenase/sangue , Mucina-1/sangue , Piridonas/uso terapêutico , Testes de Função Respiratória , Tomografia Computadorizada por Raios X , Capacidade Vital
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