title: Polymer of proline analogue with sustained antifibrotic activity in lung fibrosis.
abstract: Inhibitors of collagen such as cis-4-hydroxy-L-proline (cHyp) may ameliorate bleomycin (bleo)-induced pulmonary fibrosis. An alternating polymer of poly(ethylene glycol) (PEG)-lysine (PEG-Lys) with cHyp attached as a pendant side chain was prepared for intratracheal delivery with bioinactive trans-Hyp (tHyp) polymer as control. To test whether the cHyp polymer has prolonged lung retention and sustained antifibrotic activity, we first instilled 3H- and 14C-labeled cHyp polymer in normal rats. Lung retention was 86 +/- 9% at 6 h and 29 +/- 3% at 7 d (n = 5). Next, rats were instilled intratracheally with either saline (sal) or 1.2 U bleo, and the following treatment groups were studied: Bleo/sal; Bleo/cHyp polymer; Bleo/tHyp polymer; and Bleo/PEG-Lys + cHyp. The dose of the test agents was 150 mg/kg polymer containing 8.5 mg/kg cHyp or tHyp instilled intratracheally at 7 and 14 d after bleo. At 21 d, hydroxyproline content (mg/lung) was: Control, 1.8 +/- 0.1; Bleo/sal 4.0 +/- 0.1*; Bleo/cHyp polymer, 2.8 +/- 0.3*+; Bleo/tHyp polymer, 4.4 +/- 0.2*; and Bleo/PEG-Lys + cHyp, 4.0 +/- 0.1* (*p < 0.05 versus Control; +p < 0.05 versus Bleo/sal; n = 5/group). The cHyp polymer also reduced lung total protein content, but the decrease was not significant. The dose required to produce 50% inhibition of lung collagen was approximately 700-fold less than monomeric cHyp. Thus, the cHyp polymer is a potent, long-acting antifibrotic agent which may be useful in treating lung fibrosis.
authors.affiliation: Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Greco
authors.forename: J E
authors.initials: JE
authors.lastname: Kemnitzer
authors.forename: J D
authors.initials: JD
authors.lastname: Fox
authors.forename: J K
authors.initials: JK
authors.lastname: Choe
authors.forename: J
authors.initials: J
authors.lastname: Kohn
authors.forename: D J
authors.initials: DJ
authors.lastname: Riley
authors.forename: G J
authors.initials: GJ
authors.lastname: Poiani
mesh_terms: D000818:Animals; D001761:Bleomycin; D003094:Collagen / Q000037:antagonists & inhibitors; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006909:Hydroxyproline / Q000008:administration & dosage* / Q000031:analogs & derivatives / Q000627:therapeutic use; D007322:Instillation, Drug; D008081:Liposomes; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D011092:Polyethylene Glycols; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014132:Trachea
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D008081:Liposomes; D001761:Bleomycin; D011092:Polyethylene Glycols; D003094:Collagen; D006909:Hydroxyproline