POLYMER OF PROLINE ANALOG WITH SUSTAINED ANTIFIBROTIC ACTIVITY IN LUNG FIBROSIS

Inhibitors of collagen such as cis-4-hydroxy-L-proline (cHyp) may amel iorate bleomycin (bleo)-induced pulmonary fibrosis. An alternating pol ymer of poly(ethylene glycol) (PEG)-lysine (PEG-Lys) with cHyp attache d 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 a ctivity, we first instilled H-3- and C-14-labeled cHyp polymer in norm al 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. T he 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/s al 4.0 +/- 0.1; Bleo/cHyp polymer, 2.8 +/- 0.3*dagger; Bleo/tHyp poly mer, 4.4 +/- 0.2; and Bleo/PEG-Lys + cHyp, 4.0 +/- 0.1* (*p < 0.05 ve rsus Control; dagger 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 c ollagen was similar to 700-fold less than monomeric cHyp. Thus, the cH yp polymer is a potent, long-acting antifibrotic agent which may be us eful in treating lung fibrosis.