Mechanisms underlying pulmonary hypertension in a rat model of bronchopulmonary dysplasia.
Published: 2004
Language: eng
Number of pages: 171
Description: Abnormalities of the pulmonary circulation have long been recognised to contribute to the morbidity and mortality of bronchopulmonary dysplasia, a common condition of extremely premature infants in which oxidant stress is believed to play a major role and for which there is presently no effective treatment. The hallmark of bronchopulmonary dysplasia is an arrest in alveolar and capillary development. A major circulatory manifestation of bronchopulmonary dysplasia is pulmonary hypertension due to vasoconstriction and increased muscularisation of pulmonary resistance vessels. Animal studies suggest that altered function and structure of the pulmonary circulation may adversely affect alveolar development. Newborn rats exposed to 60% O2 for 14 days develop pulmonary hypertension and parenchymal lung abnormalities that have close morphological similarities to human bronchopulmonary dysplasia. Previous interventional studies in this model have demonstrated that the development of pulmonary hypertension is dependent upon macrophage influx to the lung and up-regulation of endothelin-1, a potent vasoconstrictor peptide. In the studies reported herein, I demonstrated that increased macrophage influx is responsible for the increased reactive oxygen species formation and protein nitration in the lungs of newborn rats exposed to 60% O2 for 14 days. A consequence of oxidant stress is the formation of 8-isoprostane, a bioactive product of lipid peroxidation, which leads to the up-regulation of endothelin-1 production in smooth muscle cells, a major cellular source in the 60% O2-exposed lung. Treatment with a thromboxane A 2 receptor antagonist, but not a cyclooxygenase-2 inhibitor, abrogated these effects, suggesting that the thromboxane A2 receptor ligand causing increased endothelin-1 in the O2-exposed lung was not a cyclooxygenase-2 product, but rather an incidental ligand, such as 8-isoprostane. Finally, the platelet-derived growth factors (-AA and -BB) and insulin-like growth factor-I are identified as mitogens, and endothelin-1 and 8-isoprostane as survival factors, of cultured pulmonary artery smooth muscle cells from infant rats, implicating them as direct mediators of pathological smooth muscle proliferation.
Notes: Adviser: Alan Keith Tanswell.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2336.