RESUMO
OBJECTIVES: The implementation of the Lung Allocation Score (LAS) in the Eurotransplant international collaborative framework decreased waiting list mortality, but organ shortage remains a significant problem. Transplantation of two single lungs from one donor into two recipients (lung twinning) may decrease waiting list mortality. We sought to analyze if this strategy can lead to an acceptable intermediate-term outcome. METHODS: Since the LAS-implementation we performed 32 paired single-lung transplantations from 16 postmortal donors. Data and outcome were analyzed retrospectively comparing recipients receiving the first lung (first twins) with recipients receiving the second lung (second twins), left versus right transplantation and restrictive versus obstructive disease. RESULTS: Survival at one year was 81% and 54% at five years. Veno-venous ECMO had been successfully used as bridge-to-transplant in three patients with ECMO-explantation immediately after surgery. Bronchial anastomotic complications were not observed in any patient. First twins and second twins exhibited similar survival (p = 0.82) despite higher LAS in first twins (median 45 versus 34, p < 0.001) and longer cold ischemic time in second twins (280 ± 83 vs. 478 ± 125 min, p < 0.001). Survival of left and right transplantation was similar (p = 0.45) with similar best post-transplant FEV1 (68 ± 15% versus 62 ± 14%, p = 0.26). Survival was similar in restrictive and obstructive disease (p = 0.28) with better post-transplant FEV1 (70 ± 15% versus 57 ± 11%, p = 0.02) in restrictive disease. CONCLUSIONS: Performing two single-lung transplantations from one donor can be performed safely with encouraging intermediate-term outcome and good functional capacity. Lung twinning maximizes the donor pool and may help to overcome severe organ shortage. CLINICAL TRIALS: This research is not a clinical trial. Thus no registration details will be provided.
Assuntos
Pneumopatias , Transplante de Pulmão , Humanos , Estudos Retrospectivos , Pulmão/cirurgia , Doadores de TecidosRESUMO
Lung cancer is the leading cause of cancer-related deaths in the western world. Squamous cell carcinoma is one of the most common histological subtypes of this malignancy. For squamous cell carcinoma of the lung (LSCC), prognostic and predictive markers still are largely missing. In a previous study, we were able to show that the expression of THSD7A shows an association with unfavorable prognostic parameters in prostate cancer. There is also a link to a high expression of FAK. There is incidence that SCARA5 might be the downstream gene of THSD7A. Furthermore, there is evidence that SCARA5 interacts with FAK. We were interested in the role of SCARA5 as a potential biomarker in LSCC. Furthermore, we wanted to know whether SCARA5 expression is linked to THSD7A positivity and to the expression level of FAK. For this reason, we analyzed 101 LSCC tumors by immunohistochemistry. Tissue microarrays were utilized. No significant association was found between SCARA5 expression and overall survival or clinicopathological parameters. There was also no significant association between THSD7A positivity and SCARA5 expression level. Moreover, no significant association was found between FAK expression level and SCARA5 expression level. SCARA5 seems not to play a major role as a biomarker in squamous cell carcinoma of the lung.
Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Masculino , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/genética , Pessoa de Meia-Idade , Idoso , Feminino , Prognóstico , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Idoso de 80 Anos ou mais , Imuno-Histoquímica , Receptores Depuradores Classe ARESUMO
BACKGROUND: Volatile propofol can be measured in exhaled air and correlates to plasma concentrations with a time delay. However, the effect of single-lung ventilation on exhaled propofol is unclear. Therefore, our goal was to evaluate exhaled propofol concentrations during single-lung compared to double-lung ventilation using double-lumen tubes. METHODS: In a first step, we quantified adhesion of volatile propofol to the inner surface of double-lumen tubes during double- and single-lumen ventilation in vitro. In a second step, we enrolled 30 patients scheduled for lung surgery in two study centers. Anesthesia was provided with propofol and remifentanil. We utilized left-sided double-lumen tubes to separately ventilate each lung. Exhaled propofol concentrations were measured at 1-min intervals and plasma for propofol analyses was sampled every 20 min. To eliminate the influence of dosing on volatile propofol concentration, exhalation rate was normalized to plasma concentration. RESULTS: In-vitro ventilation of double-lumen tubes resulted in increasing propofol concentrations at the distal end of the tube over time. In vitro clamping the bronchial lumen led to an even more pronounced increase (Δ AUC +62%) in propofol gas concentration over time. Normalized propofol exhalation during lung surgery was 31% higher during single-lung compared to double-lung ventilation. CONCLUSION: During single-lung ventilation, propofol concentration in exhaled air, in contrast to our expectations, increased by approximately one third. However, this observation might not be affected by change in perfusion-ventilation during single-lung ventilation but rather arises from reduced propofol absorption on the inner surface area of the double-lumen tube. Thus, it is only possible to utilize exhaled propofol concentration to a limited extent during single-lung ventilation. REGISTRATION OF CLINICAL TRIAL: DRKS-ID DRKS00014788 (www.drks.de).
Assuntos
Anestesia , Ventilação Monopulmonar , Propofol , Humanos , Ventilação Monopulmonar/métodos , Expiração , Remifentanil , Intubação Intratraqueal/métodosRESUMO
Lung cancer is the leading cause of cancer-related deaths in the western world, with squamous cell carcinoma being one of the most common histological subtypes. Prognostic and predictive markers are still largely missing for squamous cell carcinoma of the lung (LSCC). Several studies indicate that THSD7A might at least play a role in the prognosis of different tumors. FAK seems to play an important role in lung cancer and is discussed as a potential therapeutic target. In addition, there is evidence that FAK-dependent signaling pathways might be affected by THSD7A. For that reason, we investigated the role of THSD7A as a potential tumor marker in LSCC and whether THSD7A expression has an impact on the expression level of FAK. A total of 101 LSCCs were analyzed by immunohistochemistry using tissue microarrays. THSD7A positivity was associated with poor overall survival in female patients and showed a relation to high FAK expression in this subgroup. To our knowledge, we are the first to report these correlations in lung cancer. The results might be proof of the assumed activation of FAK-dependent signaling pathways by THSD7A and that as a membrane-associated protein, THSD7A might serve as a putative therapeutic target in LSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Laríngeas , Neoplasias Pulmonares , Humanos , Feminino , Carcinoma de Células Escamosas/patologia , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Imuno-Histoquímica , Transdução de Sinais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Laríngeas/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
BACKGROUND: The summer semester 2020, had to be restructured due to the SARS-CoV-2 pandemic and the associated contact restrictions. Here, for the first time, the established lectures in lecture halls and small group seminars could not be conducted in presence as usual. A possible tool for the implementation of medical teaching, offers the use of eLearning, online webinars and learning platforms. At present it is unclear how the SARS-CoV-2 pandemic will affect surgical teaching, how digitization will be accepted by students, and how virtual teaching can be expanded in the future. METHODS: The teaching, which was previously delivered purely through face-to-face lectures, was completely converted to digital media. For this purpose, all lectures were recorded and were available to students on demand. The seminars were held as a twice a week occurring online webinar. The block internship was also conducted as a daily online webinar and concluded with an online exam at the end. At the end of the semester, a survey of the students was carried out, which was answered by n = 192 students with an anonymized questionnaire. The questionnaire inquires about the previous and current experience with eLearning, as well as the possibility of a further development towards a purely digital university. RESULTS: There were n = 192 students in the study population. For 88%, the conversion of classes to web-based lectures represented their first eLearning experience. For 77% of all students, the digitization of teaching led to a change in the way they prepare for class. 73% of the participating students are of the opinion that eLearning lectures should continue to be offered. 54% of the students felt that eLearning lectures made more sense than face-to-face lectures. A purely virtual university could be imagined by 41% of the students. CONCLUSION: The conversion of teaching represented the first contact with eLearning for most students. Overall, the eLearning offering was experienced as positive. Due to the new teaching structure, the way of learning had already changed during the semester. Based on the new eLearning content, the already existing formats can be further expanded in the future. Nevertheless, it turned out that the practical-surgical contents and skills cannot be adequately represented by purely online offers; for this, the development of hybrid practice-oriented teaching concepts is necessary.
Assuntos
COVID-19 , COVID-19/epidemiologia , Hospitais Universitários , Humanos , Internet , Pandemias , SARS-CoV-2 , EnsinoRESUMO
It is unknown if solid organ transplant recipients are at higher risk for severe COVID-19. The management of a lung transplantation (LTx) program and the therapeutic strategies to adapt the immunosuppressive regimen and antiviral measures is a major issue in the COVID-19 era, but little is known about worldwide practice. We sent out to 180 LTx centers worldwide in June 2020 a survey with 63 questions, both regarding the management of a LTx program in the COVID-19 era and the therapeutic strategies to treat COVID-19 LTx recipients. We received a total of 78 responses from 15 countries. Among participants, 81% declared a reduction of the activity and 47% restricted LTx for urgent cases only. Sixteen centers observed deaths on waiting listed patients and eight centers performed LTx for COVID-19 disease. In 62% of the centers, COVID-19 was diagnosed in LTx recipients, most of them not severe cases. The most common immunosuppressive management included a decreased dose or pausing of the cell cycle inhibitors. Remdesivir, hydroxychloroquine, and azithromycin were the most proposed antiviral strategies. Most of the centers have been affected by the COVID-19 pandemic and proposed an active therapeutic strategy to treat LTx recipients with COVID-19.
Assuntos
COVID-19/diagnóstico , Transplante de Pulmão , Pandemias , COVID-19/terapia , Humanos , Imunossupressores/uso terapêutico , Fatores de Risco , Transplantados , Listas de EsperaRESUMO
OBJECTIVE: Pulmonary endarterectomy (PEA) is the only causative, but demanding treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH). We analyzed our results with PEA to evaluate the learning curve. METHODS: Consecutive 499 patients who underwent PEA between 1995 and 2014 were divided into two groups according to the temporal order: early cohort (n = 200, December 1995-March 2006), and late cohort (n = 299, March 2006-December 2014). We assessed perioperative outcomes after PEA as compared between the early and the late cohort also in propensity-score-matched cohorts. RESULTS: Age at the surgery was older in the late cohort (p = 0.042). Preoperative mean pulmonary artery pressure (mPAP) was 46.8 ± 11.0 mm Hg in the early cohort and 43.5 ± 112.7 mm Hg in the late cohort (p = 0.0035). The in-hospital mortality in the early and late cohorts was 14.0% (28/200) and 4.7% (14/299), respectively (p = 0.00030). The duration of circulatory arrest (CA) became much shorter in the late cohort (42.0 ± 20.5 min in the early and 24.2 ± 11.6 min in the late cohort, respectively, p < .0001). In matched cohorts, the in-hospital mortality showed no significant difference (8.7% in the early cohort and 5.2% in the late cohort, < 0.0001). The CA duration, however, was still shorter in the late cohort (p <0.0001). CONCLUSIONS: Over time, older patients have been accepted for surgery, more patients were operated for lesser severity of CTEPH. Duration of CA and mortality decreased even beyond the first 200 patients, indicating a long learning curve.
Assuntos
Competência Clínica , Endarterectomia , Hipertensão Pulmonar/cirurgia , Curva de Aprendizado , Artéria Pulmonar/cirurgia , Embolia Pulmonar/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Doença Crônica , Endarterectomia/efeitos adversos , Endarterectomia/mortalidade , Feminino , Mortalidade Hospitalar , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/mortalidade , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/terapia , Artéria Pulmonar/fisiopatologia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidade , Embolia Pulmonar/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are associated with acute and chronic bacterial infections of the lung. Excessive differentiation of basal cells to mucus-producing goblet cells can result in mucus hyperproduction and loss of mucociliary clearance in the airways of CF and COPD patients. Here, we aimed to investigate the effect of pathogen-associated molecular patterns (PAMPs) on the differentiation of human 3D bronchospheres. Primary human bronchial epithelial cells (HBECs) were differentiated to bronchospheres in the presence of bacterial flagellin and LPS and the synthetic Toll-like receptor (TLR) ligands Pam3CSK4 (TLR-2) and polyinosinic:polycytidylic acid (pIC, TLR-3). Electron and fluorescence microscopy showed that the differentiation of bronchospheres associated with the formation of lumina and appearance of cilia within 30 days after seeding. Incubation with flagellin resulted in a decreased formation of lumina and loss of cilia formation. Incubation with Pam3CSK, pIC, and LPS did not significantly affect formation of lumina and ciliation. Mucus production was strongly increased in response to flagellin and, to a lesser degree, in response to Pam3CSK4. Our results indicate that bacterial factors, such as flagellin, drive the differentiation of the respiratory epithelium towards mucus hyperproduction.
Assuntos
Brônquios/metabolismo , Flagelina/metabolismo , Depuração Mucociliar/fisiologia , Muco/metabolismo , Organoides/metabolismo , Mucosa Respiratória/metabolismo , Brônquios/microbiologia , Células Cultivadas , Flagelina/administração & dosagem , Humanos , Muco/microbiologia , Organoides/microbiologia , Organoides/ultraestrutura , Mucosa Respiratória/microbiologia , Mucosa Respiratória/ultraestruturaRESUMO
The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post-transplant outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X-rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2 /FiO2 ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long-term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.
Assuntos
Transplante de Pulmão , Transplantados , Adulto , Humanos , Pulmão , Estudos Prospectivos , Estudos Retrospectivos , Doadores de Tecidos , Resultado do TratamentoRESUMO
The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions.
Assuntos
Ensaios Clínicos como Assunto/métodos , Interpretação Estatística de Dados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Ensaios Clínicos como Assunto/estatística & dados numéricos , Determinação de Ponto Final , Seguimentos , Humanos , Projetos de Pesquisa , Avaliação da Tecnologia Biomédica/métodos , Fatores de TempoRESUMO
Both Eurotransplant (ET) and the US use the lung allocation score (LAS) to allocate donor lungs. In 2015, the US implemented a new algorithm for calculating the score while ET has fine-tuned the original model using business rules. A comparison of both models in a contemporary patient cohort was performed. The rank positions and the correlation between both scores were calculated for all patients on the active waiting list in ET. On February 6th 2017, 581 patients were actively listed on the lung transplant waiting list. The median LAS values were 32.56 and 32.70 in ET and the US, respectively. The overall correlation coefficient between both scores was 0.71. Forty-three per cent of the patients had a < 2 point change in their LAS. US LAS was more than two points lower for 41% and more than two points higher for 16% of the patients. Median ranks and the 90th percentiles for all diagnosis groups did not differ between both scores. Implementing the 2015 US LAS model would not significantly alter the current waiting list in ET.
Assuntos
Transplante de Pulmão , Seleção de Pacientes , Algoritmos , Estudos Transversais , Europa (Continente) , Humanos , Pessoa de Meia-Idade , Estados UnidosRESUMO
RATIONALE: Patients with interstitial lung disease and acute respiratory failure have a poor prognosis especially if mechanical ventilation is required. OBJECTIVES: To investigate the outcome of patients with acute respiratory failure in interstitial lung disease undergoing extracorporeal membrane oxygenation (ECMO) as a bridge to recovery or transplantation. METHODS: This was a retrospective analysis of all patients with interstitial lung disease and acute respiratory failure treated with or without ECMO from March 2012 to August 2015. MEASUREMENTS AND MAIN RESULTS: Forty patients with interstitial lung disease referred to our intensive care unit for acute respiratory failure were included in the analysis. Twenty-one were treated with ECMO. Eight patients were transferred by air from other hospitals within a range of 320 km (linear distance) for extended intensive care including the option of lung transplant. In total, 13 patients were evaluated, and eight were finally found to be suitable for lung transplantation from an ECMO bridge. Four patients from external hospitals were de novo listed during acute respiratory failure. Six patients underwent lung transplant, and two died on the waiting list after 9 and 63 days on ECMO, respectively. A total of 14 of 15 patients who did not undergo lung transplantation (93.3%) died after 40.3 ± 27.8 days on ECMO. Five out of six patients (83.3%) receiving a lung transplant could be discharged from hospital. CONCLUSIONS: ECMO is a lifesaving option for patients with interstitial lung disease and acute respiratory failure provided they are candidates for lung transplantation. ECMO is not able to reverse the poor prognosis in patients that do not qualify for lung transplantation.
Assuntos
Oxigenação por Membrana Extracorpórea/métodos , Doenças Pulmonares Intersticiais/terapia , Transplante de Pulmão , Insuficiência Respiratória/terapia , Doença Aguda , Idoso , Estudos de Casos e Controles , Doenças do Tecido Conjuntivo/complicações , Bases de Dados Factuais , Feminino , Humanos , Pneumonias Intersticiais Idiopáticas/mortalidade , Pneumonias Intersticiais Idiopáticas/terapia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/mortalidade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Reducing hyperinflated areas in chronic obstructive pulmonary disease, either surgically or endoscopically, leads to improvement of functional parameters. It is unclear if bilateral treatment with endobronchial valves (EBV) aiming at total lobar occlusion is beneficial. The aim of this study was to assess the results after staged bilateral endoscopic treatment with EBV. This is a retrospective analysis of patients with severe airflow obstruction, who were treated bilaterally with EBV in two stages, aiming at subsequent atelectasis. Pre- and postintervention lung function parameters, the 6-minute walk test (6-MWT), complications, and follow-up were recorded. Sixteen patients were treated bilaterally in two stages. There was an overall improvement in lung function from baseline to second-treatment follow-up with an increase in FEV1 (23.57-29.21% of predicted) and a decrease in residual volume (299.21-240.10% of predicted) and total lung capacity (140.78-128.71% of predicted). The 6-MWT improved up to 54 m. After each procedure, 9 of 16 patients (56.25%) developed an atelectasis of the target lobe. Overall, pneumothorax occurred in 8 of 32 procedures (25%). No patient died. Patients benefitted from the first EBV treatment. The second treatment did not lead to marked improvements compared to the first treatment. Bilateral lung volume reduction with valves is possible; however, the current results seem not to justify bilateral valve treatment as a routine approach.
Assuntos
Broncoscopia/métodos , Pneumonectomia/métodos , Pneumotórax Artificial/métodos , Implantação de Prótese/métodos , Enfisema Pulmonar/cirurgia , Idoso , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Enfisema Pulmonar/fisiopatologia , Volume Residual , Estudos Retrospectivos , Índice de Gravidade de Doença , Capacidade Pulmonar Total , Resultado do Tratamento , Capacidade Vital , Teste de CaminhadaRESUMO
BACKGROUND: Patients with a forced expiratory volume in 1 s (FEV1) below 20% of the predicted normal values (pred.) and either homogeneous emphysema or low diffusing capacity for carbon monoxide (DLCO) have a high risk for adverse events including death when undergoing surgical lung volume reduction. OBJECTIVES: We hypothesized that selected patients can benefit from endoscopic lung volume reduction (eLVR) despite a very low FEV1. METHODS: This study is a retrospective analysis of consecutive patients with severe airflow obstruction, an FEV1 ≤20% of pred., and low DLCO who were treated by eLVR with endobronchial valves (EBV) between June 2012 and January 2015. Pre- and postinterventional lung function parameters, the 6-min walking test (6-MWT) distance, adverse events, and follow-up were recorded. RESULTS: In 20 patients, there was an overall improvement in lung function with an increase in FEV1 (16.97-21.03% of pred.) and a decrease in residual volume (322-270% of pred.) and total lung capacity (144-129.06% of pred.). The 6-MWT distance improved (from 239 ± 77 to 267± 97 m overall, and from 184 ± 50 to 237 ± 101 m if patients developed an atelectasis of the target lobe). Pneumothorax occurred in 5 of the 20 patients (25%). 30-day mortality was 0%, and all patients survived to discharge. CONCLUSIONS: The patients benefitted moderately from EBV treatment despite an initially low FEV1. Some patients improved remarkably. EBV treatment in patients with an FEV1 ≤20% of pred. is generally feasible and safe. The greatest risk is pneumothorax with prolonged chest tube duration.
Assuntos
Broncoscopia/métodos , Pneumonectomia/métodos , Implantação de Prótese/métodos , Enfisema Pulmonar/cirurgia , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Pneumotórax/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Enfisema Pulmonar/fisiopatologia , Volume Residual , Estudos Retrospectivos , Índice de Gravidade de Doença , Capacidade Pulmonar Total , Resultado do Tratamento , Teste de CaminhadaRESUMO
Bacterial pathogens are a leading cause of lung infections and contribute to acute exacerbations in patients with chronic respiratory diseases. The innate immune system of the respiratory tract controls and prevents colonization of the lung with bacterial pathogens. Forkhead box transcription factor family O (FOXO) transcription factors are key regulators of cellular metabolism, proliferation, and stress resistance. In this study, our aim was to investigate the role of FOXO transcription factors in innate immune functions of respiratory epithelial cells. We show that bacterial pathogens potently activate FOXO transcription factors in cultured human respiratory epithelial cells in vitro. Infection of mice with bacterial pathogens resulted in the activation of FOXO transcription factors in alveolar and bronchial epithelial cells in vivo. Active FOXO was also detectable in human bronchial tissue obtained from subjects with different infection-related lung diseases. Small interfering RNA-mediated knockdown of FOXO in bronchial epithelial cells resulted in reduced expression of factors of the innate immune system such as antimicrobial peptides and proinflammatory cytokines, both under basal conditions and upon infection. FOXO deficiency further affected internalization of Haemophilus influenzae in bronchial epithelial cells. Finally, we show that TLR3 activates innate immune responses in a FOXO-dependent manner. In conclusion, FOXO transcription factors are involved in the cellular responses to bacterial stimuli and act as central regulators of innate immune functions in respiratory epithelial cells.
Assuntos
Fatores de Transcrição Forkhead/fisiologia , Mucosa Respiratória/imunologia , Mucosa Respiratória/metabolismo , Animais , Linhagem Celular Tumoral , Doença Crônica , Modelos Animais de Doenças , Proteína Forkhead Box O3 , Humanos , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células Mieloides/patologia , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/metabolismo , Infecções por Pseudomonas/patologia , Mucosa Respiratória/patologia , Transdução de Sinais/imunologia , Células Tumorais CultivadasRESUMO
The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia. This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection. Pannexin-1 (Px1) channels mediate the activation of caspase-1 and release of IL-1ß induced by P2X7 receptor activation. The approved drug probenecid is an inhibitor of Px1 and ATP release. In this study, we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia. Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators, such as IL-1ß. In addition, probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells. Thus, Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation.
Assuntos
Anti-Inflamatórios/uso terapêutico , Inflamação/prevenção & controle , Pneumonia Bacteriana/prevenção & controle , Probenecid/uso terapêutico , Infecções por Pseudomonas/prevenção & controle , Pseudomonas aeruginosa/isolamento & purificação , Uricosúricos/uso terapêutico , Animais , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/patologia , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/patologia , Infecções por Pseudomonas/patologiaRESUMO
BACKGROUND: Pulmonary sequestration is a congenital malformation in which nonfunctional lung tissue develops without connection to the bronchial system. The main complication is the occurrence of recurrent pneumonia. CASE PRESENTATION: We describe the case of a patient who was incidentally diagnosed with PS as part of the diagnostic algorithm for community-acquired pneumonia. Due to the relatively late diagnosis, the recurrent bronchopulmonary was conducive to the development of COPD and pulmonary emphysema. For prognostic reasons, surgical resection was performed by posterolateral thoracotomy. CONCLUSIONS: Although cigarette smoking is the main risk factor for developing COPD, recurring lung infections may have a synergistic effect. Sometimes recurrent infections are caused by a congenital malformation. Especially in adults who have had recurrent pneumonia since childhood.
RESUMO
The IL-17 family of cytokines consists of at least six members (IL-17A to -F). IL-17 directly activates epithelial cells leading to the expression of inflammatory mediators and antimicrobial factors. Recent studies showed that IL-17C is expressed by epithelial cells. It was the purpose of this study to examine the expression of IL-17 family members in respiratory epithelial cells during bacterial infection. We show that common bacterial pathogens, such as Pseudomonas aeruginosa and Haemophilus influenzae, and ligands of Toll-like receptors 3 and 5 (flagellin, polyI:C) induced the expression and release of IL-17C in cultured human bronchial epithelial cells (HBECs). The expression of IL-17A, -B, -D, or -E was not induced by bacterial stimuli in HBECs. IL-17C enhanced inflammatory responses of respiratory epithelial cells infected with P. aeruginosa. Furthermore, we demonstrate that cigarette smoke suppressed the expression of IL-17C in HBECs in response to bacterial infection and in vivo in the upper airways of mice colonized with H. influenzae. IL-17C could also be detected in bronchial tissue of subjects with infection-related lung diseases. These data show that IL-17C is involved in the innate immune response of respiratory epithelial cells and is suppressed by cigarette smoke.
Assuntos
Infecções por Haemophilus/imunologia , Haemophilus influenzae/imunologia , Imunidade Inata , Interleucina-17/imunologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Mucosa Respiratória/imunologia , Animais , Brônquios/imunologia , Brônquios/patologia , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Infecções por Haemophilus/patologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Camundongos , Infecções por Pseudomonas/patologia , Mucosa Respiratória/patologia , Fumar/imunologia , Fumar/patologia , Poluição por Fumaça de Tabaco/efeitos adversosRESUMO
BACKGROUND: Tumor cells benefit from their ability to avoid apoptosis and invade other tissues. The endoplasmic reticulum (ER) membrane protein Sec62 is a key player in these processes. Sec62 is essential for cell migration and protects tumor cells against thapsigargin-induced ER stress, which are both linked to cytosolic Ca²âº. SEC62 silencing leads to elevated cytosolic Ca²âº and increased ER Ca²âº leakage after thapsigargin treatment. Sec62 protein levels are significantly increased in different tumors, including prostate, lung and thyroid cancer. METHODS: In lung cancer, the influence of Sec62 protein levels on patient survival was analyzed using the Kaplan-Meier method and log-rank test. To elucidate the underlying pathophysiological functions of Sec62, Ca²âº imaging techniques, real-time cell analysis and cell migration assays were performed. The effects of treatment with the calmodulin antagonists, trifluoperazine (TFP) and ophiobolin A, on cellular Ca²âº homeostasis, cell growth and cell migration were compared with the effects of siRNA-mediated Sec62 depletion or the expression of a mutated SEC62 variant in vitro. Using Biacore analysis we examined the Ca²âº-sensitive interaction of Sec62 with the Sec61 complex. RESULTS: Sec62 overproduction significantly correlated with reduced patient survival. Therefore, Sec62 is not only a predictive marker for this type of tumor, but also an interesting therapeutic target. The present study suggests a regulatory function for Sec62 in the major Ca²âº leakage channel in the ER, Sec61, by a direct and Ca²âº-sensitive interaction. A Ca²âº-binding motif in Sec62 is essential for its molecular function. Treatment of cells with calmodulin antagonists mimicked Sec62 depletion by inhibiting cell migration and rendering the cells sensitive to thapsigargin treatment. CONCLUSIONS: Targeting tumors that overproduce Sec62 with calmodulin antagonists in combination with targeted thapsigargin analogues may offer novel personalized therapeutic options.
Assuntos
Calmodulina/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Membrana Transportadoras/genética , Sesterterpenos/farmacologia , Trifluoperazina/farmacologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio , Calmodulina/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Proliferação de Células , Expressão Gênica , Células HEK293 , Células HeLa , Homeostase , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/metabolismo , Dados de Sequência Molecular , Fenótipo , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/genéticaRESUMO
OBJECTIVES: Patients with chronic obstructive pulmonary disease and lung emphysema may benefit from surgical or endoscopic lung volume reduction (ELVR). Previously reported outcomes of nitinol coil-based ELVR techniques have been ambiguous. The analysis was done to analyse outcomes of ELVR with nitinol coils in patients with severe pulmonary emphysema. METHODS: From September 2013 to November 2014, our centre performed a total of 41 coil implantations on 29 patients with severe emphysema. Coils were bronchoscopically placed during general anaesthesia. Twelve out of 29 patients received staged contralateral treatments up to 112 days later to avoid bilateral pneumothorax. Lung function and 6-min walking distance were assessed 1 week prior, 1 week after as well as 6-12 months after the procedure. Patients were followed up to 48 months after ELVR and overall mortality was compared to a historic cohort. RESULTS: While coil-based ELVR led to significant short-term improvement of vital capacity (VC, +0.14 ± 0.39 l, P = 0.032) and hyperinflation (Δ residual volume/total lung capacity -2.32% ± 6.24%, P = 0.022), no significant changes were observed in 6-min walking distance or forced expiratory volume in 1 s. Benefits were short-lived, with only 15.4% and 14.3% of patients showing sustained improvements in forced expiratory volume in 1 s or residual volume after 6 months. Adverse events included haemoptysis (40%) and pneumothorax (3.4%), major complications occurred in 6.9% of cases. Overall survival without lung transplant was 63.8% after 48 months following ELVR, differing insignificantly from what BODE indices of patients would have predicted as median 4-year survival (57%) at the time of ELVR treatment. CONCLUSIONS: ELVR with coils can achieve small and short-lived benefits in lung function at the cost of major complications in a highly morbid cohort. Treatment failed to improve 4-year overall survival. ELVR coils are not worthwhile the risk for most patients with severe emphysema.