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1.
Immunity ; 56(1): 125-142.e12, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36630911

RESUMO

During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.


Assuntos
Interleucinas , Neoplasias Hepáticas , Células T Matadoras Naturais , Animais , Camundongos , Células Endoteliais/metabolismo , Interleucinas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/metabolismo , Neoplasias Colorretais/metabolismo , Interleucina 22
2.
Am J Transplant ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39098448

RESUMO

Currently, lung transplantation outcome remains inferior compared to other solid organ transplantations. A major cause for limited survival after lung transplantation is chronic lung allograft dysfunction. Numerous animal models have been developed to investigate chronic lung allograft dysfunction to discover adequate treatments. The murine orthotopic lung transplant model has been further optimized over the last years. However, different degrees of genetic mismatch between donor and recipient mice have been used, applying a single, minor, moderate, and major genetic mismatch. This review aims to reassess the existing murine mismatch models and provide a comprehensive overview, with a specific focus on their eventual histopathological presentation. This will be crucial to leverage this model and tailor it according to specific research needs.

3.
Am J Transplant ; 24(6): 944-953, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38403187

RESUMO

Chronic lung allograft dysfunction (CLAD) remains one of the major limitations to long-term survival after lung transplantation. We modified a murine model of CLAD and transplanted left lungs from BALB/c donors into B6 recipients that were treated with intermittent cyclosporine and methylprednisolone postoperatively. In this model, the lung allograft developed acute cellular rejection on day 15 which, by day 30 after transplantation, progressed to severe pleural and peribronchovascular fibrosis, reminiscent of changes observed in restrictive allograft syndrome. Lung transplantation into splenectomized B6 alymphoplastic (aly/aly) or splenectomized B6 lymphotoxin-ß receptor-deficient mice demonstrated that recipient secondary lymphoid organs, such as spleen and lymph nodes, are necessary for progression from acute cellular rejection to allograft fibrosis in this model. Our work uncovered a critical role for recipient secondary lymphoid organs in the development of CLAD after pulmonary transplantation and may provide mechanistic insights into the pathogenesis of this complication.


Assuntos
Modelos Animais de Doenças , Rejeição de Enxerto , Transplante de Pulmão , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Animais , Camundongos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Transplante de Pulmão/efeitos adversos , Aloenxertos , Progressão da Doença , Fibrose , Doença Crônica , Sobrevivência de Enxerto , Masculino , Tecido Linfoide/patologia
4.
Respiration ; 103(1): 1-9, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38052185

RESUMO

INTRODUCTION: Lung transplantation (LT) recipients are at risk of bone mineral density (BMD) loss. Pre- and post-LT BMD loss has been reported in some cross-sectional studies; however, there are limited studies regarding the serial BMD change in LT recipients. The aim of this study was to investigate the serial BMD changes and the clinical characteristics associated with BMD decline. METHODS: This was a single-center, retrospective observational study. BMD was serially measured in thoracic vertebral bodies (Th4, 7, 10) using computed tomography (CT) before and 3 and 12 months after LT. The frequency of osteoporosis and factors associated with pre-LT osteoporosis and post-LT BMD loss were evaluated. The frequency of post-LT compression fracture and its associated factors were also analyzed. RESULTS: This study included 128 adult LT recipients. LT recipients had decreased BMD (151.8 ± 42.2 mg/mL) before LT compared with age-, sex-, and smoking index-matched controls (176.2 ± 35.7 mg/mL). The diagnosis of COPD was associated with pre-LT osteoporosis. LT recipients experience further BMD decline after transplantation, and the percentage of recipients classified as exhibiting osteoporosis increased from 20% at baseline to 43% at 12 months. Recipients who had been taking no or small doses of glucocorticoids before LT had rapid BMD loss after LT. Early bisphosphonate use (within 3 months) after LT attenuated BMD loss and decreased new-onset compression fracture. CONCLUSION: LT recipients are at high risk for BMD loss and compression fracture after LT. Early bisphosphonate use may decrease BMD loss and compression fracture.


Assuntos
Fraturas por Compressão , Osteoporose , Adulto , Humanos , Densidade Óssea , Estudos Transversais , Difosfonatos , Pulmão , Osteoporose/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Transplantados , Estudos Retrospectivos
5.
Surg Today ; 54(3): 266-274, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37540232

RESUMO

PURPOSE: To elucidate the clinical impact of pathogenic organism (PO) positivity early after transplantation, we evaluated the impact of perioperative airway POs on outcomes after living-donor lobar lung transplantation (LDLLT), where the graft airway is supposed to be sterile from a healthy donor. METHOD: A retrospective review of 67 adult LDLLT procedures involving 132 living donors was performed. Presence of POs in the recipients' airways was evaluated preoperatively and postoperatively in intensive-care units. RESULTS: POs were detected preoperatively in 13 (19.4%) recipients. No POs were isolated from the donor airways at transplantation. POs were detected in 39 (58.2%) recipients postoperatively; most were different from the POs isolated preoperatively. Postoperative PO isolation was not associated with short-term outcomes other than prolonged postoperative ventilation. The 5-year overall survival was significantly better in the PO-negative group than in the PO-positive group (89.1% vs. 63.7%, P = 0.014). In the multivariate analysis, advanced age (hazard ratio [HR]: 1.041 per 1-year increase, P = 0.033) and posttransplant PO positivity in the airway (HR: 3.684, P = 0.019) significantly affected the survival. CONCLUSIONS: The airways of the living-donor grafts were microbiologically sterile. PO positivity in the airway early after transplantation negatively impacted long-term outcomes.


Assuntos
Doadores Vivos , Transplante de Pulmão , Adulto , Humanos , Pulmão/cirurgia , Estudos Retrospectivos , Complicações Pós-Operatórias/epidemiologia
6.
Cancer Sci ; 114(12): 4521-4534, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37806311

RESUMO

Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Fator de Crescimento Transformador beta1 , Vimentina/metabolismo , Fator de Crescimento Transformador beta , Genes Homeobox , Macrófagos Associados a Tumor/metabolismo , Fator A de Crescimento do Endotélio Vascular , Linhagem Celular Tumoral , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Transição Epitelial-Mesenquimal , Caderinas/metabolismo , Neoplasias Pulmonares/metabolismo , Dedos de Zinco , Pulmão/patologia , Movimento Celular
7.
Am J Transplant ; 23(9): 1451-1454, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37149042

RESUMO

ABO-incompatible (ABO-I) living-donor lobar lung transplantation (LDLLT) was successfully performed in a 14-year-old girl who suffered from bronchiolitis obliterans due to graft-versus-host disease following hematopoietic stem cell transplantation. In the ABO-I LDLLT procedure, the blood type O patient received a right lower lobe donated from her blood type B father and a left lower lobe donated from her blood type O mother. Desensitization therapy, using rituximab, immunosuppressants, and plasmapheresis, was implemented for 3 weeks prior to transplantation to reduce the production of anti-B antibodies in the recipient and prevent acute antibody-mediated rejection after ABO-I LDLLT.


Assuntos
Doadores Vivos , Transplante de Pulmão , Humanos , Feminino , Adolescente , Resultado do Tratamento , Rituximab , Imunossupressores , Transplante de Pulmão/efeitos adversos
8.
Histopathology ; 80(4): 665-676, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34747513

RESUMO

AIMS: Idiopathic pleuroparenchymal fibroelastosis (PPFE) is a rare type of idiopathic interstitial pneumonia, and pathological PPFE is also observed in patients with secondary interstitial pneumonia. This study aimed to evaluate the pathological findings associated with radiological PPFE-like lesions and the clinical and morphological features of patients with pathological PPFE. METHODS AND RESULTS: We retrospectively reviewed the pathology of the explanted lungs from 59 lung transplant recipients with radiological PPFE-like lesions. Pathological PPFE lesions were identified in 14 patients with idiopathic disease and in 12 patients with secondary disease. Pathological PPFE was associated with previous pneumothorax, volume loss in the upper lobes, and a flattened chest. Patients with idiopathic disease and those with secondary disease with pathological PPFE had similar clinical, radiological and pathological findings, whereas fibroblastic foci were more common in patients with idiopathic disease, and patients with secondary disease more frequently showed alveolar septal thickening with elastosis or fibrosis. Post-transplantation survival did not differ between patients with idiopathic and secondary disease with pathological PPFE (log-rank; P = 0.57) and was similar between patients with idiopathic disease with pathological PPFE and those with idiopathic pulmonary fibrosis (IPF) (log-rank; P = 0.62). CONCLUSIONS: Not all patients with interstitial pneumonia with radiological PPFE-like lesions have pathological PPFE. Characteristic clinical features can suggest the presence of pathological PPFE, and idiopathic and secondary cases with pathological PPFE are similar except for fibroblastic foci in idiopathic cases and alveolar septal thickening with elastosis or fibrosis in secondary cases. Patients with pathological PPFE have a similar prognosis to those with IPF after transplantation.


Assuntos
Doenças Pulmonares Intersticiais/diagnóstico , Transplante de Pulmão , Tecido Parenquimatoso/patologia , Pleura/patologia , Adulto , Feminino , Fibrose/complicações , Humanos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Surg Today ; 52(6): 923-930, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34705111

RESUMO

PURPOSE: To investigate if electromagnetic navigation bronchoscopy (ENB) improves the diagnostic yield for peripheral lung lesions from that achieved by virtual bronchoscopy navigation (VBN). METHODS: This retrospective study compared the results of 100 ENB-transbronchial lung biopsies (TBLBs) with those of 50 VBN-TBLBs at a single institution. RESULTS: ENB improved the diagnostic yield significantly compared with VBN (64.0% for 19.4 ± 9.0 mm tumors vs. 46.0% for 27.6 ± 8.9 mm tumors; p < 0.0001). Irrespective of the bronchus sign, ENB was more favorable than VBN, with 81.0% (47/58) achieved by ENB vs. 60.0% (21/35) achieved by VBN in the presence of the positive bronchus sign (p = 0.0283), and 40.5% (17/42) achieved by ENB vs. 13.3% (2/15) achieved by VBN in the absence of the bronchus sign (p = 0.0431). Univariate analysis identified tumor size (p = 0.0048), amount of intravenous sedation (p = 0.0182), registration time (p = 0.0111), minimum distance to target (p = 0.0244), and the bronchus sign (p < 0.0001) as factors that affected the yield significantly for ENB. Multivariate analysis identified the bronchus sign (odds ratio 6.74; 95% CI 1.84-24.7) and the registration time (OR 1.01; 95% CI 1.00-1.02) as significant factors. CONCLUSIONS: Despite the bronchus sign being a significant factor, ENB improved the diagnostic yield of smaller lesions significantly, compared with VBN, regardless of the bronchus sign.


Assuntos
Broncoscopia , Neoplasias Pulmonares , Broncoscopia/métodos , Fenômenos Eletromagnéticos , Humanos , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Estudos Retrospectivos
10.
Respir Res ; 22(1): 116, 2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33882928

RESUMO

BACKGROUND: Waitlist mortality due to donor shortage for lung transplantation is a serious problem worldwide. Currently, the selection of recipients in Japan is mainly based on the registration order. Hence, scientific evidence for risk stratification regarding waitlist mortality is urgently needed. We hypothesized that patient-reported dyspnea and health would predict mortality in patients waitlisted for lung transplantation. METHODS: We analyzed factors related to waitlist mortality using data of 203 patients who were registered as candidates for lung transplantation from deceased donors. Dyspnea was evaluated using the modified Medical Research Council (mMRC) dyspnea scale, and the health status was determined with St. George's Respiratory Questionnaire (SGRQ). RESULTS: Among 197 patients who met the inclusion criteria, the main underlying disease was interstitial lung disease (99 patients). During the median follow-up period of 572 days, 72 patients died and 96 received lung transplantation (69 from deceased donors). Univariable competing risk analyses revealed that both mMRC dyspnea and SGRQ Total score were significantly associated with waitlist mortality (p = 0.003 and p < 0.001, respectively) as well as age, interstitial lung disease, arterial partial pressure of carbon dioxide, and forced vital capacity. Multivariable competing risk analyses revealed that the mMRC and SGRQ score were associated with waitlist mortality in addition to age and interstitial lung disease. CONCLUSIONS: Both mMRC dyspnea and SGRQ score were significantly associated with waitlist mortality, in addition to other clinical variables such as patients' background, underlying disease, and pulmonary function. Patient-reported dyspnea and health may be measured through multi-dimensional analysis (including subjective perceptions) and for risk stratification regarding waitlist mortality.


Assuntos
Dispneia/mortalidade , Pneumopatias/mortalidade , Transplante de Pulmão , Pulmão/fisiopatologia , Inquéritos e Questionários , Listas de Espera/mortalidade , Adulto , Dispneia/diagnóstico , Dispneia/fisiopatologia , Dispneia/cirurgia , Feminino , Nível de Saúde , Humanos , Japão , Pulmão/cirurgia , Pneumopatias/diagnóstico , Pneumopatias/fisiopatologia , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
11.
Transpl Int ; 34(11): 2192-2204, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34255889

RESUMO

This study aimed to analyze the influences of single nucleotide polymorphisms (SNPs) in Fc gamma receptor IIA (FCGR2A) on postoperative outcomes after lung transplantation (LTx). We enrolled 191 lung transplant recipients [80 undergoing living-donor lobar lung transplants (LDLLTs) and 111 undergoing deceased-donor lung transplants (DDLTs)] in this study. We identified SNPs in FCGR2A (131 histidine [H] or arginine [R]; rs1801274) and reviewed the infectious complication-free survival after ICU discharge. The SNPs in FCGR2A comprised H/H (n = 53), H/R (n = 24), and R/R (n = 3) in LDLLT and H/H (n = 67), H/R (n = 42), and R/R (n = 2) in DDLT. Recipients with H/H (H/H group) and those with H/R or R/R (R group) were compared in the analyses of infectious complications. In multivariate analyses, the R group of SNPs in FCGR2A was associated with pneumonia-free survival {HR: 2.52 [95% confidence interval (CI): 1.35-4.71], P = 0.004}, fungal infection-free survival [HR: 2.50 (95% CI: 1.07-5.84), P = 0.035], and cytomegalovirus infection-free survival [HR: 2.24 (95% CI: 1.07-4.69), P = 0.032] in LDLLT, but it was not associated with infectious complication-free survival in DDLT. Therefore, in LDLLT, more attention to infectious complications might need to be paid for LTx recipients with H/R or R/R than for those with H/H.


Assuntos
Transplante de Pulmão , Polimorfismo de Nucleotídeo Único , Humanos , Japão , Pulmão , Receptores de IgG , Estudos Retrospectivos , Transplantados
12.
Sleep Breath ; 25(1): 219-225, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32399697

RESUMO

PURPOSE: Poor quality of sleep is a common feature in patients with various lung diseases and affects their health-related quality of life (HRQL). We evaluated sleep quality and HRQL in patients on the waitlist for lung transplantation in Japan. METHODS: In this prospective study, patient-reported and physiological data were collected from patients newly registered on the waitlist for lung transplantation in Japan. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) and HRQL using the St. George's Respiratory Questionnaire (SGRQ). The frequency of poor sleep quality, correlations between sleep quality and various clinical parameters, and predictive factors of sleep quality were examined. RESULTS: Of 193 patients, the three most-frequent indications for lung transplantation were interstitial pneumonia (n = 96), pulmonary complications of hematopoietic stem cell transplantation (n = 25), and pulmonary hypertension (n = 17). Poor sleep quality (PSQI > 5) was observed in 102 patients (53%) and was significantly associated with worse Hospital Anxiety and Depression Score (HADS), worse SGRQ score, worse modified Medical Research Council Dyspnea score, and shorter 6-min walk distance. However, it was not associated with sex, pulmonary function, interstitial pneumonia, or arterial blood gas. Stepwise multiple regression analysis indicated that poor sleep quality was explained significantly by HADS anxiety (23%) and SGRQ Symptoms (10%). CONCLUSION: Poor sleep quality was found to be common among patients on the lung transplantation waitlist in Japan. The two most significant factors responsible for impaired sleep quality were anxiety and respiratory symptoms. Additional care should be taken to ensuring a better quality of sleep for such patients.


Assuntos
Ansiedade/epidemiologia , Pneumopatias/epidemiologia , Transplante de Pulmão/estatística & dados numéricos , Qualidade de Vida , Transtornos Respiratórios/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Adulto , Feminino , Humanos , Japão/epidemiologia , Pneumopatias/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Listas de Espera
13.
Thorac Cardiovasc Surg ; 69(1): 101-108, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-31499540

RESUMO

BACKGROUND: Primary pulmonary sarcoma (PPS) is a rare malignant lung neoplasm, and there is very little medical evidence about treatment of PPS. The aim of this study is to clarify the clinical characteristics and therapeutic outcome of patients who underwent surgical resection for PPS. METHODS: We retrospectively reviewed the records of patients who underwent surgical resection for PPS in our institution between 1995 and 2014. Cases who only underwent biopsy were excluded. RESULTS: A total of 24 patients (18 males, 6 females), with a median age of 60 (interquartile range: 44-67) years, were analyzed. The surgical procedures performed in these patients were pneumonectomy (n = 10), lobectomy (n = 11), and wedge resection (n = 3). Complete resection was achieved in 16 patients. The pathological stages (tumor, node, metastases lung cancer classification, 8th edition) of the patients were I (n = 4), II (n = 12), III (n = 2), and IV (n = 5), and there were four cases of lymph node metastasis. The 5-year overall survival rate of the patients was 50% (95% confidence interval [CI]: 29-72). Adverse prognostic factors for overall survival were incomplete resection (hazard ratio [HR]: 4.4, 95% CI: 2.1-42), advanced pathological stage (HR 14, 95% CI: 2.8-66), higher pathological grade (HR 4.5, 95% CI: 1.2-17), and tumor size ≥ 7 cm (HR 4.7, 95% CI: 1.1-21). CONCLUSIONS: Our series of PPS revealed that incomplete resection, advanced pathological stage, higher pathological grade, and tumor size were unfavorable factors for long-term survival.


Assuntos
Neoplasias Pulmonares/cirurgia , Pneumonectomia , Sarcoma/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Pneumonectomia/efeitos adversos , Pneumonectomia/mortalidade , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Sarcoma/mortalidade , Sarcoma/secundário , Fatores de Tempo , Resultado do Tratamento , Carga Tumoral
14.
Surg Today ; 50(9): 1049-1055, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32166496

RESUMO

PURPOSE: We investigated the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to evaluate programmed cell death ligand-1 (PD-L1) expression in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A retrospective chart review of patients who underwent EBUS-TBNA between April 2017 and April 2019 was conducted. Among patients diagnosed with NSCLC, we investigated the rate of successful evaluation of tumor PD-L1 expression, compared the relevant factors between patients with evaluable and those with unevaluable PD-L1 expression, and examined the response to immune checkpoint inhibitors (ICIs) after EBUS-TBNA. RESULTS: Of the 40 patients assessed, 32 (80%) had evaluable PD-L1 expression. Patients with evaluable PD-L1 expression were older than those with unevaluable PD-L1 expression (p = 0.017), and we noted a tendency for a larger diameter of the biopsied lymph node (p = 0.12). The response rate to ICIs was 100% in patients with a tumor proportion score (TPS) ≥ 50%, 33% in those with a TPS 1-49%, and 0% in those with a TPS < 1%. CONCLUSION: The diagnostic yield of EBUS-TBNA to evaluate PD-L1 expression in advanced NSCLC appeared acceptable in association with relevant clinical outcomes after treatment with ICIs. A further prospective study with a larger sample size is required to confirm our findings.


Assuntos
Apoptose/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Brônquios , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Expressão Gênica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfonodos/metabolismo , Linfonodos/patologia , Metástase Linfática/diagnóstico , Metástase Linfática/genética , Mediastino , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
15.
Carcinogenesis ; 40(2): 324-334, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-30698677

RESUMO

CD26/dipeptidyl peptidase 4 (DPP4) is a transmembrane protein which is expressed by various malignant cells. We found that the expression of CD26/DPP4 was significantly higher in lung adenocarcinoma samples in our own patient cohort compared to normal lung tissue. We therefore hypothesize that the inhibition of CD26/DPP4 can potentially suppress lung cancer growth. The CD26/DPP4 inhibitor vildagliptin was employed on Lewis Lung Carcinoma (LLC) cell line and a human lung adenocarcinoma (H460) cell line. Two weeks after subcutaneous injection of tumor cells into C57BL/6 and CD1/nude mice, the size of LLC and H460 tumors was significantly reduced by vildagliptin. Immunohistochemically, the number of macrophages (F4/80+) and NK cells (NKp46+) was significantly increased in vildagliptin-treated tumor samples. Mechanistically, we found in vitro that lung cancer cell lines expressed increased levels of surfactant protein upon vildagliptin treatment thereby promoting the pro-inflammatory activity of macrophages. By the depletion of macrophages with clodronate and by using NK cell deficient (IL-15-/-) mice, tumors reversed to the size of controls, suggesting that indeed macrophages and NK cells were responsible for the observed tumor-suppressing effect upon vildagliptin treatment. FACS analysis showed tumor-infiltrating NK cells to express tumor necrosis-related apoptosis-inducing ligand (TRAIL) which induced the intra-cellular stress marker γH2AX. Accordingly, we found upregulated γH2AX in vildagliptin-treated tumors and TRAIL-treated cell lines. Moreover, the effect of vildagliptin-mediated enhanced NK cell cytotoxicity could be reversed by antagonizing the TRAIL receptor. Our data provide evidence that the CD26/DPP4-inhibitor vildagliptin reduces lung cancer growth. We could demonstrate that this effect is exerted by surfactant-activated macrophages and NK cells that act against the tumor via TRAIL-mediated cytotoxicity.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Vildagliptina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Hipoglicemiantes/farmacologia , Células Matadoras Naturais/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células RAW 264.7
16.
J Surg Res ; 233: 74-81, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502290

RESUMO

BACKGROUND: Human lung transplantation has evolved to an established treatment for pulmonary diseases in their end stages; however, the long-term outcome is worse when compared to all other solid transplantable organs. The major reason for this unfavorable outcome is rejection, either in its acute or chronic form, the latter termed as chronic lung allograft dysfunction. METHODS: A systematic review search was performed. RESULTS: One of the most important immune cells responsible for rejection are T cells. Beside alloreactive CD8+ T cells, CD4+ T cells play a key role during the evolvement of allograft rejection. Certain subsets of these allograft CD4+ T cells have been identified which have been shown to exert either transplant-protective or transplant-injuring properties. These effects have been proven in various experimental models, mainly in rats and mice, and allowed for the gain of important insights into these proinflammatory and anti-inflammatory characteristics including their targetability: while the subsets Th1, Th17, Th22, and Tfh cells have been shown to act in a rather proinflammatory way, Tregs, Th2, and Th9 subsets exert anti-inflammatory effects. Chronic airway obstruction is mainly induced by IL17 as shown across models. CONCLUSIONS: This review shall summarize and provide an overview of the current evidence about the role and effects of proinflammatory and anti-inflammatory CD4-+ T helper cell subsets during lung allograft rejection in experimental rodent models.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Pulmão/efeitos adversos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Modelos Animais de Doenças , Macaca fascicularis , Camundongos , Ratos
17.
Lung ; 197(2): 217-226, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30739218

RESUMO

PURPOSE: Acute allograft rejection after lung transplantation remains an unsolved hurdle. The pathogenesis includes an inflammatory response during and after transplantation. Ropivacaine, an amide-linked local anesthetic, has been shown to attenuate lung injury due to its anti-inflammatory effects. We hypothesized that the drug would also be able to attenuate acute rejection (AR) after allogeneic lung transplantation. METHODS: Allogeneic, orthotopic, single left lung transplantation was performed between BALB/c (donors) and C57BL/6 (recipients) mice. Prior to explantation, lungs were flushed with normal saline with or without ropivacaine (final concentration 1 µM). Plasma levels of tumor necrosis factor-α and interleukins - 6 and - 10 were measured 3 h after transplantation by ELISA. Lung function was assessed on postoperative day five and transplanted lungs were analyzed using histology (AR), immunohistochemistry (infiltrating leukocytes) and Western blot (phosphorylation and expression of Src and caveolin-1). RESULTS: Ropivacaine pre-treatment significantly reduced AR scores (median 3 [minimum-maximum 2-4] for control vs. 2 [1-2] for ropivacaine, p < 0.001) and plasma levels of tumor necrosis factor-α (p = 0.01) compared to control, whereas plasma concentrations of interleukin - 6 (p = 0.008) and - 10 (p < 0.001) were increased by ropivacaine. The number of T-lymphocytes infiltrating the transplanted lung was attenuated (p = 0.02), while no differences in macrophage or B-lymphocyte numbers could be observed after ropivacaine pre-treatment. Caveolin-1 phosphorylation in ropivacaine-treated lungs was diminished (p = 0.004). CONCLUSIONS: Pre-treatment of donor lungs with the local anesthetic ropivacaine diminished histological signs of AR after orthotopic left lung transplantation in mice, most likely due to reduced infiltration of T-lymphocytes into the graft.


Assuntos
Anestésicos Locais/farmacologia , Anti-Inflamatórios/farmacologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Pulmão/efeitos adversos , Pulmão/efeitos dos fármacos , Ropivacaina/farmacologia , Doença Aguda , Aloenxertos , Animais , Caveolina 1/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Mediadores da Inflamação/sangue , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fosforilação , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Fatores de Tempo
18.
J Surg Res ; 214: 270-277, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28624055

RESUMO

BACKGROUND: Although sevoflurane (Sevo) had been shown to ameliorate posttransplant injury in various organs, data available are inconsistent, particularly in the context of lung transplantation (Tx). We here investigated if preconditioning by Sevo can protect from posttransplant injury regarding both, primary graft dysfunction (PGD) and acute rejection (AR) after experimental lung Tx, thereby focusing on two important clinical outcome parameters. MATERIALS AND METHODS: Three experimental approaches were used: (1) BALB/c mice were preconditioned for 2 h with Sevo or a fentanyl cocktail (Control; n = 10); (2) syngeneic (Syn) mouse lung Tx (C57BL/6) with a Sevo-preconditioned graft followed by 18 h storage to mimic PGD (Syn-Tx, n = 12) versus controls (fentanyl cocktail); and (3) allogeneic (Allo) Tx (BALB/c, donor; C57BL/6, recipient) to mimic AR (Allo-Tx, n = 12) versus controls (fentanyl cocktail). Syn-Tx grafts were harvested on Day 1, Allo-Tx grafts on Day 3 and analyzed for histology, immunohistochemistry, blood gas analysis, and inflammatory cytokines (enzyme-linked immunosorbent assay or reverse transcription polymerase chain reaction). RESULTS: Evaluating the preconditioning effect of Sevo only showed significantly better oxygenation (P = 0.03) and a tendency toward lower levels of lung tissue messenger RNA for tumor necrosis factor-α. In Syn-Tx recipients, the Sevo group had histologically a tendency toward an attenuation of PGD and showed significantly lower levels of interleukin 6 (P = 0.01) in plasma, but higher levels of interleukin 10 (P < 0.01) in lungs. Allo-Tx grafts in Sevo Tx recipients showed attenuated AR with histologically significantly lower rejection scores (P = 0.03), fewer classical macrophages (F4/80+; P < 0.01), but more anti-inflammatory activated macrophages (M2, CD206+; P < 0.01). Functionally, the Sevo group had a tendency toward improved oxygenation. CONCLUSIONS: We demonstrated that Sevo preconditioning has protective effects on lung transplants in both, PGD and AR. The observed amelioration may be attributed to suppressed inflammatory cytokines during PGD and the induction of alternatively activated macrophages during AR. These promising data could set the base for using Sevo preconditioning in donor lungs for a human trial.


Assuntos
Rejeição de Enxerto/prevenção & controle , Transplante de Pulmão , Éteres Metílicos/uso terapêutico , Cuidados Pré-Operatórios/métodos , Disfunção Primária do Enxerto/prevenção & controle , Substâncias Protetoras/uso terapêutico , Animais , Esquema de Medicação , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Sevoflurano , Resultado do Tratamento
19.
J Surg Res ; 218: 341-347, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28985871

RESUMO

BACKGROUND: We have shown the beneficial effects of N-acetylcysteine (NAC) on posttransplant lung function, when both donor and recipient were pretreated intravenously. However, systemic treatment of multiorgan donors may not be clinically relevant. Thus, we hypothesized that ex vivo treatment of donors with nebulized NAC would be adequate to prevent from ischemia-reperfusion injury after lung transplantation. METHODS: Lungs were retrieved from domestic pigs and stored at 4°C for 24 h followed by 2 h of ex vivo lung perfusion (EVLP) to administer 50 mg/kg of NAC via nebulization in the NAC group (n = 6). The control group received nebulized saline (n = 5). Left lungs were transplanted and isolated at 1 h of reperfusion by occluding the right main bronchus and pulmonary artery, followed by 5 h of observation. Physiological data during EVLP and after reperfusion were recorded. Inflammatory response, markers of oxidative stress, and microscopic lung injury were analyzed. RESULTS: There was a trend toward better oxygenation throughout reperfusion period in the treatment group, which was accompanied by inhibited inflammatory response related to reduction in myeloperoxidase activity during EVLP and nuclear factor-κB activation at the end of reperfusion. CONCLUSIONS: Ex vivo treatment of donor lungs with inhaled NAC reduced inflammatory response via its antioxidant activity in experimental porcine lung transplantation.


Assuntos
Acetilcisteína/administração & dosagem , Sequestradores de Radicais Livres/administração & dosagem , Transplante de Pulmão , Disfunção Primária do Enxerto/prevenção & controle , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Suínos
20.
J Magn Reson Imaging ; 44(5): 1091-1098, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27185097

RESUMO

PURPOSE: To investigate the value of magnetization transfer (MT) measurements for assessment of acute rejection (AR) in a murine lung transplantation model. MATERIALS AND METHODS: Thirty mice including 15 C57BL/10 mice serving as donors and 15 C57BL/6 mice as recipients were examined in this study. MT imaging datasets were acquired on a 4.7 Tesla small animal MR scanner using a three-dimensional zero echo time sequence with a Gaussian-shaped MT prepulse with 1000° or 3000° flip angle and systematic variation of off-resonance frequencies between 1000 and 15,000 Hz. After image acquisition, the images were qualitatively assessed, magnetization transfer ratio (MTR) values were calculated and lungs were taken for histologic examination including staining with hematoxylin/eosin, Masson's trichrome (collagen), and α-smooth muscle (fibroproliferative tissue) staining. RESULTS: Lung transplantation was successfully performed in all 15 mice. All animals showed AR characterized by the presence of interstitial mononuclear cell infiltrates. There were significant differences of MTR in lungs with and without AR (P = 0.007). With a flip angle of 1000°, the largest differences between the MTR of healthy lungs and lungs with AR were observed for an off-resonance frequency of 10,000 Hz (difference MTR 1.80%) and 15,000 Hz (1.91%) and with a flip angle of 3000° at off-resonance frequencies of 6000 Hz (1.37%) and 8000 Hz (1.70%). CONCLUSION: MT measurements may provide a tool for the quantitative assessment of AR. J. Magn. Reson. Imaging 2016;44:1091-1098.


Assuntos
Rejeição de Enxerto/diagnóstico por imagem , Rejeição de Enxerto/etiologia , Transplante de Pulmão/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/cirurgia , Imageamento por Ressonância Magnética/métodos , Cirurgia Assistida por Computador/métodos , Doença Aguda , Animais , Diagnóstico Precoce , Estudos de Viabilidade , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do Tratamento
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