A major response system of the rat to inflammation and injury is the T-kininogen-T-kinin system. In these disorders, the liver immediately synthesizes enormous quantities of the protein, T- kininogen, which is followed by the release of the potent vasoactive mediator T-kinin (ile-ser-bradykinin) from T-kininogen into the blood and inflammatory fluids. Our laboratory was the first to describe the system and name the components. The significance of the system is that it represents the acute response of the body to injury and that its components, including T- kininogen, can be easily measured in the blood by procedures developed in this laboratory. We have described the isolation of two T-kininogens from rat blood whose structure is now known and shown to contain T-kinin in peptide linkage. T-kininogen differs in structure from the classic high molecular weight and low moleuclar weight kininogens. We have recognized the presence of T-kgnase, an enzyme that releases T-kinin, in inflammatory fluids and other tissues including the submandibular gland of some species. The proposed investigation seeks to further understand the pharmacological importance of the system """"""""in vivo"""""""" by investigating the components of the system in model inflammatory systems in the presence and absence of anti- inflammatory drugs. Four major approaches will be carried on over the next three years in the following order of priority: Isolation and identification of the properties of T-kgnase from the rat. 2. Quantitation of T-kgnase in tissues and fluids in the normal and inflammatory states and how anti-inflammatory agents affect this activity. This study will be carried out in the rat. 3. The affect of anti-inflammatory agents on the mRNA of pre-T-kininogen in rat liver. 4. Studies in humans with chronic arthritides and related inflammatory diseases in terms of plasma profiles of kininogens. Studies on human ascitic fluids (which have now been reported to contain T-kinin) for its relationship to T-kgnase levels. 5. Studies on T-kinin receptors especially those involving the release other mediators (prostanoids).
