Length of pressure-controlled reperfusion is critical for reducing ischaemia-reperfusion injury in an isolated rabbit lung model

<p>Abstract</p> <p>Background</p> <p>Ischaemia-reperfusion injury is still a major problem after lung transplantation. Several reports describe the benefits of controlled graft reperfusion. In this study the role of length of the initial pressure-controlled reperfusion (PCR) was evaluated in a model of isolated, buffer-perfused rabbit lungs.</p> <p>Methods</p> <p>Heart-lung blocks of 25 New Zealand white rabbits were used. After measurement of baseline values (haemodynamics and gas exchange) the lungs were exposed to 120 minutes of hypoxic warm ischaemia followed by repeated measurements during reperfusion. Group A was immediately reperfused using a flow of 100 ml/min whereas groups B, C and D were initially reperfused with a maximum pressure of 5 mmHg for 5, 15 or 30 minutes, respectively. The control group had no period of ischaemia or PCR.</p> <p>Results</p> <p>Uncontrolled reperfusion (group A) caused a significant pulmonary injury with increased pulmonary artery pressures (PAP) and pulmonary vascular resistance and a decrease in oxygen partial pressure (PO₂), tidal volume and in lung compliance. All groups with PCR had a significantly higher PO₂for 5 to 90 min after start of reperfusion. At 120 min there was also a significant difference between group B (264 ± 91 mmHg) compared to groups C and D (436 ± 87 mmHg; 562 ± 20 mmHg, p < 0.01). All PCR groups showed a significant decrease of PAP compared to group A.</p> <p>Conclusion</p> <p>Uncontrolled reperfusion results in a severe lung injury with rapid oedema formation. PCR preserves pulmonary haemodynamics and gas exchange after ischaemia and might allows for recovery of the impaired endothelial function. 30 minutes of PCR provide superior results compared to 5 or 15 minutes of PCR.</p

Pulmonary endarterectomy in the management of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a type of pulmonary hypertension, resulting from fibrotic transformation of pulmonary artery clots causing chronic obstruction in macroscopic pulmonary arteries and associated vascular remodelling in the microvasculature.Pulmonary endarterectomy (PEA) offers the best chance of symptomatic and prognostic improvement in eligible patients; in expert centres, it has excellent results. Current in-hospital mortality rates are 90% at 1 year and >70% at 10 years. However, PEA, is a complex procedure and relies on a multidisciplinary CTEPH team led by an experienced surgeon to decide on an individual's operability, which is determined primarily by lesion location and the haemodynamic parameters. Therefore, treatment of patients with CTEPH depends largely on subjective judgements of eligibility for surgery by the CTEPH team.Other controversies discussed in this article include eligibility for PEA versus balloon pulmonary angioplasty, the new treatment algorithm in the European Society of Cardiology/European Respiratory Society guidelines and the definition of an "expert centre" for the management of this condition

Interventional and pharmacological management of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is caused by obstruction of the pulmonary vasculature, leading to increased pulmonary vascular resistance and ultimately right ventricular failure, the leading cause of death in non-operated patients. This article reviews the current management of CTEPH. The standard of care in CTEPH is pulmonary endarterectomy (PEA). However, up to 40% of patients with CTEPH are ineligible for PEA, and up to 51% develop persistent/recurrent PH after PEA. Riociguat is currently the only medical therapy licensed for treatment of inoperable or persistent/recurrent CTEPH after PEA based on the results of the Phase III CHEST-1 study. Studies of balloon pulmonary angioplasty (BPA) have shown benefits in patients with inoperable or persistent/recurrent CTEPH after PEA; however, data are lacking from large, prospective, controlled studies. Studies of macitentan in patients with inoperable CTEPH and treprostinil in patients with inoperable or persistent/recurrent CTEPH showed positive results. Combination therapy is under evaluation in CTEPH, and long-term data are not available. In the future, CTEPH may be managed by PEA, medical therapy or BPA - alone or in combination, according to individual patient needs. Patients should be referred to experienced centers capable of assessing and delivering all options

Barrier functions and paracellular integrity in human cell culture models of the proximal respiratory unit.

International audienceAirway epithelial cells provide a barrier to the translocation of inhaled materials. Tight (TJ) and adherens junctions (AJ) play a key role in maintaining barrier functions, and are responsible for the selective transport of various substances through the paracellular pathway. In this study we compared a bronchial cell line (16HBE14o-) and primary bronchial cells (HBEC), both cocultivated with the fibroblast cell line Wi-38, with respect to their structural differentiation and their reaction to cytokine stimulation. HBEC formed a pseudostratified epithelial layer and expressed TJ and AJ proteins after 2 weeks in coculture. Mucus-producing and ciliated cells were found within 24 days. Additionally, a beating activity of the ciliated HBEC (14-19 Hz) could be detected. 16HBE14o-in coculture showed a multilayered growth without differentiation to a pseudostratified airway epithelium. Simultaneous exposure to TNF-a-and IFN-c-induced significant changes in barrier function and paracellular permeability in the cocultures of HBEC/Wi-38 but not in the 16HBE14o-/Wi-38. In summary, HBEC in coculture mimic the structure of native polarized bronchial epithelium showing basal, mucus-producing and ciliated cells. Our system provides an opportunity to examine the factors that influence barrier and mucociliary function of bronchial epithelium within a time frame of 3 weeks up to 3 months in an in vivo-like differentiated model

Acute Morphological and Toxicological Effects in a Human Bronchial Coculture Model after Sulfur Mustard Exposure.

International audienceSulfur mustard (SM) is a strong alkylating agent. Inhalation of SM causes acute lung injury accompanied by severe disruption of the airway barrier. In our study, we tested the acute effects after mustard exposure in an in vitro coculture bronchial model of the proximal barrier. To achieve this, we seeded normal human bronchial epithelial explant-outgrowth cells (HBEC) together with lung fibroblasts as a bilayer on filter plates and exposed the bronchial model after 31 days of differentiation to various concentrations of SM (30, 100, 300, and 500mM). The HBEC formed confluent layers, expressing functional tight junctions as measured by transepithelial electrical resistance (TER). Mucus production and cilia formation reappeared in the coculture model. TER was measured after 2 and 24 h following treatment. Depending on the different concentrations , TER decreased in the first 2 h up to 55% of the control at the highest concentration. After 24 h, TER seemed to recover because at concentrations up to 300mM values were equal to the control. SM induced a widening of intercellular spaces and a loss in cell-matrix adhesion. Mucus production increased with the result that cilia ceased to beat. Changes in the proinflammatory cytokines in-terleukin (IL)-6 and IL-8 were also observed. Apoptotic markers such as cytochrome c, p53, Fas-associated protein with death domain, and procaspase-3 were significantly induced at concentrations of less than 100mM. In summary, SM induces morphological and biochemical changes that reflect pathological effects of SM injury in vivo. It is hoped to use this coculture model to understand further the pathogenesis of SM-induced barrier injury and to search for novel approaches in SM therapy

Evaluation of the prognostic value of electrocardiography parameters and heart rhythm in patients with pulmonary hypertension

Background: Several studies have analyzed arrhythmias in patients with pulmonary hypertension (PH) and increased P-wave duration was identified as a risk factor for development of atrial fibrillation (AF). Methods: We retrospectively analyzed the incidence of arrhythmias in patients with an initial diagnosis of PH during long-term follow-up and assessed the prognostic value of electrocardiography (ECG) data. Data from 167 patients were analyzed (Dana Point Classification: Group 1: 59 patients, Group 2: 28 patients, Group 3: 39 patients, Group 4: 41 patients). Clinical, 6-min­ute walk distance test, echocardiography and right heart catheterization data were collected, and baseline/follow-up ECGs were analyzed. Results: Baseline ECGs revealed sinus rhythm in 137 patients. Thirteen patients had newly onset AF during follow-up. In 30 patients, baseline ECG showed AF. Patients with baseline AF showed higher atrial diameters and higher right atrial pressure. Patients with P-wave du­ration &gt; 0.11 s had shorter survival. Other ECG parameters (PQ-interval, QRS-width, QT-/ /QTc-interval) were not associated with survival. Mean survival times were 79.4 ± 5.4 months (sinus rhythm), 64.4 ± 12.9 months (baseline AF) and 58.8 ± 8.9 months (newly onset AF during follow-up) (p = 0.565). Conclusions: Atrial fibrillation predict adverse prognosis in patients with PH and a longer P-wave (&gt; 0.11 s) is associated with shorter survival time

Use of responder threshold criteria to evaluate the response to treatment in the phase III CHEST-1 study

BackgroundIn the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase - Stimulator Trial 1 (CHEST-1) study, riociguat improved 6-minute walking distance (6MWD) vs placebo in patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. In this study, the proportion of patients who achieved responder thresholds that correlate with improved outcome in patients with pulmonary arterial hypertension was determined at baseline and at the end of CHEST-1.MethodsPatients received placebo or riociguat individually adjusted up to 2.5 mg 3 times a day for 16 weeks. Response criteria were defined as follows: 6MWD increase ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liters/min/m2, pulmonary vascular resistance <500 dyn∙sec∙cm−5, mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg.ResultsRiociguat increased the proportion of patients with 6MWD ≥380 m, World Health Organization functional class I/II, and pulmonary vascular resistance <500 dyn∙sec∙cm−5 from 37%, 34%, and 25% at baseline to 58%, 57%, and 50% at Week 16, whereas there was little change in placebo-treated patients (6MWD ≥380 m, 43% vs 44%; World Health Organization functional class I/II, 29% vs 38%; pulmonary vascular resistance <500 dyn∙sec∙cm−5, 27% vs 26%). Similar changes were observed for thresholds for cardiac index, mixed venous oxygen saturation, N-terminal pro-brain natriuretic peptide, and right atrial pressure.ConclusionsIn this exploratory analysis, riociguat increased the proportion of patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy achieving criteria defining a positive response to therapy

Alliance or acquisition? A mechanisms‐based, policy‐capturing analysis

Research summary: While alliance researchers view prior partner‐specific alliance experience as influencing firms' subsequent alliance or acquisition decisions, empirical evidence on the alliance versus acquisition decision is surprisingly mixed. We offer a reconciliation by proposing and testing an analytical framework that recognizes prior partner‐specific experiences as heterogeneous along three fundamental dimensions: partner‐specific trust, routines, and value certainty. This allows us to use a policy‐capturing methodology to rigorously operationalize and test our mechanism‐level predictions. We find that all three mechanisms can increase the likelihood of a subsequent alliance or acquisition, and in terms of the comparative choice between alliances versus acquisitions, partner‐specific trust pulls towards alliances, and value certainty pulls towards acquisitions. We conclude with a discussion of the theoretical and empirical implications of our approach and method. Managerial summary: This study focuses on an important corporate decision: When a firm has had an alliance with another firm, how would that experience affect the likelihood of a future alliance or acquisition with that same firm? We first suggest that it will depend on three factors: the level of trust that existed in that prior alliance, the extent to which specific work routines were developed, and the degree to which the firm was able to confidently assess the value of the partner firm's resources. We then find that trust is a particularly strong predictor of future alliances, while confidence regarding value more strongly predicts future acquisitions. In this way, we demonstrate more precisely how past corporate choices can affect (consciously or unconsciously) future ones

Sex-specific differences in chronic thromboembolic pulmonary hypertension. Results from the European CTEPH registry

BACKGROUND Women are more susceptible than men to several forms of pulmonary hypertension, but have better survival. Sparse data are available on chronic thromboembolic pulmonary hypertension (CTEPH). METHODS We investigated sex-specific differences in the clinical presentation of CTEPH, performance of pulmonary endarterectomy (PEA), and survival. RESULTS Women constituted one-half of the study population of the European CTEPH registry (N = 679) and were characterized by a lower prevalence of some cardiovascular risk factors, including prior acute coronary syndrome, smoking habit, and chronic obstructive pulmonary disease, but more prevalent obesity, cancer, and thyroid diseases. The median age was 62 (interquartile ratio, 50-73) years in women and 63 (interquartile ratio, 53-70) in men. Women underwent PEA less often than men (54% vs 65%), especially at low-volume centers (48% vs 61%), and were exposed to fewer additional cardiac procedures, notably coronary artery bypass graft surgery (0.5% vs 9.5%). The prevalence of specific reasons for not being operated, including patient's refusal and the proportion of proximal vs distal lesions, did not differ between sexes. A total of 57 (17.0%) deaths in women and 70 (20.7%) in men were recorded over long-term follow-up. Female sex was positively associated with long-term survival (adjusted hazard ratio, 0.66; 95% confidence interval, 0.46-0.94). Short-term mortality was identical in the two groups. CONCLUSIONS Women with CTEPH underwent PEA less frequently than men, especially at low-volume centers. Furthermore, they had a lower prevalence of cardiovascular risk factors and were less often exposed to additional cardiac surgery procedures. Women had better long-term survival