- First opponent: Professor Kurt Stenmark, University of Colorado, USA
- Second opponent: Professor Leif Bjermer, Lund University, Sweden
- Third member and chair of the evaluation committee: Associate Professor Signe Spetalen, University of Oslo
Chair of the Defence
Professor II Kjetil Sunde, University of Oslo
Associate Professor Karl-Otto Larsen, Oslo University Hospital
Pulmonary hypertension is a serious condition, which might evolve secondary to chronic respiratory diseases and low oxygen levels in the lungs (hypoxia). There are several factors contributing to the development of pulmonary hypertension, and in this thesis we focus on pulmonary hypertension caused by hypoxia, found in several chronic respiratory diseases. We have studied hypoxia in experimental models and in mountaineers exposed to hypoxia, during ascent to Mount Everest.
Interestingly, alveolar hypoxia activates innate immunity. Our research group has previously shown that the innate immune system and the inflammasome seem to be essential in the development of hypoxia-induced pulmonary hypertension. Inflammasome-activation leads to a caspase-1-mediated inflammation. We investigated the role of caspase-1 in the development of hypoxia-induced inflammation, subsequent development of pulmonary hypertension, and alternations in cardiac function and structure.
We found attenuation of pulmonary inflammation, reduced muscularization in pulmonary arteries, and reduction in pulmonary hypertension and right heart remodelling in caspase-1 deficient mice exposed to hypoxia.
Mountaineers exposed to extreme altitude showed reduced left ventricular muscle mass, while a similar reduction in right ventricle muscle mass was not observed. One can speculate if opposing mechanisms act upon the right ventricle, by a hypertrophic stimulus due to hypoxia-induced pulmonary hypertension, opposed by wasting of the myocardium as found in the left ventricle.
Taken together, our data indicate that hypoxia induce activation of caspase-1, mediating release of IL-18 and IL-6, which lead to proliferation of smooth muscle cells in pulmonary arteries and development of pulmonary hypertension.
We have identified a pathway, which includes several therapeutic targets for treatment of pulmonary hypertension and heart failure related to alveolar hypoxia.