Mj. Greco et al., POLYMER OF PROLINE ANALOG WITH SUSTAINED ANTIFIBROTIC ACTIVITY IN LUNG FIBROSIS, American journal of respiratory and critical care medicine, 155(4), 1997, pp. 1391-1397
Citations number
32
Categorie Soggetti
Emergency Medicine & Critical Care","Respiratory System
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.