title: A small molecule very late antigen-4 antagonist can inhibit ovalbumin-induced lung inflammation.
abstract: A nonpeptidyl small molecule antagonist, compound A, to nonactivated very late antigen-4 (VLA4) was examined in lung inflammation induced by a single dose of ovalbumin challenge. Compound A presented a good pharmacokinetic property, when given intratracheally, and the blood cells from such pharmacokinetic study showed good receptor occupancy of the compound for approximately 8 hours. Compound A was then tested in an ovalbumin-induced airway inflammation model by intranasal or intravenous route of administration. There was a dose-dependent inhibition of eosinophilia in the bronchiolar lavage fluid, when compound A was given intranasally but not when it was given intravenously. For comparison, antibody to VLA4 and another compound, BIO1211, which reacts only with activated VLA4, were examined in this system. Immunohistochemical analyses of the lung tissue substantiated the findings in the bronchiolar lavage fluid. Specific staining of the major basic protein of eosinophils showed peribronchiolar infiltration of eosinophils. Some of these eosinophils were also positive for nitrotyrosine, suggesting activation of eosinophils in the lung interstitium. There was deposition of major basic protein and nitrotyrosine at the base of the perivascular endothelium, indicative of degranulation of eosinophils in the area. After intranasal treatment with compound A, eosinophils in the lungs and their activation products were substantially decreased, documenting its effectiveness in inhibiting lung inflammation.
authors.affiliation: Merck Research Laboratories, Rahway, NJ 07065, USA. gloria_koo@merck.com
authors.forename: Gloria C
authors.initials: GC
authors.lastname: Koo
authors.forename: Kashmira
authors.initials: K
authors.lastname: Shah
authors.forename: Gloria J F
authors.initials: GJ
authors.lastname: Ding
authors.forename: Jianying
authors.initials: J
authors.lastname: Xiao
authors.forename: Richard
authors.initials: R
authors.lastname: Wnek
authors.forename: George
authors.initials: G
authors.lastname: Doherty
authors.forename: Xin Chun
authors.initials: XC
authors.lastname: Tong
authors.forename: R Blake
authors.initials: RB
authors.lastname: Pepinsky
authors.forename: Ko-Chung
authors.initials: KC
authors.lastname: Lin
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
authors.forename: Douglas
authors.initials: D
authors.lastname: Kawka
authors.forename: Irwin I
authors.initials: II
authors.lastname: Singer
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001707:Biopsy, Needle; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D011014:Pneumonia / Q000188:drug therapy* / Q000473:pathology*; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity
chemical_list: D039041:Integrin alpha4beta1; D010047:Ovalbumin