A small molecule very late antigen-4 antagonist can inhibit ovalbumin-induced lung inflammation.
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.
Koo
Gloria C
GC
Merck Research Laboratories, Rahway, NJ 07065, USA. gloria_koo@merck.com
Shah
Kashmira
K
Ding
Gloria J F
GJ
Xiao
Jianying
J
Wnek
Richard
R
Doherty
George
G
Tong
Xin Chun
XC
Pepinsky
R Blake
RB
Lin
Ko-Chung
KC
Hagmann
William K
WK
Kawka
Douglas
D
Singer
Irwin I
II
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
D039041:Integrin alpha4beta1; D010047:Ovalbumin