Polymer of proline analogue with sustained antifibrotic activity in lung fibrosis

Mark J. Greco, John E. Kemnitzer, James D. Fox, Jin K. Choe, Joachim Kohn, David J. Riley, George J. Poiani

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 close required to produce 50% inhibition of lung collagen was ~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.

Original languageEnglish (US)
Pages (from-to)1391-1397
Number of pages7
JournalAmerican journal of respiratory and critical care medicine
Volume155
Issue number4
DOIs
StatePublished - 1997

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine
  • Pulmonary and Respiratory Medicine

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