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Previous studies have demonstrated substantial genetic diversification of Pseudomonas aeruginosa across sub-compartments in cystic fibrosis (CF) lungs. Here, we isolate P. aeruginosa from five different sampling areas in the upper and lower airways of an explanted CF lung, analyze ex vivo transcriptional profiles by RNA-seq, and use colony re-sequencing and deep population sequencing to determine the genetic diversity within and across the various sub-compartments. We find that, despite genetic variation, the ex vivo transcriptional profiles of P. aeruginosa populations inhabiting different regions of the CF lung are similar. Although we cannot estimate the extent to which the transcriptional response recorded here actually reflects the in vivo transcriptomes, our results indicate that there may be a common in vivo transcriptional profile in the CF lung environment. Pseudomonas aeruginosa displays substantial genetic diversification across sub-compartments in cystic fibrosis (CF) lungs. Here, Kordes et al. show that, despite genetic variation, the ex vivo transcriptional profiles of P. aeruginosa populations are similar across five different areas in an explanted CF lung.

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease harboring significant morbidity and mortality despite recent advances in therapy. Regardless of disease severity acute exacerbations (IPF-AEs) may occur leading to considerable loss of function and are the leading cause of death in IPF. Histologic features of IPF-AE are very similar to acute respiratory distress syndrome (ARDS), but the underlying mechanisms are incompletely understood. We investigated the role of the NLRP3 inflammasome in IPF and IPF-AE. Bronchoalveolar lavage (BAL) cells were sampled from patients with IPF (n = 32), IPF-AE (n = 10), ARDS (n = 7) and healthy volunteers (HV, n = 37) and the NLRP3-inflammasome was stimulated in-vitro . We found the NLRP3 inflammasome to be hyper-inducible in IPF compared to HV with increased IL-1ß and pro-IL-1ß levels on ELISA upon stimulation as well as increased caspase-1 activity measured by caspase-1p20 immunoblotting. In IPF-AE, IL-1ß was massively elevated to an extent similar to ARDS. To evaluate potential mechanisms, we co-cultured BAL cells with radiated A549 cells (a model to simulate apoptotic alveolar epithelial cells), which led to increased NLRP3 mRNA expression and increased caspase-1 dependent IL-1ß production. In the presence of a reactive oxygen species (ROS) inhibitor (diphenyleneiodonium) and a cathepsin B inhibitor (E64D), NLRP3 expression was suppressed indicating that induction of NLRP3 activation following efferocytosis of apoptotic A549 cells is mediated via ROS and cathepsin-B. In summary, we present evidence of involvement of the NLRP3 inflammasome-caspase pathway in the pathogenesis of IPF-AE, similarly to ARDS, which may be mediated by efferocytosis of apoptotic alveolar epithelial cells in IPF.

Chronic obstructive pulmonary disease (COPD) is a complex chronic respiratory disorder often caused by cigarette smoke. Cigarette smoke contains hundreds of toxic substances. In our study, we wanted to identify initial mechanisms of cigarette smoke induced changes in the distal lung. Viable slices of human lungs were exposed 24 h to cigarette smoke condensate, and the dose–response profile was analyzed. Non-toxic condensate concentrations and lipopolysaccharide were used for further experiments. COPD-related protein and gene expression was measured. Cigarette smoke condensate did not induce pro-inflammatory cytokines and most inflammation-associated genes. In contrast, lipopolysaccharide significantly induced IL-1α, IL-1β, TNF-α and IL-8 (proteins) and IL1B, IL6, and TNF (genes). Interestingly, cigarette smoke condensate induced metabolism- and extracellular matrix–associated proteins and genes, which were not influenced by lipopolysaccharide. Also, a significant regulation of CYP1A1 and CYP1B1, as well as MMP9 and MMP9/TIMP1 ratio, was observed which resembles typical findings in COPD. In conclusion, our data show that cigarette smoke and lipopolysaccharide induce significant responses in human lung tissue ex vivo, giving first hints that COPD starts early in smoking history.

AimsHeart transplantation may represent a particular risk factor for severe coronavirus infectious disease 2019 (COVID-19) due to chronic immunosuppression and frequent comorbidities. We conducted a nation-wide survey of all heart transplant centers in Germany presenting the clinical characteristics of heart transplant recipients with COVID-19 during the first months of the pandemic in Germany.Methods and resultsA multicenter survey of all heart transplant centers in Germany evaluating the current status of COVID-19 among adult heart transplant recipients was performed. A total of 21 heart transplant patients with COVID-19 was reported to the transplant centers during the first months of the pandemic in Germany. Mean patient age was 58.6 ± 12.3 years and 81.0% were male. Comorbidities included arterial hypertension (71.4%), dyslipidemia (71.4%), diabetes mellitus (33.3%), chronic kidney failure requiring dialysis (28.6%) and chronic-obstructive lung disease/asthma (19.0%). Most patients received an immunosuppressive drug regimen consisting of a calcineurin inhibitor (71.4%), mycophenolate mofetil (85.7%) and steroids (71.4%). Eight of 21 patients (38.1%) displayed a severe course needing invasive mechanical ventilation. Those patients showed a high mortality (87.5%) which was associated with right ventricular dysfunction (62.5% vs. 7.7%; p = 0.014), arrhythmias (50.0% vs. none; p = 0.012), and thromboembolic events (50.0% vs. none; p = 0.012). Elevated high-sensitivity cardiac troponin T- and N-terminal prohormone of brain natriuretic peptide were significantly associated with the severe form of COVID-19 (p = 0.017 and p < 0.001, respectively).ConclusionSevere course of COVID-19 was frequent in heart transplanted patients. High mortality was associated with right ventricular dysfunction, arrhythmias, thromboembolic events, and markedly elevated cardiac biomarkers.

Cold flush and static cold storage is the standard preservation technique for donor lungs before transplantations. Several research groups have assessed normothermic perfusion of donor lungs but all devices investigated were non-portable. We report first-in-man experience of the portable Organ Care System (OCS) Lung device for concomitant preservation, assessment, and transport of donor lungs. Between Feb 18, and July 1, 2011, 12 patients were transplanted at two academic lung transplantation centres in Hanover, Germany and Madrid, Spain. Lungs were perfused with low-potassium dextran solution, explanted, immediately connected to the OCS Lung, perfused with Steen's solution supplemented with two red-cell concentrates. We assessed donor and recipient characteristics and monitored extended criteria donor lung scores; primary graft dysfunction scores at 0, 24, 48, and 72 h; time on mechanical ventilation after surgery; length of stays in hospital and the intensive-care unit after surgery; blood gases; and survival of grafts and patients. Eight donors were female and four were male (mean age 44·5 years, range 14–72). Seven recipients were female and five were male (mean age 50·0 years, range 31–59). The preharvest donor ratio of partial pressure of oxyen (PaO2) to fractional concentration of oxygen in inspired air (FIO2) was 463·9 (SD 91·4). The final ratio of PaO2 to FIO2 measured with the OCS Lung was 471·58 (127·9). The difference between these ratios was not significant (p=0·72). All grafts and patients survived to 30 days; all recipients recovered and were discharged from hospital. Lungs can be safely preserved with the OCS Lung, resulting in complete organ use and successful transplantation in our series of high-risk recipients. In November, 2011, we began recruitment for a prospective, randomised, multicentre trial (INSPIRE) to compare preservation with OCS Lung with standard cold storage. TransMedics and German Federal Ministry of Education and Research.

The family of RNA-binding proteins (RBP) functions as a crucial regulator of multiple biological processes and diseases. However, RBP function in the clinical setting of idiopathic pulmonary fibrosis (IPF) is still unknown. We developed a practical in silico screening approach for the characterization of RBPs using multi-sources data information and comparative molecular network bioinformatics followed by wet-lab validation studies. Data mining of bulk RNA-Sequencing data of tissues of patients with IPF identified Quaking (QKI) as a significant downregulated RBP. Cell-type specific expression was confirmed by single-cell RNA-Sequencing analysis of IPF patient data. We systematically analyzed the molecular interaction network around QKI and its functional interplay with microRNAs (miRs) in human lung fibroblasts and discovered a novel regulatory miR-506-QKI axis contributing to the pathogenesis of IPF. The in silico results were validated by in-house experiments applying model systems of miR and lung biology. This study supports an understanding of the intrinsic molecular mechanisms of IPF regulated by the miR-506-QKI axis. Initially applied to human lung disease, the herein presented integrative in silico data mining approach can be adapted to other disease entities, underlining its practical relevance in RBP research.

Background: The management of multiple organ failure in the vulnerable cohort of cardiac surgery patients with cardiogenic shock remains a significant challenge, often impairing patient survival. A multimodal approach at targeting organ dysfunction seems to be a promising strategy, encompassing both hemodynamic support as well as differentiated organ replacement therapy. Materials and Methods: In our retrospective study we examined the impact of the ADVOS (advanced organ support) system on overall outcomes and survival in an all-comers group of 22 cardiac surgery patients with postoperative cardiogenic shock and multiple organ failure. Aims: The objective of the study was to assess the feasibility and potential benefits of ADVOS treatment in this patient population. Results: The standard care management in combination with ADVOS therapy corrected acid–base balance (pH 7.33 vs. 7.44, p = 0.001; base excess −3.2 vs. 2.4 mmol/L, p < 0.001). This contributed to restoring hemodynamic balance after two consecutive ADVOS treatments (vasoactive inotropic score (VIS) 59 vs. 21, p = 0.007, noradrenaline 0.470 vs. 0.180 µg/kg/min, p = 0.009). Conclusions: Our findings indicate that ADVOS treatment is both feasible and safe, with a substantial proportion of patients demonstrating improvements in organ function and overall outcomes.

(1) Objective: Bacterial resistance to conventional antibiotic therapy is an increasingly significant worldwide challenge to human health. The objective is to evaluate whether bacteriophage therapy could complement or be a viable alternative to conventional antibiotic therapy in critical cases of bacterial infection related to cardiothoracic surgery. (2) Methods: Since September 2015, eight patients with multi-drug resistant or especially recalcitrant Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli infections were treated with bacteriophage preparations as a therapy of last resort according to Article 37 of the Declaration of Helsinki. Patients had infections associated with immunosuppression after organ transplantation or had infections of vascular grafts, implanted medical devices, and surgical wounds. Individualized phage preparations were administered locally, orally, or via inhalation for different durations depending on the case. All patients remained on conventional antibiotics during bacteriophage treatment. (3) Results: Patients ranged in age from 13 to 66 years old (average 48.5 ± 16.7) with seven males and one female. Eradication of target bacteria was reached in seven of eight patients. No severe adverse side effects were observed. (4) Conclusions: Phage therapy can effectively treat bacterial infections related to cardiothoracic surgery when conventional antibiotic therapy fails.

Subgroups of patients with severe asthma are insensitive to inhaled corticosteroids and require novel therapies on top of standard medical care. IL-13 is considered one of the key cytokines in the asthma pathogenesis, however, the effect of IL-13 was mostly studied in rodents. This study aimed to assess IL-13 effect in human lung tissue for the development of targeted therapy approaches such as inhibition of soluble IL-13 or its receptor IL-4Rα subunit. Precision-cut lung slices (PCLS) were prepared from lungs of rodents, non-human primates (NHP) and humans. Direct effect of IL-13 on human lung tissue was observed on inflammation, induction of mucin5AC, and airway constriction induced by methacholine and visualized by videomicroscopy. Anti-inflammatory treatment was evaluated by co-incubation of IL-13 with increasing concentrations of IL-13/IL-13 receptor inhibitors. IL-13 induced a two-fold increase in mucin5AC secretion in human bronchial tissue. Additionally, IL-13 induced release of proinflammatory cytokines eotaxin-3 and TARC in human PCLS. Anti-inflammatory treatment with four different inhibitors acting either on the IL-13 ligand itself (anti-IL-13 antibody, similar to Lebrikizumab) or the IL-4Rα chain of the IL-13/IL-4 receptor complex (anti-IL-4Rα #1, similar to AMG 317, and #2, similar to REGN668) and #3 PRS-060 (a novel anticalin directed against this receptor) could significantly attenuate IL-13 induced inflammation. Contrary to this, IL-13 did not induce airway hyperresponsiveness (AHR) in human and NHP PCLS, although it was effective in rodent PCLS. Overall, this study demonstrates that IL-13 stimulation induces production of mucus and biomarkers of allergic inflammation in human lung tissue ex-vivo but no airway hyperresponsiveness. The results of this study show a more distinct efficacy than known from animals models and a clear discrepancy in AHR induction. Moreover, it allows a translational approach in inhibitor profiling in human lung tissue.

Dialysis-dependent (DD) patients undergoing coronary artery bypass grafting (CABG) remain a particularly high-risk population with impaired outcomes despite advances in surgical techniques. In this single-center, retrospective cohort study, 97 DD patients (2010–2015) were compared with 488 non-dialysis-dependent (NDD) controls. The primary endpoint was all-cause mortality; the secondary endpoint was major adverse cardiac and cerebrovascular events (MACCE). Median follow-up was 5.4 ± 2.1 years. DD patients had significantly higher perioperative mortality (10.3% vs. 3.1%, p = 0.002) and markedly reduced overall survival (OS) (40.8% vs. 82.1% at 5 years). Dialysis dependence conferred an 8.4-fold increase in mortality risk and a 2.6-fold increase in MACCE risk. Increasing age, diabetes, and critical preoperative state were independent predictors of an adverse long-term outcome. While arterial grafting improved survival in NDD patients, no comparable benefit was observed in DD patients, possibly due to vascular calcification, limited conduit availability, and reduced graft patency. EuroSCORE II adequately predicted perioperative mortality (AUC = 0.78 in DD patients) but demonstrated poor discriminatory power for long-term survival (AUC = 0.67 at 5 years). These findings highlight the urgent need for dialysis-specific risk models. Despite poor long-term prognosis, DD patients with low-risk EuroSCORE II profiles experienced the most relative benefit from CABG.