title: Hepoxilin analogs inhibit bleomycin-induced pulmonary fibrosis in the mouse.
abstract: 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.
authors.affiliation: Programmes in Lung Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Luo
authors.forename: Peter
authors.initials: P
authors.lastname: Demin
authors.forename: Rukshana
authors.initials: R
authors.lastname: Aslam
authors.forename: Vicky
authors.initials: V
authors.lastname: Hannam
authors.forename: A Keith
authors.initials: AK
authors.lastname: Tanswell
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Pace-Asciak
mesh_terms: 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
chemical_list: 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