ROLE OF PROSTAGLANDIN, THROMBOXANE AND RELATED AUTACOIDS

We have thus far determined the capacities of different ocular tissues such as conjunctiva, anterior uvea and cornea of various species (including monkey and human) to synthesize cyclooxygenase products: prostaglandins (PGs) PGE2, PGF2alpha, PGI2, PGD2 and thromboxane A2, and lipoxygenase products: monohydroxy acids and leukotrienes, from arachidonic acid (AA). In this proposal, we plan to study the roles these products play in the three phases (initiation, maintenance and termination) of ocular inflammation, especially the cellular inflammatory response. Their interaction with each other and other putative mediators such as histamine, bradykinin and chemotactic formylmethionyl polypeptide will be studied as well. In order to investigate the role of AA metabolites as either mediators or modulators, we will study the following using rabbits, cats and rats: 1) correlate the endogenous synthesis and release of PGs, thromboxane and leukotrienes with polymorphonuclear leukocytes (PMNs) infiltration of ocular fluids and tissues and breakdown of the blood-aqueous barrier during three phases of ocular inflammation. Three types of inflammation models will be used: a) paracentesis (no cellular response), b) endotoxin-induced uveitis (all inflammatory responses present) and c) corneal deepithelialization. 2) determine whether or not exogenous PGs and leukotrienes produce one or all inflammatory responses, administered alone or in combination with other autacoids to the normal eye. 3) determine whether or not drugs (steroidal and nonsteroidal), which interfere with AA metabolism at various enzymatic steps, affect one or all inflammatory responses in the three experimentally induced inflammation models outlined above. These studies will also be correlated with measuring the PMN count, leukotriene content and PG levels in tear fluids of volunteers with contact lens allergies. These studies will help in understanding the mechanism of mediators of ocular inflammation and development of new anti- inflammatory drugs.