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[Effect of aerosolized STAT1 antisense oligonucleotides on the expressions of cytokines and collagens in lung tissue of pulmonary fibrosis rats induced by bleomycin].

OBJECTIVE
To investigate the effects of aerosolized signal transducer and activator of transcription 1 (STAT1) antisense oligonucleotides (ASON) on the expressions of TGF-beta(1), PAI-1, collagen Type I and III and hydroxyproline in lung tissue of pulmonary fibrosis induced by bleomycin (BLM) in rats.


METHODS
Forty-five adult female Wistar rats were randomly divided into 3 groups: normal saline (NS) group, BLM group and ASON group. The BLM group and the ASON group were intratracheally instilled with BLM while the NS group was instilled with NS. The NS group and the BLM group were aerosolized with NS while the ASON group was aerosolized with STAT1 ASON on day 0, 2, 4, and 6. Then the rats were killed on day 7, 14, and 28. TGF-beta(1) and PAI-1 protein in the tissue of left lung were assessed by immunohistochemistry. The mRNA levels of collagen type I and III of right lung were measured by reverse transcriptase-polymerase chain reaction (RT-PCR). The content of hydroxyproline was also examined.


RESULTS
Compared with the BLM group, the scores of alveolitis and fibrosis in the ASON group were remarkably reduced. Both TGF-beta(1) and PAI-1 protein in lung tissue in the BLM group and the ASON group were significantly higher as compared with the NS group. Compared with the BLM group, the mRNA levels of collagen type I and III in the ASON group were decreased. At day 7, 14 and 28, the mRNA levels of collagen type I and III in the ASON group were 1.36 +/- 0.10, 1.19 +/- 0.28, 1.22 +/- 0.24 and 1.20 +/- 0.09, 0.62 +/- 0.09, 0.76 +/- 0.12, respectively, both increased significantly as compared to those in the BLM group (3.29 +/- 0.28, 2.04 +/- 0.25, 1.91 +/- 0.30 and 1.63 +/- 0.15, 1.58 +/- 0.13, 1.12 +/- 0.09, respectively). The content of hydroxyproline (mg/g) in lung tissue in the ASON group at day 7, 14 and 28 was 3.02 +/- 0.13, 3.24 +/- 0.31, and 3.60 +/- 0.16, respectively, which were lower than those of the BLM group (3.76 +/- 0.10, 3.92 +/- 0.30, and 4.62 +/- 0.28, respectively).


CONCLUSIONS
Aerosolized STAT1 ASON inhibited alveolitis and fibrosis in BLM-induced pulmonary fibrosis, via inhibition of the expression of PAI-1 and TGF-beta(1), decrease of the mRNA levels of collagen Type I and III, and the reduction of hydroxyproline production.