• 福建醫(yī)科大學(xué)附屬協(xié)和醫(yī)院基本外科(福建福州 350001);

目的  研究p38絲裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38MAPK)在重癥急性胰腺炎(severe acute pancreatitis,SAP)大鼠肺組織中的表達(dá)情況,并初步探討p38MAPK與SAP肺毛細(xì)血管內(nèi)皮屏障損傷的關(guān)系。
方法  將40只健康雄性SD大鼠隨機(jī)(隨機(jī)數(shù)字表法)分為假手術(shù)(SO)組和SAP組,SAP組又再分為3、6、12及24h4個(gè)時(shí)間點(diǎn)組,共5組,每組8只。采用胰膽管逆行注射5%?;悄懰徕c的方法建立SAP大鼠模型。采用HE染色方法觀察大鼠肺和胰腺組織的病理學(xué)改變; 采用ELISA法檢測(cè)血清腫瘤壞死因子-α(TNF-α)和白細(xì)胞介素-1β(IL-1β)水平; 采用免疫組化染色方法檢測(cè)肺組織中磷酸化p38(p-p38)蛋白和水通道蛋白1(AQP1)的表達(dá)水平; 采用實(shí)時(shí)定量熒光PCR法(real-time PCR)檢測(cè)肺組織中AQP1 mRNA的表達(dá)水平。
結(jié)果  SAP各時(shí)間點(diǎn)組大鼠肺組織充血水腫,炎癥細(xì)胞浸潤;胰腺組織可見大片壞死,部分腺葉結(jié)構(gòu)模糊甚至消失;血清TNF-α和IL-1β水平均較SO組高(P<0.05)。SO組大鼠肺組織中p-p38蛋白僅有微量表達(dá),而在SAP 3h組,p-p38蛋白的表達(dá)就明顯上調(diào),在6 h時(shí)達(dá)高峰,24h時(shí)仍高于SO組(P<0.05)。SAP各時(shí)間點(diǎn)組大鼠肺組織中AQP1 mRNA及其蛋白的表達(dá)水平均較SO組下降(P<0.05),并隨著時(shí)間的推移而逐漸下降; SAP組大鼠AQP1 mRNA的表達(dá)與TNF-α、IL-1β及p-p38蛋白之間均存在負(fù)相關(guān)關(guān)系(r=-0.87,P<0.05;r=-0.88,P<0.05;r=-0.78,P<0.05)。
結(jié)論  肺組織中AQP1蛋白表達(dá)的下調(diào)是SAP肺毛細(xì)血管內(nèi)皮屏障損傷的重要原因之一,其可能與p38MAPK的激活及炎癥因子的過度釋放有關(guān)。

引用本文: 林葆,黃鶴光,陳志耀,方海宗. 重癥急性胰腺炎大鼠p38絲裂原活化蛋白激酶的表達(dá)與肺毛細(xì)血管內(nèi)皮屏障損傷△. 中國普外基礎(chǔ)與臨床雜志, 2013, 20(3): 259-264. doi: 復(fù)制

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. 楊波, 黃鶴光, 陳大良, 等. 逆行性胰膽管注射法制作重癥急性胰腺炎大鼠模型[J]. 福建醫(yī)科大學(xué)學(xué)報(bào), 2002, 36(1):71-72.
5. 王鋒, 黃鶴光, 陸逢春, 等. 膽胰管結(jié)扎法制作大鼠胰源性肺損傷模型[J]. 中國普外基礎(chǔ)與臨床雜志, 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, 李鋒, 胡波, 等. 丹參對(duì)大鼠急性肺損傷的保護(hù)作用[J]. 中藥材, 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. 許銀姬, 陳遠(yuǎn)彬, 王麗麗, 等. 青天葵對(duì)內(nèi)毒素致急性肺損傷大鼠肺水通道蛋白1和5表達(dá)的影響[J]. 中國中西醫(yī)結(jié)合雜志, 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. 王鋒, 黃鶴光, 陸逢春, 等. 急性壞死性胰腺炎大鼠肺組織水通道蛋白-1的動(dòng)態(tài)變化及其意義[J]. 中華胰腺病雜志, 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, 湯禮軍, 戴睿武, 等. p38MAPK信號(hào)轉(zhuǎn)導(dǎo)途徑對(duì)缺血再灌注早期離體肝臟細(xì)胞因子表達(dá)的影響[J]. 中國普外基礎(chǔ)與臨床雜志, 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. 潘彩飛, 祝勝美. 異丙酚通過抑制p38激活下調(diào)氨處理的大鼠腦星形膠質(zhì)細(xì)胞AQP4的表達(dá)并減輕細(xì)胞水腫[J]. 中國病理生理雜志, 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. 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. 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. 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. 4. 楊波, 黃鶴光, 陳大良, 等. 逆行性胰膽管注射法制作重癥急性胰腺炎大鼠模型[J]. 福建醫(yī)科大學(xué)學(xué)報(bào), 2002, 36(1):71-72.
  5. 5. 王鋒, 黃鶴光, 陸逢春, 等. 膽胰管結(jié)扎法制作大鼠胰源性肺損傷模型[J]. 中國普外基礎(chǔ)與臨床雜志, 2012, 19(1):25-30.
  6. 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. 7. Pastor CM, Matthay MA, Frossard JL. Pancreatitis-associated acute lung injury:new insights[J]. Chest, 2003, 124(6):2341-2351.
  8. 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. 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. 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. 11. 李敏, 李鋒, 胡波, 等. 丹參對(duì)大鼠急性肺損傷的保護(hù)作用[J]. 中藥材, 2007, 30(4):442-444.
  12. 12. (5):366-368.
  13. 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. 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. 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. 16. 許銀姬, 陳遠(yuǎn)彬, 王麗麗, 等. 青天葵對(duì)內(nèi)毒素致急性肺損傷大鼠肺水通道蛋白1和5表達(dá)的影響[J]. 中國中西醫(yī)結(jié)合雜志, 2010, 30(8):861-866.
  17. 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. 18. 王鋒, 黃鶴光, 陸逢春, 等. 急性壞死性胰腺炎大鼠肺組織水通道蛋白-1的動(dòng)態(tài)變化及其意義[J]. 中華胰腺病雜志, 2011,.
  19. 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. 20. 王雨, 湯禮軍, 戴睿武, 等. p38MAPK信號(hào)轉(zhuǎn)導(dǎo)途徑對(duì)缺血再灌注早期離體肝臟細(xì)胞因子表達(dá)的影響[J]. 中國普外基礎(chǔ)與臨床雜志, 2009, 16(6):443-448.
  21. 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. 22. 潘彩飛, 祝勝美. 異丙酚通過抑制p38激活下調(diào)氨處理的大鼠腦星形膠質(zhì)細(xì)胞AQP4的表達(dá)并減輕細(xì)胞水腫[J]. 中國病理生理雜志, 2010, 26(1):96-100.
  23. 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. 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. 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. 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. 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.
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