title: A mucoactive drug carbocisteine ameliorates steroid resistance in rat COPD model.
abstract: Steroid insensitivity has been commonly found in chronic obstructive pulmonary disease (COPD) patients, which is mediated by the reduction of histone deacetylase (HDAC) 2. Here we aimed to establish a steroid resistant model on experimental COPD rats and evaluate the effect of carbocisteine (S-CMC), a mucoactive drug. Exposure to cigarette smoke (CS) caused marked pathological features of COPD which are insensitive to DEX associated with the down-regulation of HDAC2 expression/activity. The DEX insensitivity observed in COPD featured rats was improved by S-CMC in the aspects of inhibiting chronic lung inflammation (total and differential inflammatory cell counts, inflammatory cytokines release and inflammatory cells infiltration); ameliorating airway remodeling (thickness of airway epithelium and smooth muscle, airway fibrosis, and the level of α-SMA and TGF-β1); improving emphysema (emphysema index D2, level of MMP-9 in BALF and the expression of alpha-1 antitrypsin) and preventing impairments of lung function (PEF, IP and IP-slope). Simultaneously, down-regulation of HDAC2 expression/activity was ameliorated by S-CMC treatment. These results indicate that the rat COPD model with steroid resistance was established by active smoking in a short time frame and demonstrate that the failure of steroid therapy can be restored by S-CMC accompanied by increasing HDAC2 expression/activity, providing additional evidence that S-CMC might be used for GC resistance in COPD.
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Juan-Juan
authors.initials: JJ
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Hao-Zhong
authors.initials: HZ
authors.lastname: Lu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Zhi-Hua
authors.initials: ZH
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: yongyaocui@hotmail.com.
authors.forename: Yong-Yao
authors.initials: YY
authors.lastname: Cui
mesh_terms: D000818:Animals; D002233:Carbocysteine / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004351:Drug Resistance; D005100:Expectorants / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism; D008297:Male; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012129:Respiratory Function Tests; D012907:Smoking / Q000009:adverse effects; D013997:Time Factors
chemical_list: D016207:Cytokines; D005100:Expectorants; D005938:Glucocorticoids; D002233:Carbocysteine; D003907:Dexamethasone; D056464:Histone Deacetylase 2
keywords: COPD; Carbocisteine; Carbocisteine (PubChem CID: 193653); Cigarette smoke; Dexamethasone (PubChem CID: 5743); Histone deacetylase 2; Rat model; Steroid resistance