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1.
Am J Respir Cell Mol Biol ; 69(1): 34-44, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36848313

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive aging-related lung disease associated with increased lung cancer risk. Although previous studies have shown that IPF worsens the survival of patients with lung cancer, whether IPF independently affects cancer malignancy and prognosis remains inconclusive. Extracellular vesicles (EVs) have recently emerged as active carriers of molecular biomarkers and mediators of intercellular communication in lung homeostasis and pathogenesis. EV cargo-mediated fibroblast-tumor cell communication might participate in the development and progression of lung cancer by modulating various signaling pathways. In this study, we examined the impact of lung fibroblast (LF)-derived EVs on non-small cell lung cancer (NSCLC) malignancy in the IPF microenvironment. Here, we showed that LFs derived from patients with IPF have phenotypes of myofibroblast differentiation and cellular senescence. Furthermore, we found that IPF LF-derived EVs have markedly altered microRNA compositions and exert proproliferative functions on NSCLC cells. Mechanistically, the phenotype was attributed mainly to the enrichment of miR-19a in IPF LF-derived EVs. As a downstream signaling pathway, mir-19a in IPF LF-derived EVs regulates ZMYND11-mediated c-Myc activation in NSCLC, potentially contributing to the poor prognosis of patients with NSCLC with IPF. Our discoveries provide novel mechanistic insights for understanding lung cancer progression in the IPF microenvironment. Accordingly, blocking the secretion of IPF LF-derived EV miR-19a and their signaling pathways is a potential therapeutic strategy for managing IPF and lung cancer progression.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Fibrose Pulmonar Idiopática , Neoplasias Pulmonares , MicroRNAs , Humanos , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Pulmão/patologia , Fibrose Pulmonar Idiopática/patologia , Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Microambiente Tumoral , Proteínas de Ligação a DNA , Proteínas de Ciclo Celular/metabolismo , Proteínas Correpressoras/metabolismo
2.
J Immunol ; 207(1): 65-76, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34135057

RESUMO

Insufficient autophagic degradation has been implicated in accelerated cellular senescence during chronic obstructive pulmonary disease (COPD) pathogenesis. Aging-linked and cigarette smoke (CS)-induced functional deterioration of lysosomes may be associated with impaired autophagy. Lysosomal membrane permeabilization (LMP) is indicative of damaged lysosomes. Galectin-3 and tripartite motif protein (TRIM) 16 play a cooperative role in recognizing LMP and inducing lysophagy, a lysosome-selective autophagy, to maintain lysosome function. In this study, we sought to examine the role of TRIM16-mediated lysophagy in regulating CS-induced LMP and cellular senescence during COPD pathogenesis by using human bronchial epithelial cells and lung tissues. CS extract (CSE) induced lysosomal damage via LMP, as detected by galectin-3 accumulation. Autophagy was responsible for modulating LMP and lysosome function during CSE exposure. TRIM16 was involved in CSE-induced lysophagy, with impaired lysophagy associated with lysosomal dysfunction and accelerated cellular senescence. Airway epithelial cells in COPD lungs showed an increase in lipofuscin, aggresome and galectin-3 puncta, reflecting accumulation of lysosomal damage with concomitantly reduced TRIM16 expression levels. Human bronchial epithelial cells isolated from COPD patients showed reduced TRIM16 but increased galectin-3, and a negative correlation between TRIM16 and galectin-3 protein levels was demonstrated. Damaged lysosomes with LMP are accumulated in epithelial cells in COPD lungs, which can be at least partly attributed to impaired TRIM16-mediated lysophagy. Increased LMP in lung epithelial cells may be responsible for COPD pathogenesis through the enhancement of cellular senescence.


Assuntos
Lisossomos/imunologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Proteínas com Motivo Tripartido/imunologia , Ubiquitina-Proteína Ligases/imunologia , Células Cultivadas , Humanos , Concentração de Íons de Hidrogênio , Doença Pulmonar Obstrutiva Crônica/patologia
3.
J Immunol ; 205(5): 1256-1267, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32699159

RESUMO

Cigarette smoke (CS) induces accumulation of misfolded proteins with concomitantly enhanced unfolded protein response (UPR). Increased apoptosis linked to UPR has been demonstrated in chronic obstructive pulmonary disease (COPD) pathogenesis. Chaperone-mediated autophagy (CMA) is a type of selective autophagy for lysosomal degradation of proteins with the KFERQ peptide motif. CMA has been implicated in not only maintaining nutritional homeostasis but also adapting the cell to stressed conditions. Although recent papers have shown functional cross-talk between UPR and CMA, mechanistic implications for CMA in COPD pathogenesis, especially in association with CS-evoked UPR, remain obscure. In this study, we sought to examine the role of CMA in regulating CS-induced apoptosis linked to UPR during COPD pathogenesis using human bronchial epithelial cells (HBEC) and lung tissues. CS extract (CSE) induced LAMP2A expression and CMA activation through a Nrf2-dependent manner in HBEC. LAMP2A knockdown and the subsequent CMA inhibition enhanced UPR, including CHOP expression, and was accompanied by increased apoptosis during CSE exposure, which was reversed by LAMP2A overexpression. Immunohistochemistry showed that Nrf2 and LAMP2A levels were reduced in small airway epithelial cells in COPD compared with non-COPD lungs. Both Nrf2 and LAMP2A levels were significantly reduced in HBEC isolated from COPD, whereas LAMP2A levels in HBEC were positively correlated with pulmonary function tests. These findings suggest the existence of functional cross-talk between CMA and UPR during CSE exposure and also that impaired CMA may be causally associated with COPD pathogenesis through enhanced UPR-mediated apoptosis in epithelial cells.


Assuntos
Apoptose/fisiologia , Autofagia Mediada por Chaperonas/fisiologia , Doença Pulmonar Obstrutiva Crônica/patologia , Resposta a Proteínas não Dobradas/fisiologia , Células Cultivadas , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Pulmão/metabolismo , Pulmão/patologia , Lisossomos/metabolismo , Lisossomos/patologia , Fator 2 Relacionado a NF-E2/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça/efeitos adversos , Nicotiana/efeitos adversos
4.
Cancer Sci ; 111(11): 4154-4165, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32860290

RESUMO

Chaperone-mediated autophagy (CMA) is a lysosomal degradation pathway of selective soluble proteins. Lysosome-associated membrane protein type 2a (LAMP2A) is the key receptor protein of CMA; downregulation of LAMP2A leads to CMA blockade. Although CMA activation has been involved in cancer growth, CMA status and functions in non-small cell lung cancer (NSCLC) by focusing on the roles in regulating chemosensitivity remain to be clarified. In this study, we found that LAMP2A expression is elevated in NSCLC cell lines and patient's tumors, conferring poor survival and platinum resistance in NSCLC patients. LAMP2A knockdown in NSCLC cells suppressed cell proliferation and colony formation and increased the sensitivity to chemotherapeutic drugs in vitro. Furthermore, we found that intrinsic apoptosis signaling is the mechanism of cell death involved with CMA blockade. Remarkably, LAMP2A knockdown repressed tumorigenicity and sensitized the tumors to cisplatin treatment in NSCLC-bearing mice. Our discoveries suggest that LAMP2A is involved in the regulation of cancer malignant phenotypes and represents a promising new target against chemoresistant NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Lisossomos/metabolismo , Transdução de Sinais , Animais , Apoptose/genética , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Proteína 2 de Membrana Associada ao Lisossomo/genética , Prognóstico , Proteólise
5.
J Cachexia Sarcopenia Muscle ; 13(3): 1864-1882, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35373498

RESUMO

BACKGROUND: Sarcopenia is characterized by the loss of skeletal muscle mass and strength and is associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) exposure, a major cause for COPD, induces mitochondrial damage, which has been implicated in sarcopenia pathogenesis. The current study sought to examine the involvement of insufficient Parkin-mediated mitophagy, a mitochondrion-selective autophagy, in the mechanisms by which dysfunctional mitochondria accumulate with excessive reactive oxygen species (ROS) production in the development of COPD-related sarcopenia. METHODS: The involvement of Parkin-mediated mitophagy was examined using in vitro models of myotube formation, in vivo CS-exposure model using Parkin-/- mice, and human muscle samples from patients with COPD-related sarcopenia. RESULTS: Cigarette smoke extract (CSE) induced myotube atrophy with concomitant 30% reduction in Parkin expression levels (P < 0.05). Parkin-mediated mitophagy regulated myotube atrophy by modulating mitochondrial damage and mitochondrial ROS production. Increased mitochondrial ROS was responsible for myotube atrophy by activating Muscle Ring Finger 1 (MuRF-1)-mediated myosin heavy chain (MHC) degradation. Parkin-/- mice with prolonged CS exposure showed enhanced limb muscle atrophy with a 31.7% reduction in limb muscle weights (P < 0.01) and 2.3 times greater MuRF-1 expression (P < 0.01) compared with wild-type mice with concomitant accumulation of damaged mitochondria and oxidative modifications in 4HNE expression. Patients with COPD-related sarcopenia exhibited significantly reduced Parkin but increased MuRF-1 protein levels (35% lower and 2.5 times greater protein levels compared with control patients, P < 0.01 and P < 0.05, respectively) and damaged mitochondria accumulation demonstrated in muscles. Electric pulse stimulation-induced muscle contraction prevented CSE-induced MHC reduction by maintaining Parkin levels in myotubes. CONCLUSIONS: Taken together, COPD-related sarcopenia can be attributed to insufficient Parkin-mediated mitophagy and increased mitochondrial ROS causing enhanced muscle atrophy through MuRF-1 activation, which may be at least partly preventable through optimal physical exercise.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Sarcopenia , Ubiquitina-Proteína Ligases , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitofagia/fisiologia , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Espécies Reativas de Oxigênio/metabolismo , Sarcopenia/metabolismo , Sarcopenia/patologia , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
6.
J Extracell Vesicles ; 10(10): e12124, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34377373

RESUMO

Idiopathic pulmonary fibrosis (IPF) is characterized by devastating and progressive lung parenchymal fibrosis, resulting in poor patient prognosis. An aberrant recapitulation of developmental lung gene expression, including genes for transforming growth factor (TGF)-ß and WNT, has been widely implicated in the pathogenic IPF wound healing process that results from repetitive alveolar epithelial injury. Extracellular vesicles (EVs) have been shown to carry bioactive molecules and to be involved in various physiological and pathological processes. Here, we demonstrate that, by attenuating WNT signalling, human bronchial epithelial cell-derived EVs (HBEC EVs) inhibit TGF-ß mediated induction of both myofibroblast differentiation and lung epithelial cellular senescence. This effect of HBEC EVs is more pronounced than that observed with mesenchymal stem cell-derived EVs. Mechanistically, the HBEC EV microRNA (miRNA) cargo is primarily responsible for attenuating both myofibroblast differentiation and cellular senescence. This attenuation occurs via inhibition of canonical and non-canonical WNT signalling pathways. Among enriched miRNA species present in HBEC EVs, miR-16, miR-26a, miR-26b, miR-141, miR-148a, and miR-200a are mechanistically involved in reducing WNT5A and WNT10B expression in LFs, and in reducing WNT3A, WNT5A, and WNT10B expression in HBECs. Mouse models utilizing intratracheal administration of EVs demonstrate efficient attenuation of bleomycin-induced lung fibrosis development accompanied by reduced expression of both ß-catenin and markers of cellular senescence. These findings indicate that EVs derived from normal resident lung HBECs may possess anti-fibrotic properties. They further suggest that, via miRNA-mediated inhibition of TGF-ß-WNT crosstalk, HBEC EVs administration can be a promising anti-fibrotic modality of treatment for IPF.


Assuntos
Vesículas Extracelulares/metabolismo , Fibrose Pulmonar Idiopática/terapia , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Fator de Crescimento Transformador beta/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Senescência Celular/efeitos dos fármacos , Células Epiteliais , Humanos , Células-Tronco Mesenquimais , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Wnt/metabolismo , Proteína Wnt-5a/metabolismo , Proteína Wnt3A/metabolismo
7.
J Extracell Vesicles ; 10(8): e12092, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34122778

RESUMO

The clinical manifestations of COVID-19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID-19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID-19 symptoms at the time of their admission for discovery cohort. After symptomatic treatment without corticosteroids, 9 of the 31 patients developed severe/critical COVID-19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID-19 severity. Strikingly, we identified three distinct groups of markers (antiviral response-related EV proteins, coagulation-related markers, and liver damage-related exRNAs) with the potential to serve as early predictive biomarkers for COVID-19 severity. As the best predictive marker, EV COPB2 protein, a subunit of the Golgi coatomer complex, exhibited significantly higher abundance in patients remained mild than developed severe/critical COVID-19 and healthy controls in discovery cohort (AUC 1.00 (95% CI: 1.00-1.00)). The validation set included 40 COVID-19 patients and 39 healthy controls, and showed exactly the same trend between the three groups with excellent predictive value (AUC 0.85 (95% CI: 0.73-0.97)). These findings highlight the potential of EV COPB2 expression for patient stratification and for making early clinical decisions about strategies for COVID-19 therapy.


Assuntos
COVID-19/sangue , COVID-19/fisiopatologia , Ácidos Nucleicos Livres/sangue , Proteína Coatomer/sangue , Vesículas Extracelulares/química , Biomarcadores/sangue , COVID-19/imunologia , Humanos , Estudos Retrospectivos , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença
8.
Cancers (Basel) ; 11(6)2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-31163629

RESUMO

Background: Prostaglandin E2 (PGE2) is metabolized to prostaglandin E-major urinary metabolite (PGE-MUM). Enhanced cyclooxygenase-2 (COX-2) expression demonstrated in lung adenocarcinoma indicates increased PGE-MUM levels in patients with lung adenocarcinoma. Objectives: We aimed to elucidate the clinical usefulness of measuring PGE-MUM as an indicator of tumor burden in patients with lung adenocarcinoma. Methods: PGE-MUM was measured by a radioimmunoassay in control healthy volunteers (n = 124) and patients with lung adenocarcinoma (n = 54). Associations between PGE-MUM levels and clinical characteristics of the patients (including lung cancer stage and TNM factors (T: Tumor, N: Node, M: Metastasis) were examined. Results: PGE-MUM levels were significantly elevated in patients with lung adenocarcinoma. A PGE-MUM level of 14.9 µg/g∙Cr showed 70.4% sensitivity and 67.7% specificity for the diagnosis of lung adenocarcinoma. PGE-MUM levels tended to be positively correlated with cancer progression as determined by the TNM staging system. Advanced stage (stage III, stage IV, and recurrence) was significantly associated with high PGE-MUM levels by logistic regression analysis. No apparent correlation was demonstrated between PGE-MUM and carcinoma embryonic antigen (CEA) levels. Conclusions: PGE-MUM can be a promising biomarker reflecting the systemic tumor burden of lung adenocarcinoma.

9.
Mayo Clin Proc Innov Qual Outcomes ; 2(4): 370-377, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30560239

RESUMO

OBJECTIVE: To investigate the relationship between psoriasis and interstitial pneumonia (IP). PATIENTS AND METHODS: We analyzed the clinical data of patients with psoriasis treated with biologic agents from June 1, 2008, to June 30, 2017, retrospectively. Chest computed tomography was performed in 392 patients before treatment. The clinical characteristics and radiographic findings of these patients were evaluated. RESULTS: Of the 392 patients with psoriasis, IP was detected in 8 patients (2%). Bilateral ground-glass and/or irregular linear (reticular) opacity in the lower lung zone was the most common chest computed tomography finding. Five of the 8 patients with IP were treated with anti-interleukin (IL) 12/IL-23 or IL-17 antibodies, leading to decreased or stable IP activity. CONCLUSION: Interstitial pneumonia was detected in 2% of patients with psoriasis who needed systemic treatments. Ground-glass and/or irregular linear (reticular) opacity in the bilateral lower lobes was characteristic of IP with psoriasis. The IL-23/IL-17 axis may play important roles in the pathogenesis of IP in psoriasis.

10.
Intern Med ; 57(3): 377-381, 2018 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-29093390

RESUMO

Development of aspergilloma is common in cases with a fungus ball-like shadow in cavities due to old tuberculosis. Some reports have shown that blood clots tend to appear as a fungus ball-like shadow. A 71-year-old man with a history of pulmonary tuberculosis presented with a fungus ball-like shadow in an old cavity and hemoptysis. There was no evidence of aspergillus infection on various examinations. We confirmed a blood clot and aneurysm of an artery under direct vision by bronchoscopy. A lateral thoracic artery aneurysm was detected by angiography. Transcatheter arterial embolization was performed. After treatment, the artery aneurysm disappeared.


Assuntos
Aneurisma/diagnóstico por imagem , Corpos Estranhos/cirurgia , Hemoptise/diagnóstico , Hemoptise/cirurgia , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/diagnóstico por imagem , Trombose/diagnóstico por imagem , Idoso , Aneurisma/cirurgia , Angiografia , Broncoscopia , Embolização Terapêutica , Corpos Estranhos/diagnóstico por imagem , Fungos , Humanos , Masculino , Trombose/cirurgia , Resultado do Tratamento
11.
Respir Med Case Rep ; 21: 147-150, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28507894

RESUMO

This case report describes the re-administration of abatacept to successfully reduce the articularsymptoms of a patient with rheumatoid arthritisduring the intensive phase of anti-tuberculous therapy. A 75-year-old man developed active pulmonary tuberculosis during the administration of abatacept for rheumatoid arthritis. The patient experienced a paradoxical reaction and exacerbation of rheumatoid arthritis that caused us to discontinue the abatacept. Later re-administration of abatacept along with anti-tuberculosis treatment led to well-controlled rheumatoid arthritis without exacerbation of the tuberculosis. This case shows that re-administration of abatacept may be much safer than TNF inhibitor to treat patients who are infected with mycobacteria during thetreatment of immunological diseases such asrheumatoid arthritiswith biological agents.

12.
Respir Med Case Rep ; 20: 201-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28331797

RESUMO

It has been reported that tuberculosis (TB) worsens after cessation of tumor necrosis factor-α inhibitors and starting anti-TB treatment. Little is known about the immunological pathogenesis of this paradoxical response (PR). We report the first case of a TB patient in whom PR occurred concurrently with elevation of circulating tumor necrosis factor-α (TNFα) levels. A 75-year-old woman, who had been treated with adalimumab for SAPHO syndrome, developed disseminated TB. Soon after administration of anti-TB treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol), and after discontinuation of adalimumab, a PR occurred. Serial testing of serum cytokine levels revealed a marked increase in TNFα, and a decline in interferon-γ levels. Despite intensive treatment with antibiotics, prednisolone, noradrenaline, and mechanical ventilation, acute respiratory distress syndrome developed and she died. Thus, overproduction of TNFα after cessation of TNFα inhibitors may partially account for the pathogenesis of a PR. This supports preventative or therapeutic reinitiation of TNFα inhibitors when PR occurs. Serial monitoring of circulating inflammatory cytokine levels could lead to earlier identification of a PR.

13.
BMJ Case Rep ; 20162016 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-27872133

RESUMO

Thyroid metastases from lung cancer are very rare. A woman aged 42 years with a tumour in the lower lobe of the right lung was diagnosed as having lung adenocarcinoma positive for echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase. Positron emission tomography demonstrated fluorodeoxyglucose accumulation in the lower lobe of the right lung, the right thyroid lobe and both adrenal glands. We performed fine-needle aspiration biopsy (FNAB) and used reverse transcriptase-PCR (RT-PCR) to diagnose the patient as having metastatic lung adenocarcinoma to the thyroid gland. We believe that FNAB combined with RT-PCR can be an effective method for diagnosing metastatic lung adenocarcinoma to the thyroid gland.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/secundário , Neoplasias Pulmonares/patologia , Neoplasias da Glândula Tireoide/secundário , Adenocarcinoma/diagnóstico , Adulto , Biópsia por Agulha Fina , Feminino , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/diagnóstico
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