HDAC2 ALLEVIATES IL-17A-MEDIATED AIRWAY REMODELING IN COPD BY INHIBITING AIRWAY INFLAMMATION AND FIBROBLAST ACTIVITY

Yahui Cao, Jianfeng Peng, Fan Yang, Xiaoyi Hu, Chaowen He^*

Department of Respiratory and Critical Care Medicine, Shenzhen Longhua District Central Hospital, Shenzhen 518110, Guangdong Province, China

Objective: To investigate the effect of histone deacetylase 2 (HDAC2) and interleukin-17A (IL-17A) on airway remodeling in chronic obstructive pulmonary emphysema (COPD). 

Methods: Ten male SPF wild type (WT) mice were randomly divided into a WT air group and a WT CS group. Ten HDAC2^+/− mice were randomly divided into an HDAC2^+/− air group and an HDAC2^+/− CS group. Ten IL-17A^−/− mice were randomly divided into an IL-17A^−/− air group and an IL-17A^−/− CS group. The COPD model was induced by cigarette smoke (CS) exposure in the CS group, HDAC2^+/− CS group and IL-17A^−/− CS group, at 100 cigarettes a day, 5 days a week for 3 months. After 3 months, the mice were killed and their right lungs were taken for experiment. The expression of the HDAC2 protein in lung tissue of the WT air group and the WT CS group, and the expression of the IL-17A protein in lung tissue of the WT air group, WT CS group, HDAC2^+/− air group and HDAC2^+/− CS group were observed. The levels of chemokine ligand 1 (CXCL1), CXCL2 and IL-6, goblet cell proliferation, peribronchial collagen deposition, and smooth muscle hyperplasia in lung tissue of the CS group, HDAC2^+/− CS group, IL-17A^−/− air group and IL-17A^−/− CS group were recorded. Normal human airway epithelial cells were randomly divided into the WT air group, WT CS group and HDAC2^+/− CS group. The cells in the WT air group were not treated. The cells in the WT CS group and HDAC2^+/− CS group were induced by CS to establish a COPD cell model. The expression levels of HDAC2 in the WT air group and WT CS group, and the IL-17A expression level in the WT air group, WT CS group and HDAC2^+/− CS group, were compared. 

Results: The expression of HDAC2 protein in lung tissue of the WT CS group was significantly lower than that of the WT air group (P<0.05). The levels of CXCL1, CXCL2, IL-6, TGF-β-1, goblet cell proliferation, peribronchial collagen deposition, and smooth muscle hyperplasia in the WT CS and HDAC2^+/− CS groups were higher than those in the WT air group (P<0.05), and the levels of CXCL1, CXCL2, IL-6, TGF-β-1, goblet cell proliferation, peribronchial collagen deposition, and smooth muscle hyperplasia in lung tissue of the HDAC2^+/− CS group were higher than those of the WT group CS group was significantly higher (P<0.05). There was no significant difference in CXCL1, CXCL2, IL-6, TGF-β-1 levels, goblet cell proliferation, peribronchial collagen deposition, and smooth muscle hyperplasia between the WT air group and HDAC2^+/− air group (P>0.05). The expression levels of IL-17A protein in lung tissue of the WT CS group and the HDAC2^+/− CS group were significantly higher than that of the WT air group (P<0.05), and the expression level of IL-17A protein in lung tissue of the HDAC2^+/− CS group was significantly higher than that of the WT CS group (P<0.05). There was no significant difference in IL-17A protein expression between the WT air group and the HDAC2^+/− air group (P>0.05). The expression of HDAC2 in airway epithelium of the WT CS group was significantly lower than that of the WT air group (P<0.05). The expression level of IL-17A in airway epithelium of the WT CS group and the HDAC2^+/− CS group was significantly higher than that of the WT air group (P<0.05), and the expression level of IL-17A in the HDAC2^+/− CS group was significantly higher than that in the WT CS group (P<0.05). The levels of CXCL1, CXCL2, IL-6, TGF-β-1, goblet cell proliferation, peribronchial collagen deposition, and smooth muscle hyperplasia in the IL-17A^−/− CS group were lower than those in the WT CS group (P<0.05). 

Conclusion: HDAC2 can alleviate airway remodeling in COPD induced by IL-17A by blocking airway inflammation and fibroblast activity.