Hepoxilin analogs inhibit bleomycin-induced pulmonary fibrosis in the mouse.
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 microg/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.
Jankov
Robert P
RP
Programmes in Lung Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Luo
Xiaoping
X
Demin
Peter
P
Aslam
Rukshana
R
Hannam
Vicky
V
Tanswell
A Keith
AK
Pace-Asciak
Cecil R
CR
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use*; D000818:Animals; D001761:Bleomycin; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar
C454100:10-hydroxy-11,12-cyclopropyleicosa-5,8,14-trienoic acid methyl ester; C454099:8-hydroxy-11,12-cyclopropyleicosa-5,9,14-trienoic acid methyl ester; C453725:PBT-3 compound; D001761:Bleomycin; D015126:8,11,14-Eicosatrienoic Acid