Abstract

During the past project period mechanisms of granulocyte- mediated tissue damage, particularly endothelial injury, have been investigated. Insights into atherogenesis and pulmonary vascular leak syndromes have been gained. The active involvement of granulocytes, particularly their adhesion and production of toxic oxygen species, has been analyzed, but the participation of endothelial cells in attracting, and stimulating, effector granulocytes has been largely ignored. The proposed studies will redress this chauvinism and explore changes in intrinsic adhesivity of endothelium after its perturbation by several agonists. First, the effects of endothelial exposure to model agonists including phorbol esters, calcium ionophore, toxic oxidants, and thrombin will be studied; special attention will be directed to altered exhibition/secretion of 3 potential adhesogens produced by cultured endothelium: namely, von Willebrand Factor, Platelet Activating Factor, and thrombospondin. In addition, correlations between increased endothelial adhesivity and increased cytosolic Ca++ and protein kinase C activity of endothelium will be sought. Second, previous interest in the possible role of herpes viruses in atherogenesis will be extended by proposed studies of effects of Herpes Simplex Virus (HSV) infections of endothelial monolayers; we shall particularly probe the role of HSV-induced neo-receptors for C3b and the Fc portion of immunoglobulin in attracting granulocytes with their associated cytotoxic potential. Third, effects on endothelial integrity of two inflammatory cell constituents which can be deposited on vascular walls will be examined; that is, lactoferrin from PMNs, and monocyte tumor necrosis factor have been implicated in vascular damage wrought by immune complexes and by endotoxin shock, respectively. Their effects on endothelial adhesivity will be studied. Following the aforementioned perturbations, endothelial cytotoxicity will be measured in vitro as well as in vivo using a rabbit skin edema model.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL028935-25
Application #
3485949
Study Section
Special Emphasis Panel (NSS)
Project Start
1982-02-01
Project End
1997-01-31
Budget Start
1993-02-01
Budget End
1994-01-31
Support Year
25
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
University of Minnesota Twin Cities
Department
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Kovacs, A; Weber, M L; Burns, L J et al. (1996) Cytoplasmic sequestration of p53 in cytomegalovirus-infected human endothelial cells. Am J Pathol 149:1531-9
Balla, J; Nath, K A; Balla, G et al. (1995) Endothelial cell heme oxygenase and ferritin induction in rat lung by hemoglobin in vivo. Am J Physiol 268:L321-7
Paller, M S; Jacob, H S (1994) Cytochrome P-450 mediates tissue-damaging hydroxyl radical formation during reoxygenation of the kidney. Proc Natl Acad Sci U S A 91:7002-6
Jacob, H S (1994) Newly recognized causes of atherosclerosis: the role of microorganisms and of vascular iron overload. J Lab Clin Med 123:808-16
Belcher, J D; Balla, J; Balla, G et al. (1993) Vitamin E, LDL, and endothelium. Brief oral vitamin supplementation prevents oxidized LDL-mediated vascular injury in vitro. Arterioscler Thromb 13:1779-89
Balla, J; Belcher, J D; Balla, G et al. (1993) Oxidized low-density lipoproteins and endothelium: oral vitamin E supplementation prevents oxidized low-density lipoprotein-mediated vascular injury. Trans Assoc Am Physicians 106:128-33
Cermak, J; Balla, J; Jacob, H S et al. (1993) Tumor cell heme uptake induces ferritin synthesis resulting in altered oxidant sensitivity: possible role in chemotherapy efficacy. Cancer Res 53:5308-13
Balla, J; Jacob, H S; Balla, G et al. (1993) Endothelial-cell heme uptake from heme proteins: induction of sensitization and desensitization to oxidant damage. Proc Natl Acad Sci U S A 90:9285-9
Balla, J; Jacob, H S; Balla, G et al. (1992) Endothelial cell heme oxygenase and ferritin induction by heme proteins: a possible mechanism limiting shock damage. Trans Assoc Am Physicians 105:1-6
Jacob, H S; Visser, M; Key, N S et al. (1992) Herpes virus infection of endothelium: new insights into atherosclerosis. Trans Am Clin Climatol Assoc 103:95-104

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