[Influence of N-acetylcysteine on the cytokines and matrix metalloproteinases in chronic obstructive pulmonary disease rat models].
OBJECTIVE
To investigate the changes of interferon-gamma (IFNgamma), interleukin (IL)-4, matrix metalloproteinase (MMP)-9, MMP-12 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in smoke-induced chronic obstructive pulmonary disease (COPD) rat models and the therapeutic effect of N-acetylcysteine (NAC).


METHODS
Male Wistar rats were exposed to cigarette smoke for 3.5 months. NAC was given in the last month. Lung function was measured at the end of the study. The levels of IL-4 and IFNgamma in broncho-alveolar lavage fluid (BALF) and lung tissues were determined by ELISA. The expression of MMP-9, MMP-12 and TIMP-1 mRNA in lung tissues were determined by RT-PCR.


RESULTS
(1) In comparison with the control group, smoke exposed group presented a significant decrease in forced expiratory volume in 0.3 second (FEV(0.3))/forced vital capacity (FVC), dynamic lung compliance (Cdyn), mean alveolar numbers (MAN) and a significant increase in expiratory resistance (Re), pulmonary mean linear intercept (Lm) (P < 0.05). After treatment with NAC, FEV(0.3)/FVC, Re and Cdyn were improved significantly (P < 0.05). No significant changes were found in Lm and MAN (P > 0.05). (2) In the lung tissues of smoke exposed group, IL-4 level was 10.00 pg/ml, IFNgamma level was 19.37 pg/ml, and the IL-4/IFNgamma ratio was 0.49. In the lung tissues of the control group, they were 4.38 pg/ml, 54.94 pg/ml and 0.10, respectively. There were significant differences in these indexes between the smoke exposed group and the control group (P < 0.05). IL-4 level in the NAC group was 7.99 pg/ml which was similar to that in the smoke exposed group (P > 0.05). IFNgamma and IL-4/IFNgamma ratio were 43.40 pg/ml and 0.15, the former being significantly higher and the latter being significantly lower than those in the smoke exposed group (P < 0.05). (3) The expression of MMP-12 mRNA and MMP-12/TIMP-1 ratio in the smoke exposed group (0.36, 1.21) were significantly higher than those in the control group (0.24, 0.88) (P < 0.05). There was no difference in TIMP-1 (P > 0.05). The expression of MMP-12, TIMP-1 mRNA and the MMP-12/TIMP-1 ratio in NAC group were similar to those in the smoke exposed group (P > 0.05).


CONCLUSIONS
(1) Cigarette smoke exposure increased IL-4 and decreased IFNgamma. This may contribute to smoke-induced changes in lung function. NAC had no effect on IL-4, but increased IFNgamma, and the IL-4/IFNgamma ratio returned to normal. This might be one of the mechanisms of NAC in improving lung function. (2) Cigarette smoke promoted MMP-12 gene expression and increased the MMP-12/TIMP-1 ratio. This may play a role in smoke-induced emphysema. NAC did not alter MMP-12/TIMP-1 ratio when given in the late phase of smoke exposure. This result could explain the emphysematous changes in the NAC group.
Xu
Ling
L
Department of Respiratory Disease, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
Cai
Bai-qiang
BQ
Zhu
Yuan-jue
YJ
Guo
Zi-jian
ZJ
Zhang
Hong
H
Gu
Li
L
Xu
Xing-xiang
XX
D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008297:Male; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014028:Tobacco Smoke Pollution
D019715:Tissue Inhibitor of Metalloproteinase-1; D014028:Tobacco Smoke Pollution; D015847:Interleukin-4; D007371:Interferon-gamma; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; D053508:Matrix Metalloproteinase 12; D000111:Acetylcysteine