The long-term objective of this project is to obtain a better understanding of a new mechanism of pulmonary edema and hemorrhage, namely mechanical stress disruption of pulmonary capillaries. Pulmonary edema and is a common, serious condition and the elucidation of its mechanisms is therefore of great importance. We propose novel basic studies of the regulation of the support structures of the capillary wall, and also to continue studies of the conditions in which stress failure of the blood-gas barrier (BGB) occurs. The first group of specific aims is devoted to the regulation of the support structures of the capillary wall and includes studies of gene expression of extra cellular matrix proteins, other components of basement membranes, and growth factors in animal models where capillary wall stress is increased. These include an isolated perfused rat lung preparation where capillary wall stress is increased by raising capillary transmural pressure, or inflating the lung to high volumes. In addition we will study induced heart failure in dogs where the pulmonary capillary pressure is increased over several weeks. The second group of specific aims is devoted to conditions where the BGB fails when the capillary pressure is raised. These include the lungs of neonatal and prematurely born rabbits where the capillaries are at risk from stress failure because of the complex changes in the pulmonary circulation that occur at birth. It is possible that some cases of the infant respiratory distress syndrome are caused by stress failure of pulmonary capillaries. Our work to date on this project has been very productive. The identification of stress failure as the mechanism of pulmonary edema and hemorrhage has important clinical implications in many diseases, and it is apparently a cause of ventilator-induced lung injury. In addition, at the more basic level, this research is devoted to a fundamental bioengineering dilemma of the lung, namely, that the blood-gas barrier has to combine extreme thinness with immense strength.
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