Abstract

Based on published observations that the ventilated lung was injured during ischemia, before reperfusion, and preliminary studies suggesting that both addition of glucose and reduction of intravascular volume worsened this injury, and that antioxidant enzyme (AOE) gene expression was induced during ischemia, this proposal will investigate the following hypotheses: (1) Injury during ventilated ischemia is caused by generation of oxygen radicals, which increase permeability by activating protein kinase C (PKC) (2) Glucose may worsen this injury by augmenting oxygen radical generation or PKC activation, (3) Decreasing intravascular volume may worsen injury by altering mechanical forces acting on the vessel walls, thereby decreasing production of nitric oxide (NO). Decreased NO could exacerbate injury, as NO can scavenge superoxide anion, or activate cGMP, thereby relaxing endothelial cells and enhancing barrier function, and (4) Increased expression of AOE during ischemia may be caused by oxygen radicals or the cytokines, tumor necrosis factor- alpha and interleukin-1 (IL-1).

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002933-03
Application #
2210811
Study Section
Research Training Review Committee (RTR)
Project Start
1993-09-30
Project End
1998-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Pearse, David B; Shimoda, Larissa A; Verin, Alexander D et al. (2003) Effect of cGMP on lung microvascular endothelial barrier dysfunction following hydrogen peroxide. Endothelium 10:309-17
Pearse, D B; Becker, P M; Permutt, S (2001) Effect of changing vascular volume on measurement of protein reflection coefficient in ischemic lungs. Am J Physiol Heart Circ Physiol 280:H918-24
Becker, P M; Alcasabas, A; Yu, A Y et al. (2000) Oxygen-independent upregulation of vascular endothelial growth factor and vascular barrier dysfunction during ventilated pulmonary ischemia in isolated ferret lungs. Am J Respir Cell Mol Biol 22:272-9
Pearse, D B; Becker, P M (2000) Effect of time and vascular pressure on permeability and cyclic nucleotides in ischemic lungs. Am J Physiol Heart Circ Physiol 279:H2077-84
Becker, P M; Sanders, S P; Price, P et al. (1998) F2-isoprostane generation in isolated ferret lungs after oxidant injury or ventilated ischemia. Free Radic Biol Med 25:703-11