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Inflammatory disorders such as sepsis are a major cause of morbidity and mortality. Mitochondrial dysfunction is considered a key factor in the pathogenesis of severe inflammation. In the present study, we aimed to investigate the impact of arachidonic acid, omega-3 ( n -3) fatty acids, and n -3-derived lipid mediators 18 R -HEPE and resolvin (Rv) E1 on mitochondrial function in experimental inflammation. The results revealed that, in contrast to n -6 and n -3 fatty acids, both 18 R -HEPE and RvE1 possess anti-inflammatory and anti-apoptotic properties. Both mediators are able to restore inflammation-induced mitochondrial dysfunction, which is characterized by a decrease in mitochondrial respiration and membrane potential, as well as an imbalance of mitochondrial fission and fusion. Furthermore, inhibition of mitochondrial fission by Mdivi-1 and Dynasore reduces levels of the pro-inflammatory cytokines IL-6 and IL-8. These results suggest a novel functional mechanism for the beneficial effects of RvE1 in inflammatory reactions. [ABSTRACT FROM AUTHOR]

Background Thyroid disease is common in patients with pulmonary hypertension (PH), but its effect on long-term survival remains unknown. We examined the prognostic significance of thyroid hormone levels of free triiodothyronine (fT3) and free thyroxine and thyroid-stimulating hormone (TSH), and thyroid hormone replacement (THR) therapy in PH. Methods We conducted a retrospective analysis of 1,756 patients enrolled in the Giessen PH Registry in 1999 to 2013 with baseline thyroid function data; of these, 355, 533, 498, and 370 had pulmonary arterial hypertension (PAH); including 192 with idiopathic PAH (iPAH), PH due to left heart disease, PH due to lung diseases, and chronic thromboembolic PH (CTEPH), respectively. Thyroid function parameters associated with mortality were identified using Cox regression and Kaplan-Meier analyses. Results Transplant-free survival at 1, 3, and 5 years was 86.7%, 65.6%, and 53.0%, respectively. Absence of THR therapy was an independent predictor of death in iPAH (multivariate hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06–5.75). In patients without THR therapy, TSH levels in the lowest and highest quartiles (compared with the middle 2 quartiles) independently predicted death in iPAH (HR, 1.98; 95% CI, 1.07–3.67), whereas reduced fT3 levels were independently associated with increased death in PAH (HR, 8.30; 95% CI, 2.50–25.00) and CTEPH (HR, 1.79; 95% CI, 1.14–4.20). Conclusions Thyroid hormone levels and THR therapy are prognostic factors in iPAH, PAH, and CTEPH. Prospective studies are warranted to verify the prognostic significance of thyroid function and the effect of THR therapy in PH. [ABSTRACT FROM AUTHOR]

Abstract: Hypoxic pulmonary vasoconstriction (HPV) is an essential physiological mechanism of the lung that matches blood perfusion with alveolar ventilation to optimize gas exchange. Perturbations of HPV, as may occur in pneumonia or adult respiratory distress syndrome, can cause life-threatening hypoxemia. Despite intensive research for decades, the molecular mechanisms of HPV have not been fully elucidated. Reactive oxygen species (ROS) and changes in the cellular redox state are proposed to link O2 sensing and pulmonary arterial smooth muscle cell contraction underlying HPV. In this regard, mitochondria and NAD(P)H oxidases are discussed as sources of ROS. However, there is controversy whether ROS levels decrease or increase during hypoxia. With this background we summarize the current knowledge on the role of ROS and redox state in HPV. [ABSTRACT FROM AUTHOR]

γ-glutamyl transferase (GGT), the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers in several cardiovascular diseases, but their relevance in pulmonary hypertension (PH) is not fully understood. We aimed to assess their prognostic value in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH). We retrospectively analyzed 731 incident patients with idiopathic PAH or CTEPH who entered the Giessen PH registry during 1993–2019. A risk stratification score based on GGT, AST/ALT ratio, and NLR tertiles was compared with a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification scheme. Associations with survival were evaluated using Kaplan-Meier and Cox regression analyses. External validation was performed in 311 patients with various types of PAH or CTEPH from a second German center. GGT levels, AST/ALT, and NLR independently predicted mortality at baseline and during follow-up. The scoring system based on these biomarkers predicted mortality at baseline and during follow-up (both log-rank p < 0.001; hazard ratio [95% confidence interval], high vs low risk: baseline, 7.6 [3.9, 15.0]; follow-up, 13.3 [4.8, 37.1]). Five-year survival of low, intermediate, and high risk groups was 92%, 76%, and 51%, respectively, at baseline and 95%, 78%, and 50%, respectively, during follow-up. Our scoring system showed characteristics comparable to the ESC/ERS scheme, and predicted mortality in the validation cohort. GGT, AST/ALT, and NLR were reliable prognostic biomarkers at baseline and during follow-up, with predictive power comparable to the gold standard for risk stratification. [ABSTRACT FROM AUTHOR]

The updated hemodynamic definition of pulmonary hypertension (PH) due to interstitial lung disease (ILD) differentiates severe and non-severe phenotypes, but no further risk stratification strategy has been established or validated for severe PH due to ILD. We aimed to assess the prognostic value of a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH risk stratification scheme in severe PH due to ILD. We retrospectively analyzed 185 patients with severe PH (mean pulmonary artery pressure of ≥35 mm Hg or ≥25 mm Hg with cardiac index <2.0 liter/min/m2) due to ILD who were enrolled in the Giessen PH Registry after being referred for invasive diagnostic work-up of suspected PH during 1995‒2018. A truncated ESC/ERS risk stratification scheme (based on 8 parameters from the full scheme) was applied. Kaplan–Meier and univariate Cox regression analyses were used to evaluate transplant-free survival and hazard ratios, respectively. During follow-up (median [interquartile range]: 19 [7–40] months), 146 events occurred. Using baseline data for risk stratification, 5-year transplant-free survival of low-, intermediate-, and high-risk groups was 43%, 15%, and 4%, respectively (log-rank p = 0.010; hazard ratio of high- vs low-risk group: 3.116 [95% CI: 1.428–6.800]). Using follow-up data (at 11 [6.0–32.5] months) for risk stratification, 5-year survival of low-, intermediate-, and high-risk groups was 22%, 3%, and 0%, respectively (log-rank p = 0.005). The truncated ESC/ERS scheme was clinically useful and demonstrated prognostic relevance in severe PH due to ILD. [ABSTRACT FROM AUTHOR]

Background Pulmonary hypertension (PH) is a severe, progressive disease. Although 5 PH subgroups are recognized, reports on survival have focused mainly on pulmonary arterial hypertension (PAH). Methods Long-term transplant-free survival and its determinants were investigated in patients with PH (diagnosed by right heart catheterization) within a prospective registry at a single referral center in Giessen, Germany. Results In total, 2,067 patients were enrolled (PAH, 685 patients [33.1%]; pulmonary venous hypertension, 307 patients [14.9%]; PH due to lung diseases (LD-PH), 546 patients [26.4%; mainly interstitial lung disease and chronic obstructive pulmonary disease]; chronic thromboembolic PH, 459 patients [22.2%]; PH owing to miscellaneous/unknown causes, 70 patients [3.4%]). Median follow-up was 37 months. Differences in transplant-free survival between etiologic groups were highly significant ( p < 0.001), with 1-, 3- and 5-year survival rates of 88.2%, 72.2% and 59.4%, respectively, for those with PAH compared with 79.5%, 52.7% and 38.1%, respectively, for patients with LD-PH. Patients’ age, gender and 6-minute walk distance (6MWD), but not New York Heart Association (NYHA) functional class, associated significantly with survival across all PH subtypes in multivariate Cox regression analyses. Conclusions This is the largest single-center PH cohort described so far. Some parameters used in clinical practice do not independently predict survival. Age, gender and 6MWD outperformed NYHA functional class in predicting survival across all etiologic groups. [ABSTRACT FROM AUTHOR]

Elevated CO2 concentrations (hypercapnia) occur in patients with severe lung diseases. Here, we provide evidence that high CO2 levels decrease O2 consumption and ATP production and impair cell proliferation independently of acidosis and hypoxia in fibroblasts (N12) and alveolar epithelial cells (A549). Cells exposed to elevated CO2 died in galactose medium as well as when glucose-6-phosphate isomerase was knocked down, suggesting mitochondrial dysfunction. High CO2 levels led to increased levels of microRNA-183 (miR-183), which in turn decreased expression of IDH2 (isocitrate dehydrogenase 2). The high CO2-induced decrease in cell proliferation was rescued by α-ketoglutarate and overexpression of IDH2, whereas proliferation decreased in normocapnic cells transfected with siRNA for IDH2. Also, overexpression of miR-183 decreased IDH2 (mRNA and protein) as well as cell proliferation under normocapnic conditions, whereas inhibition of miR-183 rescued the normal proliferation phenotype in cells exposed to elevated levels of CO2. Accordingly, we provide evidence that high CO2 induces miR-183, which down-regulates IDH2, thus impairing mitochondrial function and cell proliferation. These results are of relevance to patients with hypercapnia such as those with chronic obstructive pulmonary disease, asthma, cystic fibrosis, bronchopulmonary dysplasia, and muscular dystrophies. [ABSTRACT FROM AUTHOR]

Increased release of mitochondrial superoxide has been suggested to mediate acute hypoxic pulmonary vasoconstriction (HPV) as well as chronic hypoxia-induced pulmonary hypertension (PH) and right heart remodeling. Thus, we investigated the superoxide release during HPV, chronic hypoxia-induced PH and after pulmonary arterial banding (PAB), as well as the effect of the mitochondria-targeted antioxidant MitoQ on these processes. Superoxide levels were increased in PASMC during acute hypoxia and decreased after 5 days of hypoxia. In parallel MitoQ, but not its inactive carrier substance, TPP+, significantly inhibited acute HPV and the rise in superoxide concentration induced by acute hypoxia. However, MitoQ application did not affect the hypoxia-induced proliferation of PASMC or the development of chronic hypoxia-induced PH. In contrast, MitoQ application attenuated right ventricular remodeling after chronic hypoxic exposure as well as after PAB with regard to development of right heart hypertrophy and dilatation. Increased superoxide concentration mediates acute HPV, while decreased superoxide levels were detected in chronic hypoxia-induced PH. MitoQ may be beneficial under conditions of exaggerated acute HPV and to prevent the development of right heart remodeling. [ABSTRACT FROM AUTHOR]

Introduction Increased release of mitochondrial superoxide has been suggested to mediate acute hypoxic pulmonary vasoconstriction (HPV) as well as chronic hypoxia-induced pulmonary hypertension (PH) and right heart remodeling. Thus, we investigated the superoxide release during HPV, chronic hypoxia-induced PH and after pulmonary arterial banding (PAB), as well as the effect of the mitochondria-targeted antioxidant MitoQ on these processes. Results Superoxide levels were increased in PASMC during acute hypoxia, and decreased after 5 days of hypoxia. In parallel MitoQ, but not its inactive carrier substance, TPP+, significantly inhibited acute HPV and the rise in superoxide concentration induced by acute hypoxia. However, MitoQ application did not affect the hypoxia-induced proliferation of PASMC or the development of chronic hypoxia-induced PH. In contrast, MitoQ application attenuated right ventricular remodeling after chronic hypoxic exposure as well as after PAB with regard to development of right heart hypertrophy and dilatation. Accordingly, superoxide levels were increased in the RV after PAB. Conclusion Increased superoxide concentration mediates acute HPV, while decreased superoxide levels were detected in chronic hypoxia-induced PH. MitoQ may be beneficial under conditions of exaggerated acute HPV and to prevent the development of right heart remodeling. [ABSTRACT FROM AUTHOR]