Kinetin Alleviates Bleomycin-induced Rats Pulmonary Fibrosis by Inhibiting Plasminogen Activator Inhibitor-1_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

WangXinyan , HuangKun , KangXiaowen , LiZhaoguo , YangChengcheng ,  WuXiaomei

Department of Respiratory Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150086, China;

Corresponding?author：

WuXiaomei, Email: wxylyfll@163.com

Keywords：

Pulmonary fibrosis; Kinetin; Plasminogen activator inhibitor-1; Urokinase-type plasminogen activator; Tissue-type plasminogen activator

DOI：

10.7507/1671-6205.2014011

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Objective To investigate the therapeutic effect of kinetin on bleomycin A5 (BLM-A5)-induced pulmonary fibrosis in rats. Methods Sixty female Wistar rats were randomly divided into three groups. Group A (n=20) was intratracheally injected with saline as control. Group B (n=20) were intratracheally injected with BLM-A5 to establish pulmonary fibrosis model. Group C (n=20) was intratracheally injected with BLM-A5 and received intraperitoneal injection of kinetin at 0.5 mL/100 g once daily. The rats were sacrificed on the 3^rd,7^th,14^th and 28^th day respectively. HE and Masson staining were performed to observe lung pathological changes. The contents of hydroxyproline (HYP),urokinase-type plasminogen activator (u-PA),tissue-type plasminogen activator (t-PA),and PAI-1 in lung and plasma were measured by ELISA. Results Alveolitis was most obvious on the 7^th day and pulmonary fibrosis was most severe on the 28^th day in group B compared with other two groups (P<0.05). Alveolitis and pulmonary fibrosis in group C were significantly alleviated compared with group B (P<0.05),but still more severe than group A (P<0.05). The HYP contents in group B,coincided with fibrosis,began to increase on the 7^th day and reached the peak on the 28^th day,significantly higher than those in other two groups (P<0.05). The u-PA contents of lung tissue in group B began to decline on the 3^rd day,reached the minimum on the 7^th day,and was still significantly lower than those in other two groups (P<0.05).On the 14^th day, the u-PA contents had no significant difference among three groups. The u-PA plasma contents in group B began to decline on the 3^rd day,reached the minimum and had significant difference compared with other two groups on the 7^th day (P<0.05),and there was no significantly difference among three groups after the 14^th day. The t-PA contents change of lung tissue and plasma in three groups were generally consistent with u-PA,but the t-PA plasma contents in group B were still significantly lower than those in group A on the 14^th day (P<0.05). The PAI-1 contents of lung tissue in group B began to increase on the 3^rd day,reached the maximum on the 7^th day,was still significantly higher than those in other two groups (P<0.05),and there was no significant difference among three groups on the 14^th day. The PAI-1 contents in group C decreased compared with those in group B (P<0.05),but still higher than those in group A (P<0.05),and there was no difference among them on the 14^th day. The PAI-1 plasma contents in group B began to increase on the 3^rd day,reached the maximum and was significantly higher than other two groups on the 7^th day (P<0.05),and there was no significant difference among three groups on the 14^th day. Conclusion The contents of u-PA and t-PA are increased by inhibiting PAI-1 generation in lung tissue through kinetin treatment,so that,kinetin can suppress pulmonary fibrosis induced by BLM-A5.

Citation： WangXinyan, HuangKun, KangXiaowen, LiZhaoguo, YangChengcheng, WuXiaomei. Kinetin Alleviates Bleomycin-induced Rats Pulmonary Fibrosis by Inhibiting Plasminogen Activator Inhibitor-1. Chinese Journal of Respiratory and Critical Care Medicine, 2014, 13(1): 44-48. doi: 10.7507/1671-6205.2014011 Copy

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6.	王欣燕,吳曉梅,康小文,等.骨髓間質干細胞移植對博萊霉素誘導大鼠肺纖維化的治療作用.中國呼吸與危重監護雜志,2009,8:57-62.
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10.	Sisson TH,Hanson KE,Subbotina N,et al.Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.Am J Physiol Lung Cell Mol Physiol,2002,283:L1023-L1032.
11.	Swaisgood CM,French EL,Noga C,et al.The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system.Am J Pathol,2000,157:177-187.
12.	萬兵,鄭金旭,黃新建,等.尿激酶對肺纖維化干預作用及對TGF-βl的影響.山東大學學報:醫學版,2007,45:1243-1245.
13.	Loskutoff DJ,Quigley JP.PAI-1,fibrosis,and the elusive provisional fibrin matrix.J Clin Invest,2000,106:1441-1443.
14.	McClintock D,Zhuo H,Wickersham N,et al.Biomarkers of inflammation,coagulation and fibrinolysis predict mortality in acute lung injury.Crit Care,2008,12:R41.
15.	Kubo H,Nakayama K,Yanai M,et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest,2005,128:1483-1489.

1. 班健.特發性肺纖維化的治療進展.臨床肺科雜志,2011,16:1432-1434.
2. 代靜泓,蔡后榮.特發性肺纖維化急性加重的研究進展.中國呼吸與危重監護雜志,2009,8:91-94.
3. Osterholzer JJ,Christensen PJ,Lama V,et al.PAI-1 promotes the accumulation of exudate macrophages and worsens pulmonary fibrosis following type II alveolar epithelial cell injury.J Pathol,2012,228:170-180.
4. Bhandary YP,Shetty SK,Marudamuthu AS,et al.Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system.Am J Physiol Lung Cell Mol Physiol,2012,302:L463-L473.
5. Barciszewski J,Massino F,Clark BF.Kinetin a multiactive molecule.Int J Biol Macromol,2007,40:182-192.
6. 王欣燕,吳曉梅,康小文,等.骨髓間質干細胞移植對博萊霉素誘導大鼠肺纖維化的治療作用.中國呼吸與危重監護雜志,2009,8:57-62.
7. Szapiel SV,Elson NA,Fulmer JD,et al.Bleomycin-induced interstitial pulmonary disease in the nude,athymic mouse.Am Rev Respir Dis,1979,120:893-899.
8. Gunther A,Lubke N,Ermert M,et al.Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.Am J Respir Crit Care Med,2003,168:1358-1365.
9. Eitzman DT,McCoy RD,Zheng X,et al.Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene.J Clin Invest,1996,97:232-237.
10. Sisson TH,Hanson KE,Subbotina N,et al.Inducible lung-specific urokinase expression reduces fibrosis and mortality after lung injury in mice.Am J Physiol Lung Cell Mol Physiol,2002,283:L1023-L1032.
11. Swaisgood CM,French EL,Noga C,et al.The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system.Am J Pathol,2000,157:177-187.
12. 萬兵,鄭金旭,黃新建,等.尿激酶對肺纖維化干預作用及對TGF-βl的影響.山東大學學報:醫學版,2007,45:1243-1245.
13. Loskutoff DJ,Quigley JP.PAI-1,fibrosis,and the elusive provisional fibrin matrix.J Clin Invest,2000,106:1441-1443.
14. McClintock D,Zhuo H,Wickersham N,et al.Biomarkers of inflammation,coagulation and fibrinolysis predict mortality in acute lung injury.Crit Care,2008,12:R41.
15. Kubo H,Nakayama K,Yanai M,et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.Chest,2005,128:1483-1489.

Chinese Journal of Respiratory and Critical Care Medicine

Kinetin Alleviates Bleomycin-induced Rats Pulmonary Fibrosis by Inhibiting Plasminogen Activator Inhibitor-1

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