RT Journal Article
SR Electronic
T1 Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 435
OP 440
DO 10.1124/jpet.301.2.435
VO 301
IS 2
A1 Robert P. Jankov
A1 Xiaoping Luo
A1 Peter Demin
A1 Rukshana Aslam
A1 Vicky Hannam
A1 A. Keith Tanswell
A1 Cecil R. Pace-Asciak
YR 2002
UL http://jpet.aspetjournals.org/content/301/2/435.abstract
AB Bleomycin has been suggested to incite plasma extravasation and influx of inflammatory cells leading to pulmonary fibrosis. We hypothesized that stable analogs of the 12-lipoxygenase product, hepoxilin, may attenuate these effects. We initially investigated the effects of the four hepoxilin analogs (PBT-1 to -4) coadministered intradermally with bleomycin and found that PBT-1 and -2 significantly opposed the vascular permeability effects of bleomycin in rat skin. We subsequently tested the hepoxilin analogs for their actions in opposing the intratracheal bleomycin-evoked acute inflammatory phase of lung fibrosis in the mouse, characterized by a marked accumulation of macrophages and an increase in the rate of collagen synthesis and deposition. We found that the bleomycin-evoked effects on macrophage influx were inhibited by all the hepoxilin analogs (PBT-1, -3, and -4 > PBT-2) administered i.p. for 8 days. Increased total lung collagen was completely abrogated by PBT-1 and -2, whereas PBT-3 and -4 had little effect. A dose-response study with PBT-1 indicated that the effective dose for inhibition of bleomycin-induced inflammatory and histological changes was below 10 μg/day. These studies demonstrate an in vivo action of stable analogs of hepoxilin and support an effect on inflammation and vascular permeability from these novel compounds, especially for PBT-1. The American Society for Pharmacology and Experimental Therapeutics