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Background Glucocorticoids have been widely used to treat patients with chronic obstructive pulmonary disease (COPD).Nevertheless,corticosteroid insensitivity is a major barrier to the effective treatment of COPD and its mechanism remains unclear.This study aimed to evaluate the effect of cathelicidin LL-37 on corticosteroid insensitivity in COPD rat model,and to explore the involved mechanisms.Methods COPD model was established by exposing male Wistar rats to cigarette smoke combined with intratracheal instillation of lipopolysaccharide (LPS).Inhaled budesonide and LL-37 were consequently applied to COPD models separately or collectively to confirm the effects on inflammatory cytokines (tumor necrosis factor [TNF]-α and transforming growth factor [TGF]-β) by enzymelinked immunosorbent assay (ELISA) and lung tissue histopathological morphology.Expression of histone deacetylase-2 (HDAC2) and phosphorylaton of Akt (p-AKT) in lung were also measured.Results Briefly,COPD model rats showed an increased basal release of inflammatory cytokines (lung TNF-α:45.7±6.1 vs.20.1±3.8pg/mL,P＜0.01;serum TNF-α:8.9±1.2 vs.6.7±0.5pg/mL,P=0.01;lung TGF-β:122.4±20.8 vs.81.9±10.8pg/mL,P ＜ 0.01;serum TGF-β:38.9 ± 8.5 vs.20.6 ± 2.3 pg/mL,P ＜ 0.01) and COPD related lung tissue histopathological changes,as well as corticosteroid resistance molecular profile characterized by an increase in phosphoinositde 3-kinase (PI3K)/Akt (0.5 ± 0.1 fold of control vs.0.2 ± 0.1 fold of control,P=0.04) and a decrease in HDAC2 expression and activity (expression:13.1 ± 0.4 μmol/μg vs.17.4 ± 1.1 μmol/μg,P ＜ 0.01;activity:1.1 ± 0.1 unit vs.1.4 ± 0.1 unit,P ＜ 0.01),compared with control group.In addition,LL-37 enhanced the anti-inflammatory effect of budesonide in an additive manner.Treatment with combination of inhaled corticosteroids (ICS) and LL-37 led to a significant increase of HDAC2 expression and activity (expression:15.7 ± 0.4 μmol/μg vs.14.1± 0.9 μmol/μg,P＜0.01;activity:1.3±0.1 unit vs.1.0±0.1 unit,P＜0.01),along with decrease of p-AKT compared to budesonide monotherapy (0.1 ± 0.0 fold of control vs.0.3 ± 0.1 fold of control,P ＜ 0.01).Conclusions This study suggested that LL-37 could improve the anti-inflammatory activity of budesonide in cigarette smoke and LPS-induced COPD rat model by enhancing the expression and activity of HDAC2.The mechanism of this function of LL-37 might involve the inhibition of PI3K/Akt pathway.