Regulation of the L-arginine – ADMA – Nitric Oxide (NO) Pathway in the Pulmonary Vascular Response to Hypoxia and its Role for Survival of High-Risk COPD Patients | HORIZON | CORDIS

Chronic obstructive lung disease (COPD) afflicts many individuals in Europe; the number of people affected is increasing. It is a progressive disease that causes breathlessness and physical incapacity, it is a cause of many concomitant diseases of the heart and blood vessels, and it often leads to early death. Amongst COPD patients, those who suffer from transient intervals with lack of oxygen (hypoxia), e.g. during sleep or during physical exercise, are suspected to develop a faster decline of lung function, which might be linked to intermittent phases of high blood pressure in the lung circulation (pulmonary hypertension) and to poorer prognosis. The project NO PRESSURE has been designed to study the role of chronic intermittent hypoxia on the progression of COPD and the development of pulmonary hypertension. In experimental studies, the involvement of a specific biochemical pathway that has previously been shown by our group and other researchers to be involved in hypoxia-induced pulmonary hypertension will be studied in cell culture models and in genetically modified mice. Healthy humans will be screened for the presence of genetic variants in genes coding for enzymes of this pathway; those who carry specific genetic variants will be exposed to high altitude in the European Alpes. The response of the lungs, the heart, and the blood circulation to the lack of oxygen at high altitude will be studied by us. Biosamples from a large European study of lung disease will be analyzed to find out if blood biomarkers can be identified that allow to detect COPD patients who suffer from intermittent phases of hypoxia. Finally, we will collaborate with the world’s largest study in COPD to validate our results and ascertain the links between genes, biomarkers, and disease progression. With the data generated during this project, we hope to contribute to a more sophisticated diagnosis and a more personalized therapy of COPD, one that is adjusted to the individual risk of progression. This may add to efforts of reducing the morbidity and mortality of COPD.

In the cell culture experimental part of our project, we have completed much of the cell culture work including protein and RNA analyses, respectively, in lung alveolar cells and pulmonary vascular endothelial cells. Our data so far show significant regulation of the DDAH/ADMA/NO pathway in lung alveolar cells during hypoxia, which is a novel finding. Much less regulation occurs in pulmonary endothelial cells. We have also completed the Next Generation RNA Sequencing experiments as planned in order to address the signaling pathways and redox mechanisms involved. Currently, bioinformatics-based data analysis of this data set is ongoing. The next step will be the experimental validation of our findings. We have successfully generated two new lines of cell type-specifically genetically modified mice; these animals are currently being subjected to experimental hypoxia in order to study the changes in the lungs, heart, and blood vessels. A first clinical study with humans has also already been completed; after genetic screening of more than 200 healthy young men and women, we have successfully recruited four genetically characterized groups of healthy men and women to participate in the clinical study at the High Altitude Research Station Jungfraujoch at 3,450 M above sea level. Each participant completed a baseline study at sea level as well as repeat studies on days 1 to 7 of high altitude exposure according to our study protocol. Data analyses and biochemical analyses of the acquired frozen samples are currently ongoing. Finally, we have advanced quite far regarding the final work package that focuses on translation of our experimental findings to COPD patients. For one, we have completed biomarker analysis in a large, multinational European Survey on lung health, from which we received biosamples and access to follow-up data. In this study, data analysis is ongoing. Second, we have signed an agreement with the steering committee of the world’s largest study on COPD, from which we will receive several thousand blood samples for analysis and conduct data analysis to validate our hypothesis on the association of intermittent hypoxaemia, biomarkers, and disease progression in this large cohort of COPD patients. The next step here, after receipt of the sample shipment, will be biomarker measurements that will keep our laboratory busy during the forthcoming year, followed by statistical analyses.

Whilst it is still too early in the project course to jubilee about any major breakthroughs yet, we are very confident that upon full analysis of the ALTIGENE Study, we will be able to generate significant breakthroughs in our understanding of the integrated physiological adaptations of the organism to high altitude hypoxia, including metabolic adaptation, cardiovascular adaptation – specifically adaptation of the pulmonary vasculature –, adaptation of exercise capacity, and its genetic modulation. These advances will relay to a better understanding of the pathophysiology of the impact that intermittent hypoxaemia has on the cardiometabolic system in COPD patients.

Regulation of the L-arginine – ADMA – Nitric Oxide (NO) Pathway in the Pulmonary Vascular Response to Hypoxia and its Role for Survival of High-Risk COPD Patients

Periodic Reporting for period 1 - NO PRESSURE (Regulation of the L-arginine – ADMA – Nitric Oxide (NO) Pathway in the Pulmonary Vascular Response to Hypoxia and its Role for Survival of High-Risk COPD Patients)

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