Leukocyte stimulation of intimal lesion formation is inhibited by treatment with diclofenac sodium and dexamethasone.
This investigation tested the effect of anti-inflammatory agents acting at different levels of the arachidonic acid cascade on leukocyte migration into the vessel wall. An animal model of vasculitis was used in which leukocytes stimulate migration of smooth muscle cells from the media into the intima resulting in formation of intimal lesions. In this model, an endotoxin-soaked thread is implanted in the adventitia along the ventral side of the rat femoral artery. At 2 days, subendothelial and medial leukocyte accumulation occurs exclusively in the ventral half of the vessel. At 14 days, intimal lesions composed primarily of smooth muscle cells are localized to the ventral half of the vessel. Treatment with neither the lipoxygenase inhibitor L-651,392 nor the dual cyclooxygenase and lipoxygenase inhibitor BW755C affected leukocyte migration into the vessel wall or subsequent lesion formation. Treatment with the cyclooxygenase inhibitor diclofenac sodium greatly reduced both leukocyte accumulation and lesion formation, whereas leukocyte migration and lesion formation were nearly totally inhibited by treatment with dexamethasone. Thus, it has been demonstrated that although leukocyte accumulation in the vessel wall stimulates intimal lesion formation, pharmacologic inhibition of leukocyte accumulation prevents lesion formation.
Prescott
M F
MF
Research Department, Pharmaceuticals Division, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
McBride
C K
CK
Venturini
C M
CM
Gerhardt
S C
SC
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004008:Diclofenac / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects*; D016859:Lipoxygenase Inhibitors; D008297:Male; D010640:Phenothiazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011921:Rats, Inbred WKY
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016859:Lipoxygenase Inhibitors; D010640:Phenothiazines; D004008:Diclofenac; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003907:Dexamethasone; C053726:4-bromo-2,7-dimethoxy-3H-phenothiazin-3-one