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When, as a young chief resident at the University Hospital in Lausanne, Switzerland, I needed to complete my postdoc studies with a research project, I had only one wish: to get it behind me as quickly as possible in order to resume my clinical work (and real interest) without delay. So, it was not without hesitation that, in January 1995, I accepted Professor Scherrer's offer to join his small but very active research group for 2 (long) years. In the end, my reluctant decision was made because of the opportunity to participate in one of the group's high-altitude research projects.

And, to my surprise, my first ascent to a high-altitude research laboratory at the Capanna Regina Margherita (elevation 4559 meters, located on the Swiss-Italian border) got me hooked. I haven't left Professor Scherrer's laboratory and medical research since. The reason is that I quickly learned that what initially appeared to me an exotic scientific pastime had important implications for my everyday clinical activity.

I was interested in the underlying regulatory mechanisms involved in the adaptation to high altitude. I chose as the focus of my research the most important cause of mortality at high altitude, high-altitude pulmonary edema (HAPE). At the time I started my research in this field, there was rather convincing evidence that, when exposed to high altitude, HAPE-susceptible subjects show an excessive increase in pulmonary artery pressure leading to the rupture of small blood vessels in the lung and pulmonary edema, but the mechanism was unknown. During the first two summers spent at the high-altitude laboratory, I was able to demonstrate that both a defect of the vascular endothelium (reduced synthesis of the vasorelaxant agent nitric oxide and increased production of vasoconstrictor substance endothelin-1) and increased stimulation of sympathetic vasoconstrictor nerves at the pulmonary circulation contribute to the exaggerated pulmonary vasoconstriction during high-altitude exposure.

I then turned my attention to possible genetic and or acquired defects that may predispose someone to such exaggerated pulmonary hypertension at high altitude. Based on a hypothesis derived from studies in rats, I was able to show that in humans, a transient pathological event during the first few days of life predisposes a person to exaggerated pulmonary hypertension during high-altitude exposure in adulthood. However, the most interesting outcome was that the exaggerated pulmonary hypertension did not trigger pulmonary edema during high-altitude exposure in these young adults who had suffered from a transient pulmonary vascular insult during their neonatal period. This unexpected observation suggested that during high-altitude exposure, excessive fluid flooding of the lung (caused by the disproportionate pulmonary vasoconstriction) by itself was not sufficient to trigger HAPE, and that a coexisting defect of the lung fluid clearance may be needed to result in pulmonary edema. I therefore turned my attention to the mechanisms involved in the sodium and water transport from the alveolar space to the interstitium (alveolar fluid clearance).

To this end, we developed and characterized a transgenic mouse model with a defect of the pulmonary transepithelial sodium and water transport. We could show that this defect markedly augments the susceptibility to pulmonary edema of these mice. We then turned our attention to HAPE-susceptible humans and demonstrated that they suffer from a defect of the transepithelial sodium and water transport in the lung, a defect that was further aggravated during high-altitude exposure. Most importantly, this defect indeed seems to play a role in the pathogenesis of pulmonary edema, because in HAPE-susceptible subjects, prophylactic stimulation of this transport prevents pulmonary edema during high-altitude exposure. These findings provided the very first demonstration of the importance of the alveolar fluid clearance, both in pathogenesis and as a therapeutic target, in a human form of pulmonary edema.

Stimulated by these results, I spent 2 years in Professor Matthay's group in San Francisco to pursue my work on the role of the alveolar fluid clearance in the pathogenesis of pulmonary edema. This also gave me the opportunity to learn new techniques for studying the molecular and cellular mechanisms involved in the regulation of ion and water transport across the alveolar epithelium under both normal and pathological conditions, thus simulating acute lung injury in vitro.

Recently, I returned to Dr Scherrer's group in Switzerland, and I am presently working in the Bolivian Altiplano where I am directing a research project on the role of pulmonary hypertension and transepithelial sodium transport in the pathogenesis of the respiratory distress syndrome of the newborn. Indeed, we firmly believe that our findings in HAPE can be extended to this and other frequent and clinically important forms of pulmonary edema such as the one associated with heart failure or acute respiratory distress syndrome, thereby further demonstrating the importance of medical research under extreme high-altitude conditions to medical knowledge and public health in general.

For those who would like find out more about high-altitude medicine, the best way is to attend some international congresses (Annual Meeting of the American Thoracic Society, International Hypoxia Meetings, Congress of the International Society of Mountain Medicine) during which it will be easy to meet the leaders of research groups active in this field. As in my case, it may mark the beginning of a new scientific passion.