RESUMO
Rationale: Changes in peripheral blood cell populations have been observed, but not detailed, at single-cell resolution in idiopathic pulmonary fibrosis (IPF). Objectives: We sought to provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with IPF and control subjects were profiled using 10× chromium 5' single-cell RNA sequencing. Flow cytometry was used for validation. Protein concentrations of regulatory T cells (Tregs) and monocyte chemoattractants were measured in plasma and lung homogenates from patients with IPF and control subjects. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched control subjects yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in patients with progressive and stable IPF compared with control subjects (32.1%, 25.2%, and 17.9%, respectively; P < 0.05). Total lymphocytes were decreased in patients with IPF versus control subjects and in progressive versus stable IPF (52.6% vs. 62.6%, P = 0.035). Tregs were increased in progressive versus stable IPF (1.8% vs. 1.1% of all PBMCs, P = 0.007), although not different than controls, and may be associated with decreased survival (P = 0.009 in Kaplan-Meier analysis; and P = 0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of patients with IPF. The fraction of Tregs out of all T cells was also increased in two cohorts of lung single-cell RNA sequencing. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. Conclusions: The single-cell atlas of the peripheral immune system in IPF reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).
Assuntos
Fibrose Pulmonar Idiopática , Leucócitos Mononucleares , Análise de Célula Única , Linfócitos T Reguladores , Humanos , Fibrose Pulmonar Idiopática/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , Leucócitos Mononucleares/imunologia , Progressão da Doença , Estudos de Casos e Controles , Citometria de FluxoRESUMO
Idiopathic pulmonary fibrosis is increasingly associated with nerve-driven processes and endogenous innate immune ligands such as mitochondrial DNA (mtDNA). Interestingly, a connection between these entities has not been explored. Here, we report that noradrenaline (NA) derived from the lung's adrenergic nerve supply drives α-smooth muscle actin (αSMA)-expressing fibroblast accumulation via mechanisms involving α1 adrenoreceptors and mtDNA. Using the bleomycin model, we compared ablation of the lung's adrenergic nerve supply with surgical adrenal resection and found that NA derived from local but not adrenal sources contributes to experimentally induced lung fibrosis and the emergence of an αSMA+ve fibroblast population expressing adrenoreceptor α-1D (ADRA1D). Therapeutic delivery of the α1 adrenoreceptor antagonist terazosin reversed these changes and suppressed extracellular mtDNA accumulation. Cultured normal human lung fibroblasts displayed α1 adrenoreceptors and in response to costimulation with TGFß1 and NA adopted ACTA2 expression and extracellular mtDNA release. These findings were opposed by terazosin. Evaluation of a previously studied IPF cohort revealed that patients prescribed α1 adrenoreceptor antagonists for nonpulmonary indications demonstrated improved survival and reduced concentrations of plasma mtDNA. Our observations link nerve-derived NA, α1 adrenoreceptors, extracellular mtDNA, and lung fibrogenesis in mouse models, cultured cells, and humans with IPF. Further study of this neuroinnate connection may yield new avenues for investigation in the clinical and basic science realms.
Assuntos
DNA Mitocondrial , Fibrose Pulmonar Idiopática , Camundongos , Animais , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Transdução de Sinais , Fibroblastos/metabolismo , Bleomicina/farmacologia , Adrenérgicos/metabolismo , Adrenérgicos/farmacologiaRESUMO
Sarcoidosis is a systemic granulomatous disease predominantly affecting the lungs. The mechanisms promoting disease pathogenesis and progression are unknown, although interleukin-15 (IL-15) has been associated with the immune-mediated inflammation of sarcoidosis. Because the identification of a mechanistically based, clinically relevant biomarker for sarcoidosis remains elusive, we hypothesized this role for IL-15. Pulmonary sarcoidosis granuloma formation was modeled using trehalose 6,6'-dimicolate (TDM), which was administered into wild-type and three lineages of mice: those overexpressing IL-15, deficient in IL-15, and deficient in IL-15 receptor α. The number of granulomas per lung was counted and normalized to the wild type. IL-15 concentrations were measured in the bronchoalveolar lavage (BAL) from healthy controls and subjects with sarcoidosis in our cohort, where associations between IL-15 levels and clinical manifestations were sought. Findings were validated in another independent sarcoidosis cohort. TDM administration resulted in similar granuloma numbers across all lineages of mice. IL-15 concentrations were elevated in the BAL of both human cohorts, irrespective of disease phenotypes. In exploratory analysis, an association with obesity was observed, and various other soluble mediators were identified in the BAL of both cohorts. Although IL-15 is enriched in the sarcoidosis lung, it was independent of disease pathogenesis or clinical manifestations in our mouse model and human cohorts of sarcoidosis. An association with obesity perhaps reflects the ongoing inflammatory processes of these comorbid conditions. Our findings showed that IL-15 is redundant for disease pathogenesis and clinical progression of sarcoidosis.
Assuntos
Granuloma/metabolismo , Interleucina-15/metabolismo , Fenótipo , Sarcoidose Pulmonar/patologia , Sarcoidose/metabolismo , Animais , Líquido da Lavagem Broncoalveolar/citologia , Modelos Animais de Doenças , Granuloma/patologia , Inflamação/patologia , Interleucina-15/genética , Pulmão/metabolismo , Pulmão/patologia , Sarcoidose/patologia , Sarcoidose Pulmonar/complicaçõesRESUMO
Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.
Assuntos
Pulmão/inervação , Pulmão/metabolismo , Macrófagos/metabolismo , Netrina-1/metabolismo , Fibrose Pulmonar/metabolismo , Animais , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Feminino , Pulmão/patologia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Netrina-1/genética , Norepinefrina/genética , Norepinefrina/metabolismo , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/genética , Fibrose Pulmonar/patologiaRESUMO
Megakaryocytes have been implicated in the micro-environmental abnormalities associated with fibrosis and hematopoietic failure in the bone marrow (BM) of primary myelofibrosis (PMF) patients, the Philadelphia-negative myeloproliferative neoplasm (MPN) associated with the poorest prognosis. To identify possible therapeutic targets for restoring BM functions in PMF, we compared the expression profiling of PMF BM with that of BM from essential thrombocytopenia (ET), a fibrosis-free MPN also associated with BM megakaryocyte hyperplasia. The signature of PMF BM was also compared with published signatures associated with liver and lung fibrosis. Gene set enrichment analysis (GSEA) identified distinctive differences between the expression profiles of PMF and ET. Notch, K-Ras, IL-8, and apoptosis pathways were altered the most in PMF as compared with controls. By contrast, cholesterol homeostasis, unfolded protein response, and hypoxia were the pathways found altered to the greatest degree in ET compared with control specimens. BM from PMF expressed a noncanonical transforming growth factor ß (TGF-ß) signature, which included activation of ID1, JUN, GADD45b, and genes with binding motifs for the JUN transcriptional complex AP1. By contrast, the expression of ID1 and GADD45b was not altered and there was a modest signal for JUN activation in ET. The similarities among PMF, liver fibrosis, and lung fibrosis were modest and included activation of integrin-α9 and tropomyosin-α1 between PMF and liver fibrosis, and of ectoderm-neural cortex protein 1 and FRAS1-related extracellular matrix protein 1 between PMF and lung fibrosis, but not TGF-ß. These data identify TGF-ß as a potential target for micro-environmental therapy in PMF.
Assuntos
Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Mielofibrose Primária/metabolismo , Transdução de Sinais , Trombocitemia Essencial/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologiaRESUMO
Pulmonary fibrosis is not uncommon. Usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic pulmonary fibrotic diseases and has the worst prognosis with a mean life expectancy of 3.8 years. The American Thoracic Society has provided guidelines for the accurate diagnosis of IPF.In 2014, 2 antifibrotic medications were approved in the United States that target the multiple fibrotic pathways of UIP, which increased the need for early and accurate diagnosis of IPF. The early and correct diagnosis is hampered by mimickers that include nonspecific interstitial pneumonitis, chronic hypersensitivity pneumonitis, and fibrotic sarcoidosis. Careful history taking, serologic testing, and Computer Tomography (CT) inspection can frequently make the correct diagnosis without need of invasive procedure. The purpose of this article is to share the most important aspects of the clinical and radiology presentation of IPF and its mimickers to enhance primary care clinician's ability to correctly and noninvasively diagnose UIP/IPF.
Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Guias de Prática Clínica como Assunto , Atenção Primária à Saúde/normas , Alveolite Alérgica Extrínseca/diagnóstico , Diagnóstico Diferencial , Humanos , Fibrose Pulmonar Idiopática/sangue , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/mortalidade , Pulmão/diagnóstico por imagem , Anamnese/normas , Atenção Primária à Saúde/métodos , Prognóstico , Pneumologia/normas , Sarcoidose Pulmonar/diagnóstico , Testes Sorológicos/normas , Sociedades Médicas/normas , Tomografia Computadorizada por Raios X , Estados UnidosRESUMO
BACKGROUND: Early recognition of patients with interstitial lung disease (ILD) who have an increased risk of developing acute exacerbation (AE) or preclinical AE may be clinically useful, since AE is associated with poor outcome and preventive measures would be of interest to ILD researchers. This study evaluated the relationship between elevated serum D-dimer level (≥0.4 mcg/mL) and subsequent AE or preclinical AE in patients with ILD. METHODS: This single-center, retrospective study was performed from October 2009 through September 2015 in patients with ILD who were ≥18 years old and had idiopathic pulmonary fibrosis, other idiopathic interstitial pneumonias, chronic hypersensitivity pneumonitis, ILD related to collagen tissue disease, or combined pulmonary fibrosis/emphysema. The primary outcome measure was AE development within three months from each D-dimer measurement. The secondary outcome measures were respiratory-related hospitalization, all-cause hospitalization, venous thromboembolism (VTE), and all-cause mortality within three months. RESULTS: A total of 263 patients (mean age, 64.1 years) with 374 D-dimer measurements (median, 0.44 mcg/mL) were included. The risk of developing AE was significantly higher in patients with elevated serum D-dimer level (adjusted odds ratio: 10.46; 95% CI: 1.24-88.11; p = 0.03). Patients with elevated serum D-dimer level had increased risk for respiratory-related hospitalization, all-cause hospitalization, VTE, and all-cause mortality. The other factors predictive for AE were home oxygen therapy, increased serum lactate dehydrogenase, decreased FVC, and decreased FEV1.0. CONCLUSIONS: Elevated serum D-dimer is associated with the risk of developing AE. Serum D-dimer may be used as a prognostic marker to predict AE or recognize preclinical AE.
Assuntos
Progressão da Doença , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Fibrose Pulmonar Idiopática/complicações , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Alveolite Alérgica Extrínseca/complicações , Biomarcadores/sangue , Doença Crônica , Feminino , Hospitalização/tendências , Humanos , Pneumonias Intersticiais Idiopáticas/complicações , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Fibrose Pulmonar Idiopática/fisiopatologia , L-Lactato Desidrogenase/metabolismo , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/prevenção & controle , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Avaliação de Resultados em Cuidados de Saúde , Valor Preditivo dos Testes , Prognóstico , Enfisema Pulmonar/complicações , Estudos Retrospectivos , Fatores de Risco , Tromboembolia Venosa/complicações , Tromboembolia Venosa/mortalidadeRESUMO
Aim: High-flow oxygen is often administered to patients during emergency transport and can sometimes cause respiratory acidosis with disturbed consciousness, thereby necessitating mechanical ventilation. Although oxygen titration in chronic obstructive pulmonary disease patients during emergency transport reduces mortality rates, the clinical risk factors for respiratory acidosis in emergency settings are not fully understood. Therefore, we analyzed the clinical backgrounds of patients who developed respiratory acidosis during pre-hospital transport. Methods: This was a retrospective study of patients who arrived at our hospital by emergency transport in 2010 who received high-flow oxygen while in transit. Respiratory acidosis was defined by the following arterial blood gas readings: pH, ≤7.35; PaCO 2, ≥45 mmHg; and HCO 3-, ≥24 mmol/L. The risk factors were identified using multivariable logistic regression analysis. Results: In 765 study patients, 66 patients showed respiratory acidosis. The following risk factors for respiratory acidosis were identified: age, ≥65 years (odds ratio [OR] 1.4; 95% confidence interval [CI], 0.7-2.8); transportation time, ≥10 min (OR 2.0; 95% CI, 1.1-3.7); three digits on the Japan Coma Scale (OR 3.1; 95% CI, 1.7-5.8); percutaneous oxygen saturation, ≤90% (OR 1.6; 95% CI, 0.8-3.0); tuberculosis (OR 4.5; 95% CI, 1.4-15.1); asthma (OR 1.8; 95% CI, 0.6-5.3); pneumonia (OR 1.5; 95% CI, 0.7-3.1); and lung cancer (OR 3.9; 95% CI, 1.5-10.1). These underlying diseases as risk factors included both comorbid diseases and past medical conditions. Conclusions: The factors identified may contribute to the development of respiratory acidosis. Further studies on preventing respiratory acidosis will improve the quality of emergency medical care.
RESUMO
A patient with severe cardiac dysfunction similar to dilated cardiomyopathy expired because of lung squamous cell carcinoma. He was admitted with respiratory failure and was diagnosed with congestive heart failure due to dilated cardiomyopathy based on the chest X-ray, electrocardiography, echocardiography, and coronary angiography. Chest computed tomography showed a mass shadow in the right lower lobe, and the patient was diagnosed with lung squamous cell carcinoma by bronchoscopy. The patient expired, and the autopsy revealed that a myocardial metastasis disrupted the cardiac-conduction system without dilated cardiomyopathy in myocytes. Left bundle branch block caused by myocardial metastasis presumably induced left cardiac dysfunction.
Assuntos
Bloqueio de Ramo/etiologia , Carcinoma de Células Escamosas/patologia , Cardiomiopatia Dilatada/etiologia , Neoplasias Cardíacas/complicações , Neoplasias Cardíacas/secundário , Neoplasias Pulmonares/patologia , Idoso , Bloqueio de Ramo/diagnóstico , Cardiomiopatia Dilatada/diagnóstico , Angiografia Coronária/efeitos adversos , Ecocardiografia , Eletrocardiografia , Humanos , Masculino , Tomografia Computadorizada por Raios X/efeitos adversosRESUMO
We experienced a case of nephrotic syndrome (membranous nephropathy) complicated by extensive small cell carcinoma of unknown primary etiology that was diagnosed based on the findings of bilateral cervical and mediastinal lymphadenopathy. A complete cancer response and proteinuria remission following radical chemoradiation therapy were documented. The status of a complete response and nephrosis remission persisted for more than three years. This is the first report to demonstrate the long-term survival of a patient with extensive small cell carcinoma of unknown primary etiology complicated by paraneoplastic nephrotic syndrome.
Assuntos
Carcinoma de Células Pequenas/complicações , Glomerulonefrite Membranosa/etiologia , Neoplasias Primárias Desconhecidas/complicações , Síndrome Nefrótica/etiologia , Síndromes Paraneoplásicas/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Carboplatina/administração & dosagem , Carcinoma de Células Pequenas/diagnóstico , Carcinoma de Células Pequenas/diagnóstico por imagem , Carcinoma de Células Pequenas/tratamento farmacológico , Carcinoma de Células Pequenas/secundário , Terapia Combinada , Irradiação Craniana , Edema/etiologia , Etoposídeo/administração & dosagem , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/radioterapia , Humanos , Irinotecano , Metástase Linfática , Neoplasias Primárias Desconhecidas/diagnóstico , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Síndrome Nefrótica/radioterapia , Síndromes Paraneoplásicas/tratamento farmacológico , Derrame Pleural Maligno/diagnóstico por imagem , Derrame Pleural Maligno/tratamento farmacológico , Derrame Pleural Maligno/etiologia , Proteinúria/etiologia , Radioterapia Adjuvante , Indução de Remissão , Tomografia Computadorizada por Raios XRESUMO
A 41-year-old woman, who underwent breast resection for cancer of the right breast and adjuvant chemotherapy 2 years ago, was admitted to our hospital due to shortness of breath upon exertion. High-resolution computed tomography of the chest showed small nodular opacities in the peribronchiolar area in both lungs, as well as mediastinal and hilar lymphadenopathy. A transbronchial lung biopsy revealed breast cancer metastasis and pulmonary tumor thrombotic microangiopathy (PTTM). Treatment of PTTM is rarely reported due to the difficulty of antemortem diagnosis; however, the patient was effectively treated with chemotherapy and oxygen and anticoagulation therapies for 3 months.