Polymer of proline analogue with sustained antifibrotic activity in lung fibrosis

Am J Respir Crit Care Med. 1997 Apr;155(4):1391-7. doi: 10.1164/ajrccm.155.4.9105084.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bleomycin
  • Collagen / antagonists & inhibitors
  • Delayed-Action Preparations
  • Drug Carriers
  • Hydroxyproline / administration & dosage*
  • Hydroxyproline / analogs & derivatives
  • Hydroxyproline / therapeutic use
  • Instillation, Drug
  • Liposomes
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Polyethylene Glycols
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Trachea

Substances

  • Delayed-Action Preparations
  • Drug Carriers
  • Liposomes
  • Bleomycin
  • Polyethylene Glycols
  • Collagen
  • Hydroxyproline