Polymorphonuclear leukocytes (PMN) play a role in the development of high permeability edema (HPLE) in many animal models but the mechanisms by which PMN cause the edema are not all known. Using an in vitro model of the endothelium, I will examine the ability of nonoxidant, nonproteolytic neutrophil-derived cationic proteins to mediate edema formation. Previous work has shown that cationic agents are able to increase vascular permeability in many different capillary beds. In preliminary studies it was found that neutrophil cationic proteins, inactive neutrophil elastase and the polycation protamine can increase albumin transfer across an endothelium. Protamine also increased the hydraulic conductivity (LP) of the endothelium. The proposed study will focus on determining the mechanism of action of these cationic proteins. Initial studies will focus on confirming the ability of these agents to increase albumin permeability and the hydraulic conductivity of the endothelium. The importance of the cationic charge of these molecules in their effects on endothelial integrity will also be evaluated. Later studies will focus on how these cationic molecules alter the endothelium including the effect of neutralizing the negative luminal surface charge on endothelium, the direct toxicity of these cationic proteins to endothelial cells, the action of the cationic proteins on the lipid membrane of endothelial cells, and the ability of the cationic proteins to unmask surface receptors on the endothelial cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08HL001844-01
Application #
3082235
Study Section
(SRC)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Nygaard, S D; Ganz, T; Peterson, M W (1993) Defensins reduce the barrier integrity of a cultured epithelial monolayer without cytotoxicity. Am J Respir Cell Mol Biol 8:193-200
Peterson, M W; Gruenhaupt, D (1992) Protamine interaction with the epithelial cell surface. J Appl Physiol 72:236-41
Peterson, M W; Geist, L J; Schwartz, D A et al. (1991) Outcome after cardiopulmonary resuscitation in a medical intensive care unit. Chest 100:168-74
Peterson, M W; Gruenhaupt, D (1990) A23187 increases permeability of MDCK monolayers independent of phospholipase activation. Am J Physiol 259:C69-76
Peterson, M W; Gruenhaupt, D (1990) Protamine increases the permeability of cultured epithelial monolayers. J Appl Physiol 68:220-7
Hampson, F; Monick, M; Peterson, M W et al. (1989) Immune mediators increase adherence of T-lymphocytes to human lung fibroblasts. Am J Physiol 256:C336-40
Peterson, M W (1989) Neutrophil cathepsin G increases transendothelial albumin flux. J Lab Clin Med 113:297-308
Peterson, M W; Gruenhaupt, D; Shasby, D M (1989) Neutrophil cathepsin G increases calcium flux and inositol polyphosphate production in cultured endothelial cells. J Immunol 143:609-16
Peterson, M W; Nugent, K M; Jolles, H et al. (1988) Uniformity of bronchoalveolar lavage in patients with pulmonary sarcoidosis. Am Rev Respir Dis 137:79-84
Rochat, T; Casale, J; Hunninghake, G W et al. (1988) Neutrophil cathepsin G increases permeability of cultured type II pneumocytes. Am J Physiol 255:C603-11

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