Is arginase a potential drug target in tobacco-induced pulmonary endothelial dysfunction?

International audienceBackgroundTobacco-induced pulmonary vascular disease is partly driven by endothelial dysfunction. The bioavailability of the potent vasodilator nitric oxide (NO) depends on competition between NO synthase-3 (NOS3) and arginases for their common substrate (L-arginine). We tested the hypothesis whereby tobacco smoking impairs pulmonary endothelial function via upregulation of the arginase pathway.MethodsEndothelium-dependent vasodilation in response to acetylcholine (Ach) was compared ex vivo for pulmonary vascular rings from 29 smokers and 10 never-smokers. The results were expressed as a percentage of the contraction with phenylephrine. We tested the effects of L-arginine supplementation, arginase inhibition (by N(omega)-hydroxy-nor-l-arginine, NorNOHA) and NOS3 induction (by genistein) on vasodilation. Protein levels of NOS3 and arginases I and II in the pulmonary arteries were quantified by Western blotting.ResultsOverall, vasodilation was impaired in smokers (relative to controls; p < 0.01). Eleven of the 29 smokers (the ED+ subgroup) displayed endothelial dysfunction (defined as the absence of a relaxant response to Ach), whereas 18 (the ED− subgroup) had normal vasodilation. The mean responses to 10−4 M Ach were −23 ± 10% and 31 ± 4% in the ED+ and ED− subgroups, respectively (p < 0.01). Supplementation with L- arginine improved endothelial function in the ED+ subgroup (−4 ± 10% vs. -32 ± 10% in the presence and absence of L- arginine, respectively; p = 0.006), as did arginase inhibition (18 ± 9% vs. -1 ± 9%, respectively; p = 0.0002). Arginase I protein was overexpressed in ED+ samples, whereas ED+ and ED− samples did not differ significantly in terms of NOS3 expression. Treatment with genistein did not significantly improve endothelial function in ED+ samples.ConclusionOverexpression and elevated activity of arginase I are involved in tobacco-induced pulmonary endothelial dysfunction

Single-lung transplantation in patients with previous contralateral pneumonectomy: technical aspects and results

Objective: Single-lung transplantation (SLTX) in patients with previous contralateral pneumonectomy (PN) is a rarely observed situation. Intrathoracic anatomical changes caused by mediastinal shift may complicate the surgical procedure. We collected observations from different transplantation centres to analyse the technical aspects and results. Patients and methods: Between July 1990 and September 2008, 14 patients (seven women and seven men) with previous PN underwent SLTX for end-stage pulmonary failure. Patients were categorised in three groups according to lung disease: cystic fibrosis bronchiectasis (group 1; n = 4), non-cystic fibrosis bronchiectasis (group 2; n = 6) and bronchioloalveolar carcinoma (group 3; n = 4). We reviewed patients' characteristics according to mediastinal shift, thoracic approach, bypass cannula procedure, perioperative difficulties and immediate and long-term results. Results: Median age was 19.5, 33.5 and 52.5 years in groups 1, 2 and 3, respectively; there were nine left and five right cases of SLTX. Surgery was performed by sternotomy (n = 4), anterolateral thoracotomy (n = 4), clamshell (n = 4) or posterolateral thoracotomy (n = 2). Cannulas for bypass were inserted into femoral (n = 7) or central vessels (n = 5) or both (n = 2). Mediastinal shift did not complicate surgical procedure but rendered cannulation more difficult with ensuing cardiopulmonary bypass dysfunction (n = 3) and early bronchial complications (n = 2). In-hospital mortality rate was 29% (4 out of 14 patients), including two deaths due to perioperative difficulties linked to mediastinal shift. Median global survival was 108 months. Median survival was higher in group 2 (108 months vs 1 month in the other groups) and in case of PN during childhood (n = 6, median survival 108 months corresponding to one death). Conclusions: SLTX after PN is associated with high perioperative morbidity and mortality due to mediastinal shift. Best results are observed in patients undergoing PN for non-cystic fibrosis bronchiectasis and during childhood. Anatomical changes induced by PN must be anticipated to adapt the thoracic approach and cardiopulmonary bypass access. © 2009 European Association for Cardio-Thoracic Surgery.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Superior vena cava graft infection in thoracic surgery: a retrospective study of the French EPITHOR database

International audienceAbstract OBJECTIVES To report our experience on the management of superior vena cava graft infection. METHODS Between 2001 and 2018, patients with superior vena cava synthetic graft or patch reconstruction after resection of intrathoracic tumours or benign disease were selected retrospectively from the French EPITHOR database and participating thoracic centres. Our study population includes patients with superior vena cava graft infection, defined according to the MAGIC consensus. Superior vena cava synthetic grafts in an empyema or mediastinitis were considered as infected. RESULTS Of 111 eligible patients, superior vena cava graft infection occurred in 12 (11.9%) patients with a polytetrafluoroethylene graft secondary to contiguous contamination. Management consisted of either conservative treatment with chest tube drainage and antibiotics (n = 3) or a surgical graft-sparing strategy (n = 9). Recurrence of infection appears in 6 patients. Graft removal was performed in 2 patients among the 5 reoperated patients. The operative mortality rate was 25%. CONCLUSIONS Superior vena cava graft infection may develop as a surgical site infection secondary to early mediastinitis or empyema. Graft removal is not always mandatory but should be considered in late or recurrent graft infection or in infections caused by aggressive microorganisms (virulent or multidrug resistant bacteria or fungi)

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

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Analysis of spontaneous tumor-specific CD4 T-cell immunity in lung cancer using promiscuous HLA-DR telomerase-derived epitopes: potential synergistic effect with chemotherapy response.

International audiencePURPOSE: To investigate the presence and impact of spontaneous telomerase-specific CD4 T-cell responses in cancer patients. EXPERIMENTAL DESIGN: A multistep approach was used to design novel pan-HLA-DR-restricted peptides from telomerase. T-cell clones isolated from cancer patients were used to characterize the polarization of telomerase-specific CD4 response. The presence of spontaneous CD4 T-cell response against telomerase was monitored in 84 metastatic non-small cell lung cancer (NSCLC) patients before first-line chemotherapy (CT) using IFN-γ ELISPOT assay. Then we analyzed the impact of the pretherapeutic telomerase-specific CD4 T immunity on clinical outcome in patients according to their respective response to CT. RESULTS: We described four novel telomerase-derived CD4 epitopes referred as universal cancer peptides (UCP) that effectively bind to most commonly found human MHC class II alleles. UCP-specific CD4 T-cell repertoire is present in human and UCP-specific CD4 T-cell clones generated from cancer patients exhibited high avidity and are Th1 polarized. Significant frequency (38%) of naturally occurring UCP-specific T-cell responses were detected before CT in advanced NSCLC but not in healthy volunteers. This response was shown to significantly increase overall survival (OS) of patients responding to CT (Median OS: 53 vs. 40 weeks, P = 0.034). CONCLUSIONS: These results show for the first time a potential synergistic effect of telomerase-specific CD4 T-cell response with CT response in NSCLC and underline the potential role of tumor-specific CD4 T-cell response on the efficiency of conventional anticancer therapy

Impact of Donor, Recipient and Matching on Survival After High Emergency Lung Transplantation in France

Introduction: Since July 2007, the French high emergency lung transplantation (HELT) allocation procedure prioritises available lung grafts to waiting patients with imminent risk of death. The relative impacts of donor, recipient and matching on the outcome following HELT remain unknown. We aimed at deciphering the relative impacts of donor, recipient and matching on the outcome following HELT in an exhaustive administrative database. Methods: All lung transplantations performed in France were prospectively registered in an administrative database. We retrospectively reviewed the procedures performed between July 2007 and December 2015, and analysed the impact of donor, recipient and matching on overall survival after the HELT procedure by fitting marginal Cox models. Results: During the study period, 2335 patients underwent lung transplantation in 11 French centres. After exclusion of patients with chronic obstructive pulmonary disease/emphysema, 1544 patients were included: 503 HELT and 1041 standard lung transplantation allocations. HELT was associated with a hazard ratio for death of 1.41 (95% CI 1.22-1.64; p<0.0001) in univariate analysis, decreasing to 1.32 (95% CI 1.10-1.60) after inclusion of recipient characteristics in a multivariate model. A donor score computed to predict long-term survival was significantly different between the HELT and standard lung transplantation groups (p=0.014). However, the addition of donor characteristics to recipient characteristics in the multivariate model did not change the hazard ratio associated with HELT. Conclusions: This exhaustive French national study suggests that HELT is associated with an adverse outcome compared with regular allocation. This adverse outcome is mainly related to the severity status of the recipients rather than donor or matching characteristics