The long-term objective of this project is to obtain a better understanding of the properties of the pulmonary blood-gas barrier and, in particular, the conditions under which stress failure occurs resulting in pulmonary edema and hemorrhage. Pulmonary edema is a common, serious condition and elucidation of its mechanisms is therefore of great importance. The first group of Specific Aims is devoted to a better understanding of the factors responsible for the strength of the blood-gas barrier. Since it is now recognized that two distinct mechanisms are responsible for increasing stress in the barrier, namely increased capillary transmural pressure, and the forces resulting from lung inflation, we plan to compare the structure of the barrier in animals that expand their lungs with animals that have a virtually rigid lung, that is the bird. We shall also measure the minimal thickness of the blood-gas barrier by morphometric techniques and relate this to the breaking stress of type IV collagen. The second Specific Aim is devoted to failure of the blood-gas barrier. We shall look at the lungs of ducks, geese and chickens where the barrier is known to be extremely thin, and recent work shows a surprising degree of bleeding into the alveolar spaces. A final Specific Aim is devoted to a related project, namely the vulnerability of pleural capillaries under conditions of negative pressure breathing. Our work to date on this project has been very productive. The identification of stress failure has clarified various aspects of human pathology such as the mechanism of high-altitude pulmonary edema, and the damage to pulmonary capillaries caused by high states of lung inflation. We also discovered the mechanism of exercise-induced pulmonary hemorrhage in racehorses. In addition, at the more basic level, this research is devoted to a fundamental biological dilemma of the lung, namely how the blood-gas barrier combines extreme thinness with immense strength. ? ?
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