Expression of p38 Mitogen-Activated Protein Kinase and Pulmonary Capillary Barrier Injury in Rats with Severe Acute Pancreatitis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

LIN Bao ,  HUANG Heguang , CHEN Zhiyao , FANG Haizong

Department of General Surgery， Affiliated Union Hospital of Fujian Medical University， Fuzhou 350001， Fujian Province， China;

Corresponding author：

HUANG Heguang, Email: hhuang2@yahoo.com.cn

Keywords：

Severe acute pancreatitis; Lung injury; Inflammatory cytokines; p38 mitogen-activated protein kinase; Aquaporin 1; Rat

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Objective 　To investgate the expression of p38 mitogen-activated protein kinase （p38MAPK） in lung tissue of rats with severe acute pancreatitis （SAP）， and to explore the relationship between p38MAPK and pulmonary capillary barrier injury.
Methods 　Forty male and healthy Sprague-Dawley （SD） rats were randomly （random number method） divided into sham operation （SO） group and SAP group， then rats of SAP group were sub-divided into 3， 6， 12， and 24 h group， each group enrolled 8 rats， respectively. SAP model rats were established by injecting 5% sodium taurocholate solution retrograde into the biliopancreatic duct. ELISA method was used to test the serum tumor necrosis factor-α （TNF-α） and interleukin-1β （IL-1β）， and pathological changes in lung and pancreas tissues were observed by HE staining. Immunohischemistry method was used to detect phosphorylated p38 （p-p38） protein and aquaporin 1 （AQP1） protein of lung tissues. The expression level of AQP1 mRNA was measured by quantitative real-time PCR. Results　Hyperemia， edema， and inflammatory cell infiltration were observed in lung tissues， abundance of necrosis， part gland structure fuzzy or even disappear were observed in pancreas tissues of all 4 time point groups. Compared with SO group， levels of serum TNF-α and IL-1β were significantly higher in 4 time point groups （P＜0.05）. Lower expression level of p-p38 protein was detected in lung tissues of SO group， while in the early stage of SAP （SAP 3 h group）， the expression level of p-p38 protein significantly increased， which peaked in 6 h group and was still higher than SO group in 24 h group （P＜0.05）. Compared with SO group， the expression levels of AQP1 mRNA and protein were significantly lower in all 4 time point groups （P＜0.05）， which had negative correlation with the levels of serum TNF-α，IL-1β， and the expression level of p-p38 protein （r=-0.87， P＜0.05；r=-0.88， P＜0.05；r=-0.78， P＜0.05）. Conclusion 　The decrease of AQP1 protein in lung tissue is one of the vital causes for pulmonary capillary barrier injury in SAP， which probably works by the activation of p38MAPK and the excessive release of inflammatory cytokines.

Citation： LIN Bao,HUANG Heguang,CHEN Zhiyao,FANG Haizong,.. Expression of p38 Mitogen-Activated Protein Kinase and Pulmonary Capillary Barrier Injury in Rats with Severe Acute Pancreatitis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2013, 20(3): 259-264. doi: Copy

1.	Bai Y， Yao HX， Hu ML， et al. Effects of shenmai injection on pulmonary aquaporin 1 in rats following traumatic brain injury[J]. Chin Med J， 2011， 124(3)：457-460.
2.	Togbe D， Schnyder-Candrian S， Schnyder B， et al. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury[J]. Int J Exp Pathol， 2007， 88(6)：387-391.
3.	Sim YS， Kim SY， Kim EJ， et al. Impaired expression of MAPK is associated with the downregulation of TNF-α， IL-6， and IL-10 in mycobacterium abscessus lung disease[J]. Tuberc Respir Dis (Seoul)， 2012， 72(3)：275-283.
4.	杨波，黄鹤光，陈大良，等. 逆行性胰胆管注射法制作重症急性胰腺炎大鼠模型[J]. 福建医科大学学报， 2002， 36(1)：71-72.
5.	王锋，黄鹤光，陆逢春，等. 胆胰管结扎法制作大鼠胰源性肺损伤模型[J]. 中国普外基础与临床杂志， 2012， 19(1)：25-30.
6.	Hartwig W， Werner J， Müller CA， et al. Surgical management of severe pancreatitis including sterile necrosis[J]. J Hepatobiliary Pancreat Surg， 2002， 9(4)：429-435.
7.	Pastor CM， Matthay MA， Frossard JL. Pancreatitis-associated acute lung injury：new insights[J]. Chest， 2003， 124(6)：2341-2351.
8.	Effros RM， Darin C， Jacobs ER， et al. Water transport and the distribution of aquaporin-1 in pulmonary air spaces[J]. J Appl Physiol， 1997， 83(3)：1002-1016.
9.	Song Y， Fukuda N， Bai C， et al. Role of aquaporins in alveolar fluid clearance in neonatal and adult lung， and in oedema formationfollowing acute lung injury：studies in transgenic aquaporin null mice[J]. J Physiol， 2000， 525 Pt 3：771-779.
10.	Fan Q， Zhao P， Li J， et al. 17β-Estradiol administration attenuates seawater aspiration-induced acute lung injury in rats[J]. Pulm Pharmacol Ther， 2011， 24(6)：673-681.
11.	李敏，李锋，胡波，等. 丹参对大鼠急性肺损伤的保护作用[J]. 中药材， 2007， 30(4)：442-444.
12.	(5)：366-368.
13.	Zhang YW， Bi LT， Hou SP， et al. Reduced lung water transport rate associated with downregulation of aquaporin-1 and aquaporin-5 in aged mice[J]. Clin Exp Pharmacol Physiol， 2009， 36(7)：734-738.
14.	Müllertz KM， Strøm C， Trautner S， et al. Downregulation of aquaporin-1 in alveolar microvessels in lungs adapted to chronic heart failure[J]. Lung， 2011， 189(2)：157-166.
15.	Su X， Song Y， Jiang J， et al. The role of aquaporin-1 (AQP1) expression in a murine model of lipopolysaccharide-induced acute lung injury[J]. Respir Physiol Neurobiol， 2004， 142(1)：1-11.
16.	许银姬，陈远彬，王丽丽，等. 青天葵对内毒素致急性肺损伤大鼠肺水通道蛋白1和5表达的影响[J]. 中国中西医结合杂志， 2010， 30(8)：861-866.
17.	Wang F， Huang H， Lu F， et al. Acute lung injury and change in expression of aquaporins 1 and 5 in a rat model of acute pancreatitis[J]. Hepatogastroenterology， 2010， 57(104)：1553-1562.
18.	王锋，黄鹤光，陆逢春，等. 急性坏死性胰腺炎大鼠肺组织水通道蛋白-1的动态变化及其意义[J]. 中华胰腺病杂志， 2011，.
19.	Kyriakis JM， Avruch J. Mammalian mitogen-activated proteinkinase signal transduction pathways activated by stress and inflam-mation[J]. Physiol Rev， 2001， 81(2)：807-869.
20.	王雨，汤礼军，戴睿武，等. p38MAPK信号转导途径对缺血再灌注早期离体肝脏细胞因子表达的影响[J]. 中国普外基础与临床杂志， 2009， 16(6)：443-448.
21.	Mukhopadhyay S， Mukherjee S， Smith M， et al. Activation of MAPK/AP-1 signaling pathway in lung injury induced by 2-chloroethyl ethyl sulfide， a mustard gas analog[J]. Toxicol Lett， 2008， 181(2)：112-117.
22.	潘彩飞，祝胜美. 异丙酚通过抑制p38激活下调氨处理的大鼠脑星形胶质细胞AQP4的表达并减轻细胞水肿[J]. 中国病理生理杂志， 2010， 26(1)：96-100.
23.	Wei S， Huang Q， Li J， et al. Taurine attenuates liver injury by downregulating phosphorylated p38MAPK of Kupffer cells in rats with severe acute pancreatitis[J]. Inflammation， 2012， 35(2)：690-701.
24.	Yubero S， Ramudo L， Manso MA， et al. Mechanisms of dexamethasone-mediated chemokine down-regulation in mild and severe acute pancreatitis[J]. Biochim Biophys Acta， 2009， 1792(12)：1205-1211.
25.	Ramudo L， Manso MA， Sevillano S， et al. Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells duringacute pancreatitis induced by bile-pancreatic duct obstruction[J]. J Pathol， 2005， 206(1)：9-16.
26.	Wagner AC， Metzler W， Höfken T， et al. p38 map kinase is expressed in the pancreas and is immediately activated following cerulein hyperstimulation[J]. Digestion， 1999， 60(1)：41-47.
27.	Pereda J， Sabater L， Cassinello N， et al. Effect of simultaneous inhibition of TNF-alpha production and xanthine oxidase in experimental acute pancreatitis：the role of mitogen activated protein kinases[J]. Ann Surg， 2004， 240(1)：108-116.

1. Bai Y， Yao HX， Hu ML， et al. Effects of shenmai injection on pulmonary aquaporin 1 in rats following traumatic brain injury[J]. Chin Med J， 2011， 124(3)：457-460.
2. Togbe D， Schnyder-Candrian S， Schnyder B， et al. Toll-like receptor and tumour necrosis factor dependent endotoxin-induced acute lung injury[J]. Int J Exp Pathol， 2007， 88(6)：387-391.
3. Sim YS， Kim SY， Kim EJ， et al. Impaired expression of MAPK is associated with the downregulation of TNF-α， IL-6， and IL-10 in mycobacterium abscessus lung disease[J]. Tuberc Respir Dis (Seoul)， 2012， 72(3)：275-283.
4. 杨波，黄鹤光，陈大良，等. 逆行性胰胆管注射法制作重症急性胰腺炎大鼠模型[J]. 福建医科大学学报， 2002， 36(1)：71-72.
5. 王锋，黄鹤光，陆逢春，等. 胆胰管结扎法制作大鼠胰源性肺损伤模型[J]. 中国普外基础与临床杂志， 2012， 19(1)：25-30.
6. Hartwig W， Werner J， Müller CA， et al. Surgical management of severe pancreatitis including sterile necrosis[J]. J Hepatobiliary Pancreat Surg， 2002， 9(4)：429-435.
7. Pastor CM， Matthay MA， Frossard JL. Pancreatitis-associated acute lung injury：new insights[J]. Chest， 2003， 124(6)：2341-2351.
8. Effros RM， Darin C， Jacobs ER， et al. Water transport and the distribution of aquaporin-1 in pulmonary air spaces[J]. J Appl Physiol， 1997， 83(3)：1002-1016.
9. Song Y， Fukuda N， Bai C， et al. Role of aquaporins in alveolar fluid clearance in neonatal and adult lung， and in oedema formationfollowing acute lung injury：studies in transgenic aquaporin null mice[J]. J Physiol， 2000， 525 Pt 3：771-779.
10. Fan Q， Zhao P， Li J， et al. 17β-Estradiol administration attenuates seawater aspiration-induced acute lung injury in rats[J]. Pulm Pharmacol Ther， 2011， 24(6)：673-681.
11. 李敏，李锋，胡波，等. 丹参对大鼠急性肺损伤的保护作用[J]. 中药材， 2007， 30(4)：442-444.
12. (5)：366-368.
13. Zhang YW， Bi LT， Hou SP， et al. Reduced lung water transport rate associated with downregulation of aquaporin-1 and aquaporin-5 in aged mice[J]. Clin Exp Pharmacol Physiol， 2009， 36(7)：734-738.
14. Müllertz KM， Strøm C， Trautner S， et al. Downregulation of aquaporin-1 in alveolar microvessels in lungs adapted to chronic heart failure[J]. Lung， 2011， 189(2)：157-166.
15. Su X， Song Y， Jiang J， et al. The role of aquaporin-1 (AQP1) expression in a murine model of lipopolysaccharide-induced acute lung injury[J]. Respir Physiol Neurobiol， 2004， 142(1)：1-11.
16. 许银姬，陈远彬，王丽丽，等. 青天葵对内毒素致急性肺损伤大鼠肺水通道蛋白1和5表达的影响[J]. 中国中西医结合杂志， 2010， 30(8)：861-866.
17. Wang F， Huang H， Lu F， et al. Acute lung injury and change in expression of aquaporins 1 and 5 in a rat model of acute pancreatitis[J]. Hepatogastroenterology， 2010， 57(104)：1553-1562.
18. 王锋，黄鹤光，陆逢春，等. 急性坏死性胰腺炎大鼠肺组织水通道蛋白-1的动态变化及其意义[J]. 中华胰腺病杂志， 2011，.
19. Kyriakis JM， Avruch J. Mammalian mitogen-activated proteinkinase signal transduction pathways activated by stress and inflam-mation[J]. Physiol Rev， 2001， 81(2)：807-869.
20. 王雨，汤礼军，戴睿武，等. p38MAPK信号转导途径对缺血再灌注早期离体肝脏细胞因子表达的影响[J]. 中国普外基础与临床杂志， 2009， 16(6)：443-448.
21. Mukhopadhyay S， Mukherjee S， Smith M， et al. Activation of MAPK/AP-1 signaling pathway in lung injury induced by 2-chloroethyl ethyl sulfide， a mustard gas analog[J]. Toxicol Lett， 2008， 181(2)：112-117.
22. 潘彩飞，祝胜美. 异丙酚通过抑制p38激活下调氨处理的大鼠脑星形胶质细胞AQP4的表达并减轻细胞水肿[J]. 中国病理生理杂志， 2010， 26(1)：96-100.
23. Wei S， Huang Q， Li J， et al. Taurine attenuates liver injury by downregulating phosphorylated p38MAPK of Kupffer cells in rats with severe acute pancreatitis[J]. Inflammation， 2012， 35(2)：690-701.
24. Yubero S， Ramudo L， Manso MA， et al. Mechanisms of dexamethasone-mediated chemokine down-regulation in mild and severe acute pancreatitis[J]. Biochim Biophys Acta， 2009， 1792(12)：1205-1211.
25. Ramudo L， Manso MA， Sevillano S， et al. Kinetic study of TNF-alpha production and its regulatory mechanisms in acinar cells duringacute pancreatitis induced by bile-pancreatic duct obstruction[J]. J Pathol， 2005， 206(1)：9-16.
26. Wagner AC， Metzler W， Höfken T， et al. p38 map kinase is expressed in the pancreas and is immediately activated following cerulein hyperstimulation[J]. Digestion， 1999， 60(1)：41-47.
27. Pereda J， Sabater L， Cassinello N， et al. Effect of simultaneous inhibition of TNF-alpha production and xanthine oxidase in experimental acute pancreatitis：the role of mitogen activated protein kinases[J]. Ann Surg， 2004， 240(1)：108-116.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Expression of p38 Mitogen-Activated Protein Kinase and Pulmonary Capillary Barrier Injury in Rats with Severe Acute Pancreatitis

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