Fibrin deposition and leukocyte accumulation are classic hallmarks of inflammation and tissue injury in virtually all tissues. In recent years increasing research has begun to focus on the mediators and mechanisms which control extravascular fibrin deposition and leukocyte accumulation. Unfortunately very little is known about the contribution of fibrin and leukocytes to endocular inflammation in general, and corneal endothelial cells injury specifically. To closely investigate the role of fibrin and leukocytes in CEC injury we have developed the following specific hypothesis. We hypothesize that injury to ocular tissue, whether initiated by immunologic, infectious or chemical agents, will immediately trigger local fibrinogen metabolism characterized by both fibrin deposition and fibrinolysis. This fibrinogen metabolism results in the generation of phlogistic fibrinogen-derived factors or FDF (e.g. fibrin, and fibrinopeptides) which then mediates a two step process of CEC injury. In Step 1 fibrin deposition and metabolism results in direct and immediate CEC injury, characterized by CEC retraction and vacuolization with the resulting loss of cellular integrity and function. Step 2 of the FDF induced CEC injury is initiated by the resulting local production of FDF and CEC-derived leukocyte chemotactic factors (LCF). These locally produced chemotactic factors specifically induce 1) the hyperadherence of leukocytes to CEC; 2) the migration of these leukocytes between CEC and beneath CEC onto Decemet's membrane; 3) the activation of leukocytes in situ, productive of tissue-toxic factors such as oxygen metabolites and proteases which amplify CEC injury and corneal edema. Thus, both fibrin(ogen) metabolites and CEC-derived factors likely collaborate as important phlogistic mediators that can directly and indirectly injure CEC, ultimately resulting in a loss of CEC number and function as well as corneal inflammation. Thus identifying the various mediators and mechanisms that control FDF induced CEC injury is clearly central to the development of therapeutic approaches to minimize corneal injury. To this end we have developed the following Specific Aims.
Specific Aim 1 : To determine the mediators and mechanisms by which fibrinogen derived factors (FDF) induce injury of corneal endothelial cells (CEC) in vitro.
Specific Aim 2 : To characterize the leukocyte chemotactic factors which are produced in response to fibrinogen derived factor mediated CEC injury in vitro.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY004131-06
Application #
3258618
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1982-04-01
Project End
1992-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Connecticut
Department
Type
School of Medicine & Dentistry
DUNS #
City
Farmington
State
CT
Country
United States
Zip Code
06030
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