Effect of histone deacetylase 2 and 4 activity on connective tissue disease associated pulmonary fibrosis in mice

Abstract

Objective: To investigate the effect of histone deacetylase (HDAC) activity on connective tissue diseases (CTD) associated pulmonary fibrosis (PF) in mice. Methods: A single tracheal administration of bleomycin induced PF in C57BL/6J male mice was performed to establish a PF model. The experimental mice were divided into three groups: bleomycin group (group B, n = 16) which was given bleomycin A2 physiological saline solution 2.5 μl/g body weight, saline group (Group C, n = 16) which was given physiological saline solution 2.5 μl/g body weight and no operation group (group N, n = 16). At 7, 14 and 21 days after administration, the animals were randomly killed and their specimens were collected. The activity of HDAC2 and HDAC4 was detected by colorimetry. Hematoxylin-eosin staining was used to evaluate pulmonary alveolitis and Masson staining for pulmonary fibrosis. The variance, correlation and binary variable correlation were analyzed. Results: The HDAC2 activity in lung tissue of mice in the bleomycin group was significantly higher than that in the no operation group (2.00±0.40 vs 1.00±0.23, P<0.05) and the saline group (2.00±0.40 vs 1.48±0.33, P<0.05). The HDAC2 activity in the bleomycin group was significantly higher than that in the no operation group (2.40±0.28 vs 1.00±0.23, P<0.01, 2.23±0.41 vs 1.00±0.23, P<0.01) and the saline group (2.40±0.28 vs 1.39±0.23, P<0.05, 2.23±0.41 vs 1.35±0.42, P<0.05). The change trend of HDAC2 activity between the bleomycin group and the saline group was different. There was no significant difference in HDAC4 activity in lung tissue of mice between the bleomycin group, the no operation group and the saline group. 14 days after tracheal administration, HDAC4 activity in the bleomycin group and the saline group were significantly higher than that in the no operation group (1.18±0.36 vs 1.00±0.12, P<0.01, 1.09±0.33 vs 1.00±0.12, P<0.01). HDAC2 activity in lung tissue of mice was positively correlated with pathological scores of alveolitis (r=0.428, P<0.01) and pulmonary fibrosis (r=0.508, P<0.01). HDAC4 activity in lung tissue of mice was positively correlated with the pathological scores of alveolitis (r=0.355, P<0.05) and pulmonary fibrosis (r=0.457, P<0.01). Binary linear regression analysis showed that HDAC2 activity had a stronger effect on the process of PF lesions than HDAC4 activity in lung tissue of mice. Conclusions: When pulmonary fibrosis occurred in mice, the activities of HDAC2 and 4 in pulmonary fibrosis were significantly increased. The activity of HDAC2 increased rapidly and lastingly, and the activity of HDAC4 fluctuated significantly and increased briefly. Changes in HDAC2 activity have stronger effects on alveolitis and fibrosis than HDAC4.