RESUMO
Macrophages contribute to post-transplant lung rejection. Disulfiram (DSF), an anti-alcoholic drug, has an anti-inflammatory effect and regulates macrophage chemotactic activity. Here, we investigated DSF efficacy in suppressing acute rejection post-lung transplantation. Male Lewis rats (280-300 g) received orthotopic left lung transplants from Fisher 344 rats (minor histocompatibility antigen-mismatched transplantation). DSF (0.75 mg/h) monotherapy or co-solvent only (50% hydroxypropyl-ß-cyclodextrin) as control was subcutaneously administered for 7 days (n = 10/group). No post-transplant immunosuppressant was administered. Grades of acute rejection, infiltration of immune cells positive for CD68, CD3, or CD79a, and gene expression of monocyte chemoattractant protein and pro-inflammatory cytokines in the grafts were assessed 7 days post-transplantation. The DSF-treated group had significantly milder lymphocytic bronchiolitis than the control group. The infiltration levels of CD68+ or CD3+ cells to the peribronchial area were significantly lower in the DSF than in the control groups. The normalized expression of chemokine ligand 2 and interleukin-6 mRNA in allografts was lower in the DSF than in the control groups. Validation assay revealed interleukin-6 expression to be significantly lower in the DSF than in the control groups. DSF can alleviate acute rejection post-lung transplantation by reducing macrophage accumulation around peripheral bronchi and suppressing pro-inflammatory cytokine expression.
Assuntos
Dissulfiram , Rejeição de Enxerto , Transplante de Pulmão , Macrófagos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Animais , Transplante de Pulmão/efeitos adversos , Rejeição de Enxerto/prevenção & controle , Rejeição de Enxerto/imunologia , Masculino , Dissulfiram/farmacologia , Dissulfiram/uso terapêutico , Ratos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Aloenxertos , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Quimiocina CCL2/metabolismo , Pulmão/patologia , Pulmão/efeitos dos fármacosRESUMO
Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1, and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3, and H3K27ac) by CUT&Tag assay and ASCL1 knockdown followed by RNA sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs, such as miR-7, miR-375, miR-200b-3p, and miR-429, leading to repression of their targets, whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC (e.g., co-targeting of YAP1 by miR-9 and miR-375). Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences.
Assuntos
Neoplasias Pulmonares , MicroRNAs , Carcinoma de Pequenas Células do Pulmão , Humanos , Carcinoma de Pequenas Células do Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismoRESUMO
INTRODUCTION: Information on drug-induced interstitial lung disease (DILD) is limited due to its low incidence. This study investigated the frequencies of drug categories with potential risk in patients developing DILD during hospitalisation and analysed the risk of developing DILD associated with each of these drugs. METHODS: Using a Japanese national inpatient database, we identified patients without interstitial pneumonia on admission who developed DILD and required corticosteroid therapy during hospitalisation from July 2010 to March 2016. We conducted a nested case-control study; four controls from the entire non-DILD patient cohort were matched to each DILD case on age, sex, main diagnosis, admission year and hospital. We defined 42 classified categories of drugs with 216 generic names as drugs with potential risk of DILD, and we identified the use of these drugs during hospitalisation for each patient. We analysed the association between each drug category and DILD development using conditional logistic regression analyses. RESULTS: We retrospectively identified 2342 patients who developed DILD. After one-to-four case-control matching, 1541 case patients were matched with 5677 control patients. Six drug categories were significantly associated with the increased occurrence of DILD. These included epidermal growth factor receptor inhibitors (OR: 16.84, 95% CI 9.32 to 30.41) and class III antiarrhythmic drugs (OR: 7.01, 95% CI 3.86 to 12.73). Statins were associated with reduced risk of DILD (OR: 0.68, 95% CI 0.50 to 0.92). CONCLUSIONS: We demonstrated significant associations between various drug categories and DILD. Our findings provide useful information on drug categories with potential risk to help physicians prevent and treat DILD.
Assuntos
Doenças Pulmonares Intersticiais , Preparações Farmacêuticas , Estudos de Casos e Controles , Humanos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/epidemiologia , Inibidores de Proteínas Quinases , Estudos RetrospectivosRESUMO
BACKGROUND AND OBJECTIVE: Patients with idiopathic pulmonary fibrosis (IPF) often develop postoperative severe respiratory complications such as acute exacerbation. Pirfenidone, an oral anti-fibrotic drug, may reduce the incidence of such complications. However, the preventive effect of pirfenidone on postoperative severe respiratory complications remains unclear. METHODS: We identified patients with IPF who underwent surgery with general anaesthesia from July 2010 to March 2018 using the Diagnosis Procedure Combination database. We compared the occurrence of postoperative severe respiratory complications (receiving mechanical ventilation under endotracheal intubation and/or intravenous infusion of a high-dose corticosteroid and in-hospital death within 30 days after surgery) between patients who did and did not receive preoperative treatment with pirfenidone. Pearson's chi-square test and logistic regression analysis fitted with a generalized estimating equation were conducted in 1:4 propensity score-matched patients. RESULTS: Among 631 patients identified, 19% were treated with pirfenidone before surgery. The 30-day mortality rate was 3.1% and 1.7% in the control patients (n = 510) and pirfenidone-treated patients (n = 121), respectively. In the propensity score-matched population, preoperative treatment with pirfenidone was significantly associated with a lower proportion of postoperative severe respiratory complications (OR: 0.24; 95% CI: 0.07-0.76; p = 0.015). CONCLUSION: In this Japanese nationwide cohort, preoperative treatment with pirfenidone was significantly associated with a lower risk of postoperative severe respiratory complications in patients with IPF. Preoperative pirfenidone may thus be useful in preventing postoperative severe respiratory complications in patients with IPF who are planning to undergo surgery with general anaesthesia.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridonas , Anti-Inflamatórios não Esteroides/farmacologia , Mortalidade Hospitalar , Humanos , Fibrose Pulmonar Idiopática/complicações , Japão/epidemiologia , Pontuação de Propensão , Piridonas/uso terapêutico , Resultado do TratamentoRESUMO
TAZ (transcriptional coactivator with PDZ-binding motif) and YAP (Yes-associated protein) are key molecules of the Hippo pathway. Recent studies revealed that these molecules are essential in lung development; however, the precise signaling cascade involving these molecules and the differences in their roles during lung development remain unknown. We aimed to investigate YAP and TAZ functions using lung epithelium-specific Taz and Yap conditional knockout mice. We generated lung epithelium-specific Taz and Yap conditional knockout mice and investigated the functions of YAP and TAZ in lung development. Selective TAZ deficiency in mouse lung epithelial cells resulted in abnormal alveolarization, which mimics lung emphysema, in adults, whereas YAP deficiency caused disruption of bronchial morphogenesis during the embryonic stage. We report that TAZ and YAP are sequentially expressed in the lung and that this could explain their different phenotypes. Furthermore, we report that YAP stimulates Shh (Sonic hedgehog) expression and regulates the FGF (fibroblast growth factor)-SHH feedback loop, thereby contributing to normal bronchial morphogenesis. We also found that TGF-ß (transforming growth factor-ß) stimulation induced Shh expression in the lung epithelial cells, and both TAZ and YAP are essential in this novel pathway. Our results provide a novel insight into the molecular mechanisms underlying lung development and contribute to a better understanding of the characteristics of TAZ and YAP.
Assuntos
Proteínas Hedgehog/metabolismo , Pulmão/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-yes/genética , Transativadores/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Knockout , Organogênese , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Rheumatoid arthritis (RA)-associated interstitial lung disease (ILD), a primary cause of mortality in patients with RA, has limited treatment options. A previously established RA model in D1CC transgenic mice aberrantly expressed major histocompatibility complex class II genes in joints, developing collagen II-induced polyarthritis and anti-cyclic citrullinated peptide antibodies and interstitial pneumonitis, similar to those in humans. Molecular hydrogen (H2 ) is an efficient antioxidant that permeates cell membranes and alleviates the reactive oxygen species-induced injury implicated in RA pathogenesis. We used D1CC mice to analyse chronic lung fibrosis development and evaluate H2 treatment effects. We injected D1CC mice with type II collagen and supplied them with H2 -rich or control water until analysis. Increased serum surfactant protein D values and lung densities images were observed 10 months after injection. Inflammation was patchy within the perilymphatic stromal area, with increased 8-hydroxy-2'-deoxyguanosine-positive cell numbers and tumour necrosis factor-α, BAX, transforming growth factor-ß, interleukin-6 and soluble collagen levels in the lungs. Inflammatory and fibrotic changes developed diffusely within the perilymphatic stromal area, as observed in humans. H2 treatment decreased these effects in the lungs. Thus, this model is valuable for studying the effects of H2 treatment and chronic interstitial pneumonia pathophysiology in humans. H2 appears to protect against RA-ILD by alleviating oxidative stress.
Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Hidrogênio/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Animais , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Bovinos , Colágeno Tipo II/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Hidrogênio/farmacologia , Pulmão/patologia , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/patologia , Masculino , Camundongos , Camundongos Transgênicos , Estresse Oxidativo/efeitos dos fármacos , Proteína D Associada a Surfactante Pulmonar/sangue , Proteína X Associada a bcl-2/metabolismoRESUMO
Naftopidil, an α-1 adrenoceptor antagonist with few adverse effects, is prescribed for prostate hyperplasia. Naftopidil inhibits prostate fibroblast proliferation; however, its effects on lung fibroblasts and fibrosis remain largely unknown. Two normal and one idiopathic pulmonary fibrosis human lung fibroblast lines were cultured with various naftopidil concentrations with or without phenoxybenzamine, an irreversible α-1 adrenoceptor inhibitor. We examined the incorporation of 5-bromo-2'-deoxyuridine into DNA and lactic acid dehydrogenase release by enzyme-linked immunosorbent assay, cell cycle analysis by flow cytometry, scratch wound-healing assay, and mRNA expressions of type IV collagen and α-smooth muscle actin by polymerase chain reaction. Effects of naftopidil on bleomycin-induced lung fibrosis in mice were evaluated using histology, micro-computed tomography, and surfactant protein-D levels in serum. Naftopidil, dose-dependently but independently of phenoxybenzamine, inhibited 5-bromo-2'-deoxyuridine incorporation in lung fibroblasts. Naftopidil induced G1 cell cycle arrest, but lactic acid dehydrogenase release and migration ability of lung fibroblasts were unaffected. Naftopidil decreased mRNA expressions of type IV collagen and α-smooth muscle actin in one normal lung fibroblast line. Histological and micro-computed tomography examination revealed that naftopidil attenuated lung fibrosis and decreased serum surfactant protein-D levels in bleomycin-induced lung fibrosis in mice. In conclusion, naftopidil may have therapeutic effects on lung fibrosis.
Assuntos
Proliferação de Células/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibrose Pulmonar Idiopática/prevenção & controle , Pulmão/efeitos dos fármacos , Naftalenos/farmacologia , Piperazinas/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Bleomicina , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Células Cultivadas , Fibroblastos/metabolismo , Humanos , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/metabolismo , Pulmão/patologia , Camundongos Endogâmicos C57BL , Proteína D Associada a Surfactante Pulmonar/sangue , Microtomografia por Raio-XRESUMO
Although mammalian target of rapamycin inhibitors (mTORi) are used to treat various malignancies, they frequently induce active alveolitis and dyslipidemia. Abnormal lipid metabolism affects alveolar surfactant function and results in pulmonary disorders; however, the pathophysiology of lung injury and its relationship with lipid metabolism remain unknown. We investigated the relationship between lipid metabolism and alveolar epithelial injury, focusing on peroxisome proliferator-activated receptor-γ (PPAR-γ) as a lipid stress-related factor in mTORi-induced lung injury. We clinicopathologically examined three patients with mTORi-induced lung injury. We constructed an mTORi injury mouse model using temsirolimus in mice (30 mg/kg/day), with the vehicle control and bleomycin injury groups. We also constructed a cultured alveolar epithelial cell injury model using temsirolimus (0-40 µM) in the mouse lung epithelial cell line MLE-12 and performed analysis with or without pioglitazone (PPAR-γ agonist) treatment. All three patients had dyslipidemia and lung lesions of hyperplastic pneumocytes with foamy and enlarged changes. In the mouse model, temsirolimus induced significantly higher levels of total cholesterol and free fatty acids in serum and higher levels of surfactant protein D in serum and BAL fluid with an increase in inflammatory cytokines in the lung compared to control. Temsirolimus also induced hyperplastic foamy pneumocytes with increased lipid-associated spots and larger round electron-lucent bodies compared to the control or bleomycin groups in microscopic analyses. Multiple lipid-associated spots within the cytoplasm were also induced by temsirolimus administration in MLE-12 cells. Temsirolimus downregulated PPAR-γ expression in mouse lung and MLE-12 cells but upregulated cleaved caspase-3 in MLE-12 cells. Pioglitazone blocked the upregulated cleaved caspase-3 expression in MLE-12 cells. The pathogenesis of mTORi-induced lung disease may be involved in alveolar epithelial injury, via lipid metabolic stress associated with downregulated PPAR-γ expression. Focusing on the relationship between lipid metabolic stress and alveolar epithelial injury represents a potentially novel approach to the study of pulmonary damage.
Assuntos
Células Epiteliais Alveolares/metabolismo , Antineoplásicos/efeitos adversos , Everolimo/efeitos adversos , Metabolismo dos Lipídeos , Lesão Pulmonar/induzido quimicamente , Idoso , Células Epiteliais Alveolares/ultraestrutura , Animais , Linhagem Celular , Citocinas/metabolismo , Feminino , Humanos , Hiperlipidemias/induzido quimicamente , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , PPAR gama/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
BACKGROUND: Recent advances in bronchoscopy utilizing endobronchial ultrasound (EBUS) as well as lung cancer therapy may have driven physicians to perform diagnostic bronchoscopy (DB) for high-risk patients. OBJECTIVES: The aim of this study was to clarify the relationship between hospital volume (HV) and outcomes of DB. METHODS: We collected data on inpatients with lung cancer who underwent DB from July 2010 to March 31, 2014. The annual HV of DB was classified as "very low" (≤50 cases/year), "low" (51-100 cases/year), "high" (101-300 cases/year), or "very high" (> 300 cases/year). The primary outcome was all-cause 7-day mortality after DB. Multivariable logistic regression fitted with a generalized estimation equation was performed to evaluate the association between HV and all-cause 7-day mortality after DB, adjusted for patient background factors. RESULTS: We identified a total of 77,755 eligible patients in 954 hospitals. All-cause 7-day mortality was 0.5%. Compared with the low-volume group, 7-day mortality was significantly lower in the high-volume group (odds ratio [OR] = 0.69, 95% confidence interval [CI]: 0.52-0.92, p = 0.010), and a similar trend was shown in the very-high-volume group (OR = 0.67; 95% CI: 0.43-1.05, p = 0.080). Radial EBUS with the guide sheath method and EBUS-guided transbronchial needle aspiration showed a significantly lower 7-day mortality. CONCLUSIONS: All-cause 7-day mortality was inversely associated with HV. The risk of DB in patients with lung cancer should be recognized, and the exploitation of EBUS may help reduce mortality after DB.
Assuntos
Broncoscopia/métodos , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/mortalidade , Hospitais/estatística & dados numéricos , Pacientes Internados/estatística & dados numéricos , Neoplasias Pulmonares/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte/tendências , Feminino , Seguimentos , Mortalidade Hospitalar/tendências , Humanos , Japão/epidemiologia , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências , Adulto JovemRESUMO
BACKGROUND: Bronchial asthma is a chronic airway disease characterized by eosinophilic airway inflammation. Lung fibroblasts activated by IL-13 serve as important sources of chemokines, such as eotaxins, contributing to persistent eosinophilic inflammation. Src-homology 2-containing protein (CISH), belonging to the suppressor of cytokine signaling (SOCS) family, acts as a negative regulator of cytokine induction. The aim of this study was to elucidate the role of CISH in the production of eosinophil chemotactic chemokines in human lung fibroblasts. METHODS: Normal human lung fibroblasts were stimulated by IL-13, and global gene expression profile was assessed by cDNA microarray. Expression changes and downstream of IL-13 signaling were evaluated by quantitative RT-PCR, ELISA or western blotting. Loss- and gain-of-function analyses of CISH were performed by small interfering RNA and vector overexpression, respectively. RESULTS: Ingenuity pathway analysis revealed that IL-13 induced chemokine signaling, including the eotaxin family, while significantly suppressing IFN-α/ß signaling. Among eight SOCS family members, CISH was most strongly induced by IL-13 via phosphorylation of signal transducer and activator of transcription 6 (STAT6). Loss- and gain-of-function studies demonstrated that CISH negatively regulated the expression of CCL26. CONCLUSIONS: These findings suggest that CISH plays a key role in the eosinophilic inflammation associated with bronchial asthma by regulating IL-13-induced CCL26 production. Augmentation of CISH function could be a novel approach for treating eosinophilic inflammation in severe asthma.
Assuntos
Quimiocina CCL26/metabolismo , Fibroblastos/metabolismo , Interleucina-13/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Células Cultivadas , Quimiocina CCL26/genética , Eosinofilia/metabolismo , Humanos , Pulmão , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
BACKGROUND: Asthma is a chronic airway inflammatory disease characterized by airway remodeling, in which the bronchial smooth muscle (BSM) cells play an important role. Periostin, a biomarker that reflects Th2-driven inflammatory diseases such as asthma, may play an important role in the asthmatic airway. Although periostin is mainly produced in airway epithelial cells and fibroblasts after interleukin (IL)-13 stimulation, whether BSM cells produce periostin remains unclear. Therefore, we investigated periostin production in BSM cells and the mechanisms involved. METHODS: Human BSM cells were cultured, and the effect of IL-13 stimulation on periostin production was evaluated using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). We evaluated the phosphorylation of signal transducer and activator of transcription factor 6 (STAT6), extracellular signal-regulated kinase (ERK)1/2, and Akt after IL-13 stimulation. Furthermore, using ELISA, we evaluated the influence of several phosphorylation inhibitors on periostin production. RESULTS: Periostin mRNA expression increased in a dose- and time-dependent manner after IL-13 stimulation; periostin production was induced 24 and 48 h after stimulation. IL-13 stimulation induced the phosphorylation of STAT6, ERK1/2, and Akt. IL-13-induced periostin production was attenuated by inhibiting STAT6 phosphorylation and strongly suppressed by inhibiting mitogen-activated protein kinase kinase 1/2 phosphorylation or phosphatidylinositol 3-kinase (PI3K) phosphorylation. CONCLUSIONS: BSM cells produced periostin after IL-13 stimulation, via the JAK/STAT6, ERK1/2, and PI3K/Akt pathways. Understanding the mechanism of periostin production in BSM cells may help to clarify asthma pathogenesis.
Assuntos
Asma/imunologia , Brônquios/imunologia , Moléculas de Adesão Celular/metabolismo , Miócitos de Músculo Liso/fisiologia , Remodelação das Vias Aéreas , Moléculas de Adesão Celular/genética , Células Cultivadas , Humanos , Interleucina-13/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais , Regulação para CimaRESUMO
An association between chemotherapy and venous thromboembolic events (VTEs) in patients with cancer is well established, with cisplatin (CDDP) being one of the most well-studied risk factors. However, whether CDDP is more strongly associated with occurrence of VTEs than carboplatin (CBDCA) or nedaplatin (CDGP) is controversial. Our purposes were to characterize patients with lung cancer and in-hospital VTEs, identify risk factors associated with VTEs, and compare the risks associated with CDDP-based versus CBDCA/CDGP-based chemotherapy. We retrospectively identified patients with lung cancer who underwent platinum-based chemotherapy from April 2012 to March 2015 from a national inpatient database in Japan. We used multivariable logistic regression analysis to analyze associations between various factors, including chemotherapy regimens and VTE. Of 235 104 eligible patients, 675 (0.29%) had VTEs after receiving platinum-based chemotherapy while hospitalized. Multivariable analysis showed that age, activity of daily living index, and invasive medical procedures were significant risk factors for the occurrence of VTE. Furthermore, CDDP-based chemotherapy was associated with a higher rate of VTE than CBDCA/CDGP-based chemotherapy (adjusted odds ratio: 1.35; 95% confidence interval: 1.08-1.68; P<0.01). In conclusion, CDDP-based chemotherapy is a stronger risk factor for VTEs than CBDCA/CDGP-based chemotherapy in patients with lung cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Feminino , Humanos , Japão/epidemiologia , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Estudos Retrospectivos , Risco , Tromboembolia Venosa/induzido quimicamente , Adulto JovemRESUMO
BACKGROUND: The optimal postoperative treatment strategy for small cell lung cancer (SCLC) remains unclear, especially in patients with lymph node metastasis. We aimed to compare the outcomes of patients with SCLC and lymph node metastasis treated with postoperative adjuvant chemotherapy or chemoradiotherapy. METHODS: We retrospectively collected data on patients with postoperative SCLC diagnosed with N1 and N2 lymph node metastasis from the Diagnosis Procedure Combination database in Japan, between July 2010 and March 2015. We extracted data on patient age, sex, comorbidities, and TNM classification at lung surgery; operative procedures, chemotherapy drugs, and radiotherapy during hospitalization; and discharge status. Recurrence-free survival was compared between the chemotherapy and chemoradiotherapy groups using multivariable Cox regression analysis. RESULTS: Median recurrence-free survival was 1146 days (95% confidence interval [CI], 885-1407) in the chemotherapy group (n = 489) and 873 days (95% CI, 464-1282) in the chemoradiotherapy group (n = 75). There was no significant difference between these after adjusting for patient backgrounds (hazard ratio, 1.29; 95% CI, 0.91-1.84). CONCLUSIONS: There was no significant difference in recurrence-free survival between patients with SCLC and N1-2 lymph node metastasis treated with postoperative adjuvant chemotherapy and chemoradiotherapy. Further randomized clinical trials are needed to address this issue.
Assuntos
Quimiorradioterapia , Quimioterapia Adjuvante , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Japão , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Carcinoma de Pequenas Células do Pulmão/epidemiologia , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do TratamentoRESUMO
Early fibrotic lesions are thought to be the initial findings of fibrogenesis in idiopathic interstitial pneumonias, but little is known about their properties. Type IV collagen comprises six gene products, α1-α6, and although it is known as a major basement membrane component, its abnormal deposition is seen in fibrotic lesions of certain organs. We studied the expression of type I and III collagen and all α chains of type IV collagen in lung specimens from patients with usual interstitial pneumonia (UIP) or organizing pneumonia (OP) via immunohistochemistry. With cultured lung fibroblasts, we analyzed the expression and function of all α chains of type IV collagen via immunohistochemistry, western blotting, real-time quantitative PCR, and a Boyden chamber migration assay after the knockdown of α1 and α2 chains. Although we observed type I and III collagens in early fibrotic lesions of both UIP and OP, we found type IV collagen, especially α1 and α2 chains, in early fibrotic lesions of UIP but not OP. Fibroblasts enhanced the expression of α1 and α2 chains of type IV collagen after transforming growth factor-ß1 stimulation. Small interfering RNA against α1 and α2 chains increased fibroblast migration, with upregulated phosphorylation of focal adhesion kinase (FAK), and adding medium containing fibroblast-produced α1 and α2 chains reduced the increased levels of fibroblast migration and phosphorylation of FAK. Fibroblasts in OP were positive for phosphorylated FAK but fibroblasts in UIP were not. These results suggest that fibroblasts in UIP with type IV collagen deposition, especially α1 and α2 chains, have less ability to migrate from early fibrotic lesions than fibroblasts in OP without type IV collagen deposition. Thus, type IV collagen deposition in early fibrotic lesions of UIP may be implicated in refractory pathophysiology including migration of lesion fibroblasts via a FAK pathway.
Assuntos
Movimento Celular/fisiologia , Colágeno Tipo IV/metabolismo , Fibroblastos/metabolismo , Fibrose Pulmonar Idiopática/metabolismo , Idoso , Células Cultivadas , Colágeno Tipo IV/análise , Colágeno Tipo IV/genética , Feminino , Quinase 1 de Adesão Focal/metabolismo , Humanos , Pulmão/citologia , Masculino , Pessoa de Meia-Idade , FosforilaçãoRESUMO
BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a new technique for obtaining high-quality and large-sized lung tissues, as compared to transbronchial forceps biopsy (TBFB), and is useful in the diagnosis of diffuse lung disease (DLD). We aimed to evaluate the safety of TBLC as compared to TBFB in DLD patients in Japan using a nationwide database. METHODS: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from April 1, 2020 to March 31, 2022. Eligible patients (n = 9673) were divided into the following two groups: those who underwent TBFB (TBFB group, n = 8742) and TBLC (TBLC group, n = 931). To compare the outcomes between the two groups, a stabilized inverse probability of treatment weighting (IPTW) was applied using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 28-day mortality, complications (mechanical ventilation, pneumothorax, and bleeding), and length of hospital stay after bronchoscopy. RESULTS: The crude in-hospital mortality rates were 3.2% and 0.9% in the TBFB and TBLC groups, respectively. The stabilized IPTW analysis showed no significant difference in the in-hospital mortality rates between the two groups; the odds ratio of the TBLC group as compared with the TBFB group was 0.73 (95% confidence interval: 0.34-1.60; p = 0.44). Moreover, the secondary outcomes did not significantly differ between the two groups. CONCLUSIONS: TBLC for DLD patients had a similar mortality and complication rates as TBFB.
Assuntos
Broncoscopia , Pneumopatias , Pulmão , Humanos , Masculino , Feminino , Japão , Biópsia/métodos , Biópsia/efeitos adversos , Idoso , Estudos Retrospectivos , Broncoscopia/métodos , Broncoscopia/efeitos adversos , Pessoa de Meia-Idade , Pulmão/patologia , Pneumopatias/patologia , Criocirurgia/métodos , Mortalidade Hospitalar , Bases de Dados Factuais , Tempo de Internação , Instrumentos Cirúrgicos , Pneumotórax/etiologia , Pneumotórax/epidemiologiaRESUMO
Objective The effect of Rikkunshito, a Japanese herbal Kampo medicine, on chemotherapy-induced nausea and vomiting (CINV) has been evaluated in several small prospective studies, with mixed results. We retrospectively evaluated the antiemetic effects of Rikkunshito in patients undergoing cisplatin-based chemotherapy using a large-scale database in Japan. Methods The Diagnosis Procedure Combination inpatient database from July 2010 to March 2019 was used to compare adult patients with malignant tumors who had received Rikkunshito on or before the day of cisplatin administration (Rikkunshito group) and those who had not (control group). Antiemetics on days 2 and 3 and days 4 and beyond following cisplatin administration were used as surrogate outcomes for CINV. Patient backgrounds were adjusted using the stabilized inverse probability of treatment weighting, and outcomes were compared using univariable regression models. Results We identified 669 and 123,378 patients in the Rikkunshito and control groups, respectively. There were significantly fewer patients using intravenous 5-HT3-receptor antagonists in the Rikkunshito group (odds ratio, 0.38; 95% confidence interval, 0.16-0.87; p=0.023) on days 2 and 3 of cisplatin-based chemotherapy. Conclusion The reduced use of antiemetics on day 2 and beyond of cisplatin administration suggested a beneficial effect of Rikkunshito in palliating the symptoms of CINV.
Assuntos
Antieméticos , Antineoplásicos , Medicamentos de Ervas Chinesas , Adulto , Humanos , Antieméticos/uso terapêutico , Antieméticos/efeitos adversos , Cisplatino/uso terapêutico , Japão , Medicina Kampo , Estudos Prospectivos , Estudos Retrospectivos , Náusea/induzido quimicamente , Náusea/tratamento farmacológico , Vômito/induzido quimicamente , Vômito/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Antineoplásicos/efeitos adversosRESUMO
BACKGROUND: The association between reflux esophagitis and pulmonary function remains controversial. Thus, evaluating the relationship between endoscopic reflux esophagitis and changes in pulmonary function over time in a nonsmoking population is an important clinical issue. METHODS: In this single-center retrospective cohort study, a medical examination database at Kameda Medical Center Makuhari was employed to identify nonsmokers who underwent upper gastrointestinal endoscopy and spirometry in 2010 and were followed up in 2015. Gastroenterologists carefully double-checked the diagnosis of reflux esophagitis. Multiple linear regression analyses were performed to compare the decline in the percentage of predicted vital capacity (%VC), forced vital capacity (%FVC), and forced expiratory volume in 1 s (%FEV1) between participants with reflux esophagitis and those without. Furthermore, using multivariable logistic regression analyses, we evaluated the factors associated with rapid decline in %VC, %FVC, and %FEV1, which is defined as a decrease of >10% in each parameter over the 5-year observation period. RESULTS: We identified 3098 eligible subjects, including 72 and 44 participants who had a Los Angeles classification grade A and B-C (severe) reflux esophagitis in 2010, respectively. The decline in %VC was significantly larger in the participants with severe reflux esophagitis than in the control subjects (standardized coefficient, -0.037; 95% confidence interval, -0.071 to -0.004). Moreover, reflux esophagitis was significantly associated with a rapid decline in %VC and %FVC but not in %FEV1 (P for trend: 0.009, 0.009, and 0.276, respectively). CONCLUSIONS: Severe reflux esophagitis among nonsmokers had clinical disadvantages in terms of a decline in %VC.
Assuntos
Esofagite Péptica , Humanos , Esofagite Péptica/fisiopatologia , Esofagite Péptica/diagnóstico , Esofagite Péptica/etiologia , Estudos Retrospectivos , Masculino , Pessoa de Meia-Idade , Feminino , Capacidade Vital , não Fumantes/estatística & dados numéricos , Estudos de Coortes , Volume Expiratório Forçado , Adulto , Pulmão/fisiopatologia , Idoso , Testes de Função RespiratóriaRESUMO
Survivin, an inhibitor of apoptosis, regulates cell division and is a potential target for anticancer drugs because many cancers express high survivin levels. However, whether survivin would be toxic to human lung cells and tissues has not been determined. This report clarified the involvement of survivin in acute lung injury. We used immunohistochemical analysis, immunoelectron microscopy, and real-time reverse transcription-quantitative polymerase chain reaction to study survivin expression and localization in injured mouse and human lungs. We also used cultured human lung epithelial cells (BEAS-2B and A549) to study survivin cytoprotection. Nuclei and cytoplasm of epithelial cells in day 3 and day 7 models of bleomycin-injured lung showed survivin-positive results, which is consistent with upregulated survivin mRNA expression. These nuclei also evidenced double positive findings for proliferating cell nuclear antigen and survivin. Day 7 models had similar Smac/DIABLO-positive and survivin-positive cell distributions. The cytoplasm and nuclei of epithelial cells in lesions with diffuse alveolar damage manifested strong survivin-positive findings. Bleomycin stimulation in both epithelial cell lines upregulated expression of survivin and apoptosis-related molecules. Suppression of survivin expression with small interfering RNA rendered human lung epithelial cells susceptible to bleomycin-induced damage, with markedly upregulated activation of caspase-3, caspase-7, poly (ADP-ribose) polymerase, and lactate dehydrogenase activity and an increased number of dead cells compared with mock small interfering RNA-treated cells. Overexpression of survivin via transfection resulted in these epithelial cells being resistant to bleomycin-induced cell damage, with reduced activation of apoptosis-related molecules and lactate dehydrogenase activity and fewer dead cells compared with results for mock-transfected cells. Survivin, acting at the epithelial cell level that depends partly on apoptosis inhibition, is therefore a key mediator of cytoprotection in acute lung injury. Understanding the precise role of survivin in normal lung cells is required for the development of therapeutic survivin.
Assuntos
Apoptose/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar/metabolismo , Proteínas Repressoras/metabolismo , Síndrome do Desconforto Respiratório/metabolismo , Mucosa Respiratória/metabolismo , Adulto , Idoso , Animais , Antibióticos Antineoplásicos/efeitos adversos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Resistência a Medicamentos , Feminino , Humanos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose/genética , Pulmão/efeitos dos fármacos , Pulmão/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Interferência de RNA , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Síndrome do Desconforto Respiratório/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/ultraestrutura , Survivina , Regulação para Cima/efeitos dos fármacosRESUMO
Of the idiopathic interstitial pneumonias (IIPs), usual interstitial pneumonia (UIP) and diffuse alveolar damage (DAD) usually have poor prognoses. The prognoses of cryptogenic organizing pneumonia (COP) and nonspecific interstitial pneumonia (NSIP) are usually more favorable. Although several reports have described neovascularization in COP and UIP, this aspect of UIP has not been compared with NSIP. In this study, we evaluated neovascularization in intra-alveolar fibrotic lesion of cases of fibrosing NSIP (f-NSIP) (n = 26) and UIP (n = 25). In the f-NSIP group, a considerable degree of neovascularization was observed compared to the UIP group and bud type intra-alveolar fibrosis showed a greater degree of neovascularization compared to the mural-incorporation and obliterative types of intra-alveolar fibrosis. Real-time reverse transcription polymerase chain reaction revealed a significantly greater expression of VEGF-A mRNA in f-NSIP than in UIP. The expression of matrix metalloproteinase-2 (MMP-2) mRNA also showed significantly higher in f-NSIP than UIP. The greater VEGF-A and MMP-2 expression may play a role in the pathogenesis of neovascularization in early intra-alveolar fibrotic lesions in f-NSIP.