LIPOSOME ENCAPSULATION IMPROVES THE EFFECT ED ANTIFIBROTIC AGENT IN RAT LUNG FIBROSIS

We studied whether the therapeutic efficacy of the antifibrotic agent cis-4-hydroxy-L-proline (cHyp) in preventing bleomycin-induced pulmona ry fibrosis in rats is enhanced by intratracheal delivery in liposomes . Dual-radiolabeled liposomes were used to study the distribution and stability of liposomes after intratracheal instillation. Lung retentio n was > 20% 1 wk after intratracheal instillation of 9 mu mol phosphol ipid, and liposomes were intact as indicated by the ratio of the lipid and aqueous-phase markers remaining unchanged. For the fibrosis study , groups of rats were instilled with 1.2 U bleomycin (Bleo) and treate d 1 and 2 wk later by single intratracheal instillation of test compou nds. The control group received 0.3 ml saline (Bleo/sal). The treated groups received 9 mu mol phospholipid in 0.3 ml of the following lipos ome preparations: empty liposomes (Bleo/lip), liposomes and 100 mg/kg of free unencapsulated cHyp (Bleo/lip/cHyp), and 100 mg/kg of liposome -encapsulated cHyp (Bleo/lip-cHyp). At 3 wk, fibrosis (mg hydroxyproli ne/g weight lung) by groups was as follows: control, 2.6 +/- 0.1 (SEM) ; Bleo/sal, 3.2 +/- 0.1, Bleo/lip, 3.2 +/- 0.1, and Bleo/lip/cHyp, 3.1 +/- 0.1, p < 0.05 compared with control; Bleo/lip-cHyp, 2.6 +/- 0.1, p < 0.05 compared with Bleo/sal, n = 3 to 6. Histologic grading of fib rosis did not show decreased fibrosis in the Bleo/lip-cHyp group, prob ably because of the focal nature of the fibrotic lesions. We conclude that cHyp encapsulated in liposomes prevents bleomycin-induced fibrosi s by biochemical measurements. Delivery of antifibrotic agents to the lung in carrier vehicles promotes retention and may enhance their effi cacy in treating bleomycin-induced pulmonary fibrosis.