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 language||English (US)|
|Number of pages||7|
|Journal||American journal of respiratory and critical care medicine|
|State||Published - 1997|
All Science Journal Classification (ASJC) codes
- Critical Care and Intensive Care Medicine
- Pulmonary and Respiratory Medicine