The long-term objective of this project is to obtain a better understanding of a hitherto unrecognized mechanism of pulmonary edema and hemorrhage, namely mechanical stress disruption of pulmonary capillaries. Pulmonary edema is a common, serious condition which complicates many forms of heart and lung disease, and the elucidation of its mechanisms is therefore of great importance. In studies to date, we have found that when the pulmonary capillary pressure is raised in anesthetized rabbits to 40 mmHg and above, disruption of the capillary endothelium and alveolar epithelium occurs in numerous locations. We propose to continue to elucidate the principal forces acting on the capillary wall. 1.) Circumferential wall tension caused by the transmural pressure. this factor will be studied by perfusing the lung with autologous blood at increased capillary pressures in an anesthetized rabbit preparation, rapidly fixing the capillaries by infusion of glutaraldehyde at the same pressure, and examining the ultrastructural appearances by electron microscopy. 2.) Surface tension of the alveolar lining layer. Since the studies to date indicate that capillaries bulge into the alveolar spaces at high pressures, the surface tension of the alveolar lining layer presumably contributes considerable support. this factor will be studied by abolishing the surface tension by saline-filling of the lung. the ultrastructure of the capillary wall will then be studied as indicated above. 3.) The tension of the tissue elements in the alveolar wall associated with lung inflation. this factor is studied by altering lung volume in a systematic manner at known capillary transmural pressures. Measurements will also be made in dog and rat lung to determine if the findings on the rabbit are species dependent. Studies will also be done after the capillary pressure has been raised for different periods of time. The effects of pulsatile pressure will be compared with steady pressure. the biochemical and cellular composition of the resulting alveolar edema fluid will be investigated. Different types of tissue fixation will be compared (e.g. airway fixation vs. vascular perfusion). Capillary morphology will be studied in racehorses and dogs which are known to bleed into their lungs after heavy exercise. Finally the ultrastructure of capillaries of dog lungs exposed to chronically elevated venous pressure will be studied. The identification of stress failure as a mechanism of pulmonary edema has important clinical implications. There is evidence that it plays an important role in high altitude pulmonary edema, neurogenic pulmonary edema, and pulmonary hemorrhage in racehorses. At a 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 great strength.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL046910-01A2
Application #
3366080
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1993-09-01
Project End
1997-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
1
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Breen, Ellen C; Tang, Kechun (2003) Calcyclin (S100A6) regulates pulmonary fibroblast proliferation, morphology, and cytoskeletal organization in vitro. J Cell Biochem 88:848-54
Maron, M B; Fu, Z; Mathieu-Costello, O et al. (2001) Effect of high transcapillary pressures on capillary ultrastructure and permeability coefficients in dog lung. J Appl Physiol 90:638-48
Breen, E C (2000) Mechanical strain increases type I collagen expression in pulmonary fibroblasts in vitro. J Appl Physiol 88:203-9
Gerard, A B; McElroy, M K; Taylor, M J et al. (2000) Six percent oxygen enrichment of room air at simulated 5,000 m altitude improves neuropsychological function. High Alt Med Biol 1:51-61
West, J B (2000) Invited review: pulmonary capillary stress failure. J Appl Physiol 89:2483-9;discussion 2497
Breen, E C; Fu, Z; Normand, H (1999) Calcyclin gene expression is increased by mechanical strain in fibroblasts and lung. Am J Respir Cell Mol Biol 21:746-52
Hopkins, S R; Schoene, R B; Henderson, W R et al. (1998) Sustained submaximal exercise does not alter the integrity of the lung blood-gas barrier in elite athletes. J Appl Physiol 84:1185-9
Luks, A M; van Melick, H; Batarse, R R et al. (1998) Room oxygen enrichment improves sleep and subsequent day-time performance at high altitude. Respir Physiol 113:247-58
West, J B; Mathieu-Costello, O (1998) Stress-induced injury of pulmonary capillaries. Proc Assoc Am Physicians 110:506-12
Roca, J; Gavin, T P; Jordan, M et al. (1998) Angiogenic growth factor mRNA responses to passive and contraction-induced hyperperfusion in skeletal muscle. J Appl Physiol 85:1142-9

Showing the most recent 10 out of 25 publications