Cathelicidin LL-37 restoring glucocorticoid function in smoking and lipopolysaccharide-induced airway inflammation in rats / 中华医学杂志(英文版)
Chinese Medical Journal
;
(24): 569-576, 2019.
Article
in English
| WPRIM
| ID: wpr-774811
ABSTRACT
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 enzyme-linked immunosorbent assay (ELISA) and lung tissue histopathological morphology. Expression of histone deacetylase-2 (HDAC2) and phosphorylation 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 ± 3.8 pg/mL, P < 0.01; serum TNF-α 8.9 ± 1.2 vs. 6.7 ± 0.5 pg/mL, P = 0.01; lung TGF-β 122.4 ± 20.8 vs. 81.9 ± 10.8 pg/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 phosphoinositide 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.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pharmacology
/
Smoking
/
Lipopolysaccharides
/
Tumor Necrosis Factor-alpha
/
Rats, Wistar
/
Phosphatidylinositol 3-Kinases
/
Antimicrobial Cationic Peptides
/
Pulmonary Disease, Chronic Obstructive
/
Therapeutic Uses
/
Drug Therapy
Type of study:
Prognostic study
Limits:
Animals
/
Humans
/
Male
Language:
English
Journal:
Chinese Medical Journal
Year:
2019
Type:
Article
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