Ralf-Harto Hübner

Streptococcus pneumoniae–Induced Oxidative Stress in Lung Epithelial Cells Depends on Pneumococcal Autolysis and Is Reversible by Resveratrol

BACKGROUND Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide. During pneumococcal pneumonia, the human airway epithelium is exposed to large amounts of H2O2 as a product of host and pathogen oxidative metabolism. Airway cells are known to be highly vulnerable to oxidant damage, but the pathophysiology of oxidative stress induced by S. pneumoniae and the role of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant systems of the host are not well characterized. METHODS For gluthation/gluthathion disulfide analysis BEAS-2B cells, primary broncho-epithelial cells (pBEC), explanted human lung tissue and mouse lungs were infected with different S. pneumoniae strains (D39, A66, R6x, H2O2/pneumolysin/LytA- deficient mutants of R6x). Cell death was proven by LDH assay and cell viability by IL-8 ELISA. The translocation of Nrf2 and the expression of catalase were shown via Western blot. The binding of Nrf2 at the catalase promoter was analyzed by ChIP. RESULTS We observed a significant induction of oxidative stress induced by S. pneumoniae in vivo, ex vivo, and in vitro. Upon stimulation, the oxidant-responsive transcription factor Nrf2 was activated, and catalase was upregulated via Nrf2. The pneumococci-induced oxidative stress was independent of S. pneumoniae-derived H2O2 and pneumolysin but depended on the pneumococcal autolysin LytA. The Nrf2 inducer resveratrol, as opposed to catalase, reversed oxidative stress in lung epithelial cells. CONCLUSIONS These observations indicate a H2O2-independent induction of oxidative stress in lung epithelial cells via the release of bacterial factors of S. pneumoniae. Resveratrol might be an option for prevention of acute lung injury and inflammatory responses observed in pneumococcal pneumonia.

Modifying Post-Operative Medical Care after EBV Implant May Reduce Pneumothorax Incidence.

Objective Endoscopic lung volume reduction (ELVR) with valves has been shown to improve COPD patients with severe emphysema. However, a major complication is pneumothoraces, occurring typically soon after valve implantation, with severe consequences if not managed promptly. Based on the knowledge that strain activity is related to a higher risk of pneumothoraces, we asked whether modifying post-operative medical care with the inclusion of strict short-term limitation of strain activity is associated with a lower incidence of pneumothorax. Methods Seventy-two (72) emphysematous patients without collateral ventilation were treated with bronchial valves and included in the study. Thirty-two (32) patients received standard post-implantation medical management (Standard Medical Care (SMC)), and 40 patients received a modified medical care that included an additional bed rest for 48 hours and cough suppression, as needed (Modified Medical Care (MMC)). Results The baseline characteristics were similar for the two groups, except there were more males in the SMC cohort. Overall, ten pneumothoraces occurred up to four days after ELVR, eight pneumothoraces in the SMC, and only two in the MMC cohorts (p=0.02). Complicated pneumothoraces and pneumothoraces after upper lobe treatment were significantly lower in MMC (p=0.02). Major clinical outcomes showed no significant differences between the two cohorts. Conclusions In conclusion, modifying post-operative medical care to include bed rest for 48 hours after ELVR and cough suppression, if needed, might reduce the incidence of pneumothoraces. Prospective randomized studies with larger numbers of well-matched patients are needed to confirm the data.

Lung perfusion and emphysema distribution affect the outcome of endobronchial valve therapy.

The exclusion of collateral ventilation (CV) and other factors affect the clinical success of endoscopic lung volume reduction (ELVR). However, despite its benefits, the outcome of ELVR remains difficult to predict. We investigated whether clinical success could be predicted by emphysema distribution assessed by computed tomography scan and baseline perfusion assessed by perfusion scintigraphy. Data from 57 patients with no CV in the target lobe (TL) were retrospectively analyzed after ELVR with valves. Pulmonary function tests (PFT), St George’s Respiratory Questionnaire (SGRQ), and 6-minute walk tests (6MWT) were performed on patients at baseline. The sample was grouped into high and low levels at the median of TL perfusion, ipsilateral nontarget lobe (INL) perfusion, and heterogeneity index (HI). These groups were analyzed for association with changes in outcome parameters from baseline to 3 months follow-up. Compared to baseline, patients showed significant improvements in PFT, SGRQ, and 6MWT (all P≤0.001). TL perfusion was not associated with changes in the outcome. High INL perfusion was significantly associated with increases in 6MWT (P=0.014), and high HI was associated with increases in forced expiratory volume in 1 second (FEV1), (P=0.012). Likewise, there were significant correlations for INL perfusion and improvement of 6MWT (r=0.35, P=0.03) and for HI and improvement in FEV1 (r=0.45, P=0.001). This study reveals new attributes that associate with positive outcomes for patient selection prior to ELVR. Patients with high perfusions in INL demonstrated greater improvements in 6MWT, while patients with high HI were more likely to respond in FEV1.

Role of Pneumococcal Autolysin for KLF4 Expression and Chemokine Secretion in Lung Epithelium

In severe pneumococcal pneumonia, the delicate balance between a robust inflammatory response necessary to kill bacteria and the loss of organ function determines the outcome of disease. In this study, we tested the hypothesis that Krueppel-like factor (KLF) 4 may counter-regulate Streptococcus pneumoniae-related human lung epithelial cell activation using the potent proinflammatory chemokine IL-8 as a model molecule. Pneumococci induced KLF4 expression in human lung, in primary human bronchial epithelial cells, and in the lung epithelial cell line BEAS-2B. Whereas proinflammatory cell activation depends mainly on the classical Toll-like receptor 2-mitogen-activated protein kinase or phosphatidylinositide 3-kinase and NF-κB pathways, the induction of KLF4 occurred independently of these molecules but relied, in general, on tyrosine kinase activation and, in part, on the src kinase family member yamaguchi sarcoma viral oncogene homolog (yes) 1. The up-regulation of KLF4 depended on the activity of the main pneumococcal autolysin LytA. KLF4 overexpression suppressed S. pneumoniae-induced NF-κB and IL-8 reporter gene activation and release, whereas small interfering RNA-mediated silencing of KLF4 or yes1 kinase led to an increase in IL-8 release. The KLF4-dependent down-regulation of NF-κB luciferase activity could be rescued by the overexpression of the histone acetylase p300/cAMP response element-binding protein-associated factor. In conclusion, KLF4 acts as a counter-regulatory transcription factor in pneumococci-related proinflammatory activation of lung epithelial cells, thereby potentially preventing lung hyperinflammation and subsequent organ failure.

Bronchial Injury After Atrial Fibrillation Ablation Using the Second-Generation Cryoballoon

Cryoballon ablation of atrial fibrillation may be associated with bronchial damage, but the factors causing this are poorly characterized.1–5 Eleven consecutive patients were included in this prospective, single-center pilot study (German Clinical Trials Register No. DRKS00011273). All patients experienced paroxysmal (n=9; 82%) or persistent atrial fibrillation and were treated with the second-generation 28 mm cryoballon (Medtronic, Inc, Minneapolis, MN). The day after cryoballon ablation, a bronchoscopy was performed to assess for bronchial injury (BI) in all patients. In addition, body plethysmography was conducted before and after the procedure. The evaluations of the bronchoscopies were performed in a blinded fashion by 2 independent pulmonologists (R.-H.H., M.P.). This study conforms to the guiding principles of the Declaration of Helsinki of 2014 and was approved by the local ethics committee (EA/111/16). In all 11 patients (6 women; mean age, 66±8.8 years), pulmonary vein isolation (PVI) of all pulmonary veins (PVs) was successfully performed. Preexisting diseases were coronary artery disease (9.1%) and arterial hypertension (55%). The mean left atrial diameter was 50.4±7.2 mm. Five patients (45%) were under anticoagulation with apixaban and 6 (55%) with rivaroxaban. The mean CHA2DS2-Vasc Score was 1.9±1.1. The procedure was performed under deep sedation using propofol, midazolam, and fentanyl. All patients were breathing spontaneously. After transseptal puncture, anatomic localization of the PVs was identified with intravenous contrast injection under fluoroscopy. The Achieve catheter (Medtronic, …

Comparison of distinctive models for calculating an interlobar emphysema heterogeneity index in patients prior to endoscopic lung volume reduction

Background The degree of interlobar emphysema heterogeneity is thought to play an important role in the outcome of endoscopic lung volume reduction (ELVR) therapy of patients with advanced COPD. There are multiple ways one could possibly define interlobar emphysema heterogeneity, and there is no standardized definition. Purpose The aim of this study was to derive a formula for calculating an interlobar emphysema heterogeneity index (HI) when evaluating a patient for ELVR. Furthermore, an attempt was made to identify a threshold for relevant interlobar emphysema heterogeneity with regard to ELVR. Patients and methods We retrospectively analyzed 50 patients who had undergone technically successful ELVR with placement of one-way valves at our institution and had received lung function tests and computed tomography scans before and after treatment. Predictive accuracy of the different methods for HI calculation was assessed with receiver-operating characteristic curve analysis, assuming a minimum difference in forced expiratory volume in 1 second of 100 mL to indicate a clinically important change. Results The HI defined as emphysema score of the targeted lobe (TL) minus emphysema score of the ipsilateral nontargeted lobe disregarding the middle lobe yielded the best predicative accuracy (AUC =0.73, P=0.008). The HI defined as emphysema score of the TL minus emphysema score of the lung without the TL showed a similarly good predictive accuracy (AUC =0.72, P=0.009). Subgroup analysis suggests that the impact of interlobar emphysema heterogeneity is of greater importance in patients with upper lobe predominant emphysema than in patients with lower lobe predominant emphysema. Conclusion This study reveals the most appropriate ways of calculating an interlobar emphysema heterogeneity with regard to ELVR.

A diagnostic predicament: activated sarcoidosis or pulmonary histoplasmosis. A case report

We report a case of a 41‐year‐old man presenting with persisting fevers over 2 weeks. The patient had spent 4 weeks in Central America. He was in control of a stable stage II sarcoidosis. Laboratory and various microbiological tests as well as chest radiography led to no diagnosis. Activated sarcoidosis was hypothesized as the most likely diagnosis. However, we considered an infectious process as a differential diagnosis, in detail, the travel history imposed histoplasmosis. Chest‐CT documented localized interstitial consolidations. Bronchoscopy with bronchoalveolar lavage (BAL) and biopsy was performed. Results of BAL fluid, biopsy, distinct sarcoidosis serum markers and a borderline positive histoplasmosis‐serology yielded in a diagnostic dilemma as no distinct diagnosis was drawable. After the patient was already started on a prednisolone trial, the final diagnosis – pulmonary histoplasmosis – could be achieved via positive culture and PCR out of the BAL fluid. This case shows the difficult differentiation between an acute exacerbation of a chronic pulmonary disease and a concomitant infection, which was especially aggravated in this case as the histoplasmosis masqueraded an acute picture of sarcoidosis.

COPD treatment: about collateral channels and collapsing airways.

Collateral channels inside the human lungs? This phenomenon, first described by Kohn [1] in 1893, is the subject of recent investigations in the field of endoscopic lung volume reduction (ELVR) for the treatment of severe chronic obstructive pulmonary disease (COPD). ELVR with valves is a new and promising therapeutic option for irreversibly damaged emphysematous lungs. The aim of the therapy is the complete occlusion of a lobe, with endobronchial one-way valves delivered through a bronchoscope to intentionally induce a targeted atelectasis of the most damaged lobe. Many studies have described improvements in lung function, quality of life and exercise capacity in a subset of severe COPD patients, where interlobar collateral ventilation was an exclusion criterion for valve treatment [2–8]. Interlobar collateral ventilation is defined as the ventilation of alveolar structures through passages or channels that bypass the normal airways, and includes the interalveolar pores of Kohn, the bronchiole–alveolar communications of Lambert and the interbronchiolar pathways of Martin [9–14]. Collateral ventilation is present not only in COPD lungs, but also in healthy lungs [15]. The physiological function of the collateral channels is still unknown; in COPD patients they might provide channels of low resistance to better ventilate less emphysematous lung segments. The importance of collateral ventilation was ignored for over a century, but now, with their role in ELVR and the development of new bronchoscopic techniques, the study of these little channels has gained enormously in importance. Dynamic airway collapse during Chartis doesn’t identify the presence of collateral channels in that specific lobe http://ow.ly/YGV0G

Interventionelle bronchologische Therapie@@@Interventional bronchological therapy: Eine kritische Bestandsaufnahme@@@A critical evaluation

ZusammenfassungHintergrundChronisch obstruktive Lungenerkrankungen (COPD) sind unheilbare, progredient fortschreitende Erkrankungen, die durch eine irreversible Obstruktion der kleinen Atemwege gekennzeichnet sind. Insbesondere wenn medikamentöse Behandlungsversuche bei Patienten mit schwerer COPD nicht den gewünschten Erfolg bringen, steht ein neues Therapiekonzept zur kausalen Behandlung der Lungenüberblähung zur Verfügung: die endoskopische Lungenvolumenreduktion. Man unterscheidet die reversible okkludierende Behandlung mit endobronchialen Ventilen von den irreversiblen nicht okkludierenden Verfahren wie Thermoablation, Bronchialkleber, Stents und Spiralen.MethodenEs erfolgte ein systematischer Vergleich der wichtigsten Verfahren der Lungenvolumenreduktion bezüglich klinischer Outcomes und Komplikationsprofil basierend auf Literaturrecherchen und klinischer Erfahrung.ErgebnisseEine vollständige Okklusion bei heterogen verteiltem Lungenemphysem und kompletten Fissuren sind die wichtigsten Prädiktionsmarker für eine erfolgreiche Ventiltherapie. Wichtigste Komplikation ist die hohe Pneumothoraxrate. Die ähnlich wirksamen irreversiblen Verfahren könnten für Patienten mit Kollateralverbindungen zwischen den Lungenlappen eine mögliche Therapieoption darstellen, wobei die Studienlage für endgültige Schlussfolgerungen noch nicht ausreichend ist.SchlussfolgerungZusammengefasst stellen interventionelle bronchologische Maßnahmen für COPD-Patienten mit ausgeprägtem Emphysem und fortgeschrittenem Krankheitsstadium eine neue Therapiemöglichkeit dar. Noch ist kein Verfahren zur breiten Anwendung im klinischen Alltag geeignet.AbstractBackgroundChronic obstructive pulmonary disease (COPD) is an incurable progressive disease which is characterized by an irreversible occlusion of the small airways. Especially when pharmaceutical treatment attempts do not bring the desired success in patients with severe COPD, a new therapeutic concept for causal treatment of pulmonary emphysema is now available: endoscopic lung volume reduction. A differentiation is made between reversible occlusive treatment with endobronchial valves and irreversible nonocclusive procedures, such as thermoablation, bronchial glue, stents and spirals.MethodsA systematic comparison of the most important procedures for lung volume reduction with respect to clinical outcome and complication profile was carried out based on a literature search and clinical experience.ResultsA complete occlusion in heterogeneously distributed lung emphysema and complete fissures are the most important predictive markers for successful valve therapy. The most important complication is the high rate of pneumothorax. The similarly effective irreversible procedure can be a possible therapy option for patients with collateral connections between the lung lobes but the current evidence from studies is insufficient for final conclusions to be drawn.ConclusionIn summary interventional bronchological measures represent a new therapy option for COPD patients with severe emphysema and advanced disease stage. However, none of the procedures are currently suitable for broad application in the clinical routine.

Interventionelle bronchologische TherapieInterventional bronchological therapy

ZusammenfassungHintergrundChronisch obstruktive Lungenerkrankungen (COPD) sind unheilbare, progredient fortschreitende Erkrankungen, die durch eine irreversible Obstruktion der kleinen Atemwege gekennzeichnet sind. Insbesondere wenn medikamentöse Behandlungsversuche bei Patienten mit schwerer COPD nicht den gewünschten Erfolg bringen, steht ein neues Therapiekonzept zur kausalen Behandlung der Lungenüberblähung zur Verfügung: die endoskopische Lungenvolumenreduktion. Man unterscheidet die reversible okkludierende Behandlung mit endobronchialen Ventilen von den irreversiblen nicht okkludierenden Verfahren wie Thermoablation, Bronchialkleber, Stents und Spiralen.MethodenEs erfolgte ein systematischer Vergleich der wichtigsten Verfahren der Lungenvolumenreduktion bezüglich klinischer Outcomes und Komplikationsprofil basierend auf Literaturrecherchen und klinischer Erfahrung.ErgebnisseEine vollständige Okklusion bei heterogen verteiltem Lungenemphysem und kompletten Fissuren sind die wichtigsten Prädiktionsmarker für eine erfolgreiche Ventiltherapie. Wichtigste Komplikation ist die hohe Pneumothoraxrate. Die ähnlich wirksamen irreversiblen Verfahren könnten für Patienten mit Kollateralverbindungen zwischen den Lungenlappen eine mögliche Therapieoption darstellen, wobei die Studienlage für endgültige Schlussfolgerungen noch nicht ausreichend ist.SchlussfolgerungZusammengefasst stellen interventionelle bronchologische Maßnahmen für COPD-Patienten mit ausgeprägtem Emphysem und fortgeschrittenem Krankheitsstadium eine neue Therapiemöglichkeit dar. Noch ist kein Verfahren zur breiten Anwendung im klinischen Alltag geeignet.AbstractBackgroundChronic obstructive pulmonary disease (COPD) is an incurable progressive disease which is characterized by an irreversible occlusion of the small airways. Especially when pharmaceutical treatment attempts do not bring the desired success in patients with severe COPD, a new therapeutic concept for causal treatment of pulmonary emphysema is now available: endoscopic lung volume reduction. A differentiation is made between reversible occlusive treatment with endobronchial valves and irreversible nonocclusive procedures, such as thermoablation, bronchial glue, stents and spirals.MethodsA systematic comparison of the most important procedures for lung volume reduction with respect to clinical outcome and complication profile was carried out based on a literature search and clinical experience.ResultsA complete occlusion in heterogeneously distributed lung emphysema and complete fissures are the most important predictive markers for successful valve therapy. The most important complication is the high rate of pneumothorax. The similarly effective irreversible procedure can be a possible therapy option for patients with collateral connections between the lung lobes but the current evidence from studies is insufficient for final conclusions to be drawn.ConclusionIn summary interventional bronchological measures represent a new therapy option for COPD patients with severe emphysema and advanced disease stage. However, none of the procedures are currently suitable for broad application in the clinical routine.