Hepoxilin analogs inhibit bleomycin-induced pulmonary fibrosis in the mouse

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 301; no. 2; p. 435
• Main Authors: Jankov, Robert P, Luo, Xiaoping, Demin, Peter, Aslam, Rukshana, Hannam, Vicky, Tanswell, A Keith, Pace-Asciak, Cecil R
• Format: Journal Article
• Language: English
• Published: United States 01-05-2002
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - therapeutic use; Animals; Bleomycin; Disease Models, Animal; Male; Mice; Mice, Inbred CBA; Pulmonary Fibrosis - chemically induced; Pulmonary Fibrosis - drug therapy; Rats; Rats, Wistar
• DOI: 10.1124/jpet.301.2.435
• ISSN: 0022-3565

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.