title: Involvement of chymase in allergic conjunctivitis of guinea pigs.
abstract: It has been reported that chymase activity was increased in allergic conjunctivitis patients and this activity was correlated with the severity of the disease. However, the precise roles of chymase in allergic conjunctivitis are unclear, and whether chymase inhibitors are effective for allergic conjunctivitis has not been reported even in experimental animal models. In this study, the roles of chymase in the pathogenesis were evaluated using a selective chymase inhibitor, ONO-WH-236, in a guinea pig model of allergic conjunctivitis induced by cedar pollen. Sensitized guinea pigs were challenged by the pollen, followed by assessing redness and edema in the conjuntiva, and counting the frequency of eye scratching as an itch-associated response. Treatment with the ONO-WH-236 (40 and 80 mg/kg, p.o.) dose-dependently inhibited the induction of redness, edema and scratching behavior. An anti-histaminic drug, ketotifen (3 mg/kg, p.o.), also significantly inhibited conjunctivitis symptoms. Chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge. The increase in chymase activity was inhibited by in vivo treatment with ONO-WH-236. Interestingly, increased histamine in the ophthalmic lavage fluid immediately after the challenge was also inhibited by the chymase inhibitor. Administration of human recombinant chymase by eye dropping (0.09 and 0.9 μg/eye) dose-dependently induced scratching behavior, which was inhibited by not only ONO-WH-236 but also ketotifen; however, chymase administration induced only weak redness in the conjunctiva, which was resistant to treatment with anti-histaminic drugs. In conclusion, it was suggested that chymase was released from mast cells after antigen challenge, followed by the induction of conjunctivitis symptoms through histamine release from mast cells. Thus, chymase could be a potential target for pharmacotherapy for allergic conjunctivitis.
authors.affiliation: Department of Pharmacology, Kyoto Pharmaceutical University, 5 Nakauchi, Misasagi, Yamashina, Kyoto 607-8414, Japan. nabe@mb.kyoto-phu.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nabe
authors.forename: Yurie
authors.initials: Y
authors.lastname: Kijitani
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Kitagawa
authors.forename: Emi
authors.initials: E
authors.lastname: Sakano
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ueno
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujii
authors.forename: Shintaro
authors.initials: S
authors.lastname: Nakao
authors.forename: Masaru
authors.initials: M
authors.lastname: Sakai
authors.forename: Shinji
authors.initials: S
authors.lastname: Takai
mesh_terms: D000485:Allergens / Q000494:pharmacology; D000818:Animals; D053818:Chymases / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D003233:Conjunctivitis, Allergic / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000502:physiology; D007665:Ketotifen / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000473:pathology; D011058:Pollen; D011537:Pruritus / Q000517:prevention & control; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D000485:Allergens; D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D011994:Recombinant Proteins; D006632:Histamine; D053818:Chymases; D007665:Ketotifen
keywords: 7-amino-4-methylcoumarin; AMC; CIS; DMSO; IL; MC(T); MC(TC); NO; NOS; OLF; PAR; allergic conjunctivitis; allergic itch; cedar pollen; chymase; conjuctivitis intensity score; dimethyl sulfoxide; histamine; interleukin; mast cells; nitric oxide; nitric oxide synthase; ophthalmic lavage fluid; protease-activated receptor; scratching; tryptase-positive mast cells; tryptase-positive, chymase-positive mast cells