丙酸氟替卡松对体外培养鼻粘膜上皮细胞和体内鼻息肉组织中水通道蛋白5表达的影响
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摘要
目的
水通道蛋白是近年新发现的一组膜蛋白,它在体内液体转运和某些腺体分泌方面具有重要作用。迄今为止,大多数研究仅局限于AQPS与下呼吸道粘膜的关系及意义,AQPS是否在上呼吸道粘膜,尤其是鼻黏膜组织水肿的形成以及腺体分泌中起一定作用,很少见文献报道。
本文通过丙酸氟替卡松( FP)对体外原代及传代培养的鼻粘膜上皮细胞和体内鼻息肉组织中水通道蛋白5(AQP5)表达的影响,初步探讨AQP5在鼻息肉病情发展不同阶段中的可能机制。
方法
1、将人鼻粘膜上皮细胞进行体外原代细胞培养14天,待细胞繁殖传代后,FP组细胞加入丙酸氟替卡松浓度为0.2%的1640完全培养液,非FP组细胞加入不含丙酸氟替卡松的1640完全培养液继续培养,7天后爬片用丙酮固定,采用免疫组织化学技术检测细胞爬片中AQP5的表达。并测定阳性细胞的光密度值和灰度值。
2、将12例慢性鼻窦炎鼻息肉患者(均为初发型),三个月内无局部及全身激素使用史,取其鼻息肉组织,术前应用FP喷雾剂喷鼻7d ,治疗7d后于术中再次取其鼻息肉组织,术后病理均证实为鼻息肉组织,采用免疫组化技术检测鼻息肉组织中AQP5的表达和分布。并测定阳性细胞的光密度值和灰度值。
结果
1、在体外培养的鼻粘膜上皮细胞FP组的水通道蛋白5表达增加,其灰度值明显降低(p<0.05),光度值则升高(p<0.05);配对t检验有统计学意义。
2、鼻息肉组织的免疫组化染色显示,AQP5在FP组和非FP组息肉组织中的分布基本一致:主要分布在腺体细胞,淋巴管细胞,上皮细胞及各种炎症细胞中。
3、在体内鼻息肉组织中,患者使用FP后鼻息肉体积明显缩小,用药后水通道蛋白5在腺体细胞和淋巴管细胞中表达减少,其灰度值明显升高(p<0.05),光密度值则明显低于使用前(p<0.05)。配对t检验有统计学意义。
结论
在FP作用下培养的鼻粘膜上皮细胞中的AQP5表达增加,可能解释在体情况下有利于组织间液的排除,减轻鼻粘膜及轻度的鼻息肉的水肿,而在鼻息肉组织中,应用FP后,鼻息肉体积缩小,水肿减轻,可能与AQP5在腺体和淋巴管细胞中表达减少有关,说明AQP5在鼻息肉的形成和发展过程中起到一定的作用,并推测其在鼻息肉的病程的早期和晚期作用机制应该是不同的。
Objective
Aquaporins (AQPs) is a kind of membranous protein found odd-come-shortly,which play an important part in the liquid transfer and some secretory function. So far, a lot of research only studied between AQPs and sub-airway mucosa. There is few paper about the relationship between AQPs and up-airway mucosa’s edema and secretory function, special the nasal mucosa.
Our research confirmed the expression and distribution of AQP5 in the two kinds of nasal polyps by immunochemistry. It is to discuss the pathology function of the AQP5 in nasal polyps.
Methods
Choose from these inpatients who came into our department to receive nasal polyps resection. AQP5 were studied in 20 samples nasal polyps without AR (Group NAR) and 16 samples with AR (Group AR) with immunochemistric staing, by its integrated light intensity and its grey step.
Results
1、The grey step of AQP5 in the cells of FP-using group is lower obviously than using FP before(p<0.05),the light intensity is higher obviously than using FP before(P<0.05).
2、immunohistochemical staining technique showed that the distribution of AQP5 in the two groups was in accordance with that in nasal polyps on the whole. AQP5 expressed mainly in the glandular cells、lymphocytes、epithelial cells and inflamnatory cells.
3、In the nasal polyps of FP-using group,the size of nasal polyps become much smaller than using FP before.The grey step of AQP5 in both glandular cells and lymphocyte is higher obviously than using FP before(P<0.05) but the light intensity is lower obviously than using FP before(P<0.05).
Conclusions
the expressions of AQP5 in cells which treated with FP became higher than cells which untreated,It indicated that when treated with FP,interstitial fluid can effuse easily,the concha nasalis media and the concha nasalis inferior became smaller and smaller. After nasal polyps samples treated with FP,the poloyps became smaller.At the same time,the expressions of AQP5 in glandular cells and lymphocyte became lower .There may be relationship between these.It can indicate that AQP5 contributed to edema of nasal polyps.
水通道蛋白是近年新发现的一组膜蛋白,它在体内液体转运和某些腺体分泌方面具有重要作用。迄今为止,大多数研究仅局限于AQPS与下呼吸道粘膜的关系及意义,AQPS是否在上呼吸道粘膜,尤其是鼻黏膜组织水肿的形成以及腺体分泌中起一定作用,很少见文献报道。
本文通过丙酸氟替卡松( FP)对体外原代及传代培养的鼻粘膜上皮细胞和体内鼻息肉组织中水通道蛋白5(AQP5)表达的影响,初步探讨AQP5在鼻息肉病情发展不同阶段中的可能机制。
方法
1、将人鼻粘膜上皮细胞进行体外原代细胞培养14天,待细胞繁殖传代后,FP组细胞加入丙酸氟替卡松浓度为0.2%的1640完全培养液,非FP组细胞加入不含丙酸氟替卡松的1640完全培养液继续培养,7天后爬片用丙酮固定,采用免疫组织化学技术检测细胞爬片中AQP5的表达。并测定阳性细胞的光密度值和灰度值。
2、将12例慢性鼻窦炎鼻息肉患者(均为初发型),三个月内无局部及全身激素使用史,取其鼻息肉组织,术前应用FP喷雾剂喷鼻7d ,治疗7d后于术中再次取其鼻息肉组织,术后病理均证实为鼻息肉组织,采用免疫组化技术检测鼻息肉组织中AQP5的表达和分布。并测定阳性细胞的光密度值和灰度值。
结果
1、在体外培养的鼻粘膜上皮细胞FP组的水通道蛋白5表达增加,其灰度值明显降低(p<0.05),光度值则升高(p<0.05);配对t检验有统计学意义。
2、鼻息肉组织的免疫组化染色显示,AQP5在FP组和非FP组息肉组织中的分布基本一致:主要分布在腺体细胞,淋巴管细胞,上皮细胞及各种炎症细胞中。
3、在体内鼻息肉组织中,患者使用FP后鼻息肉体积明显缩小,用药后水通道蛋白5在腺体细胞和淋巴管细胞中表达减少,其灰度值明显升高(p<0.05),光密度值则明显低于使用前(p<0.05)。配对t检验有统计学意义。
结论
在FP作用下培养的鼻粘膜上皮细胞中的AQP5表达增加,可能解释在体情况下有利于组织间液的排除,减轻鼻粘膜及轻度的鼻息肉的水肿,而在鼻息肉组织中,应用FP后,鼻息肉体积缩小,水肿减轻,可能与AQP5在腺体和淋巴管细胞中表达减少有关,说明AQP5在鼻息肉的形成和发展过程中起到一定的作用,并推测其在鼻息肉的病程的早期和晚期作用机制应该是不同的。
Objective
Aquaporins (AQPs) is a kind of membranous protein found odd-come-shortly,which play an important part in the liquid transfer and some secretory function. So far, a lot of research only studied between AQPs and sub-airway mucosa. There is few paper about the relationship between AQPs and up-airway mucosa’s edema and secretory function, special the nasal mucosa.
Our research confirmed the expression and distribution of AQP5 in the two kinds of nasal polyps by immunochemistry. It is to discuss the pathology function of the AQP5 in nasal polyps.
Methods
Choose from these inpatients who came into our department to receive nasal polyps resection. AQP5 were studied in 20 samples nasal polyps without AR (Group NAR) and 16 samples with AR (Group AR) with immunochemistric staing, by its integrated light intensity and its grey step.
Results
1、The grey step of AQP5 in the cells of FP-using group is lower obviously than using FP before(p<0.05),the light intensity is higher obviously than using FP before(P<0.05).
2、immunohistochemical staining technique showed that the distribution of AQP5 in the two groups was in accordance with that in nasal polyps on the whole. AQP5 expressed mainly in the glandular cells、lymphocytes、epithelial cells and inflamnatory cells.
3、In the nasal polyps of FP-using group,the size of nasal polyps become much smaller than using FP before.The grey step of AQP5 in both glandular cells and lymphocyte is higher obviously than using FP before(P<0.05) but the light intensity is lower obviously than using FP before(P<0.05).
Conclusions
the expressions of AQP5 in cells which treated with FP became higher than cells which untreated,It indicated that when treated with FP,interstitial fluid can effuse easily,the concha nasalis media and the concha nasalis inferior became smaller and smaller. After nasal polyps samples treated with FP,the poloyps became smaller.At the same time,the expressions of AQP5 in glandular cells and lymphocyte became lower .There may be relationship between these.It can indicate that AQP5 contributed to edema of nasal polyps.
引文
1. Christian Müller,Matthias Sendler and Jan-Peter Hildebrandt, Downregulation of aquaporins 1 and 5 in nasal gland by osmotic stress in ducklings, Anas platyrhynchos: implications for the production of hypertonic fluid, THE JOURNAL OF EXPERIMENTAL BIOLOGY,2006, 209:4067-4076.
2.张欣欣,郭永清,张文杰,等, Na+通道与鼻息肉形成关系的初步研中华耳鼻咽喉科杂志,2000,35 ( 5):359-362。
3. Connolly DL, Shanahan CM,Weissberg PL. The aquaporin1A family of water channel protein. Int J Biochem Cell Biol, 1998, 30: 169-173.
4. Atílio Maximino Fernandes,Fabiana Cardoso Pereira Valera,Wilma T. Anselmo-Lima,Mechanism of action of glucocorticoids in nasal polyposis,Rev Bras Otorrinolaringol,2008,74(2):279-83.
5. Raina S, Preston G M, Guggino W B, et al. Molecular cloning and characterization of an aqquaporin cDNA from salivary, lacrimal, and respiratory tissues[J]. J Biol Chem, 1995, 270: 1908-1912.
6. Yang F, Kawedia J D, Menon A G. Cyclic AMP regulates aquaporin -5 expression at both transcriptional and post-transcriptional levels through a protein kinase A pathaway[J].J Biol Chem, 2003, 278:32173-32180.
7. Ma T, Song Y, Gillespie A, et al. Defective secretion of saliva in trans-genic micelacking aquaporin-5 water channels[J]. J Biol Chem, 1999, 274:20071-20074.
8. Benson M. Pathophysiological effects of glucocorticoids on nasalpolyps: an update. Curr Opin Allergy Clin Immunol 2005;5:31-5.
9. Benitez P, Alobid I, Haro J, Berenguer J, Bernal-Sprekelsen M,Pujols L, Picado C, Mullol J. A short course of oral prednisone followed by intranasal budesonide is an effective treatment of severe nasal polyps. Laryngoscope 2006,116:770-5.
10.中华医学会耳鼻咽喉科学分会,中华耳鼻咽喉科杂志编辑委员会,变应性鼻炎诊断标准及疗效评定标准(1997年修订,海口),中华耳鼻咽喉科杂志,1998,33:134-135。
11. Nielsen S, King LS, Christensen BM, et al. Aquaporins in complex tissues:Ⅱ. Subcellular distribution in respiratory and glandular tissues of rat. Am J Physiol. 1997;273:1549-1561.
12. King LS, Nielsen S, Agre P. Aquaporins in complex tissues:Ⅰ. Developmental patterns in respiratory and glandular tissues of rat. Am J Physiol. 1997;273:1541-1548.
13. Song Y, Verkman AS. Aquauaporin-5 dependent fluid secretion in airway submucosal glands. J Biol Chem, 2001, 276: 41288-41292.
14. Mladina R, Clement P, Lopadin A,Mann W, Passali D. International Consensus on Nasal Polyposis 2002-2004. Eur Arch Otorhinolaryngol 2005;262(6):519-21.
15. Fokkens W,Lund V,Bachert C,Clement P,Hellings P, Holmstrom M et al. EAACI position paper on rhinosinusitis and nasal polyps executive summary. Allergy 2005;60(5):583-601.
16. Bachert C, Watelet, JB,Gevaert P,Cauwenberge,PV.Pharmacological management of nasal polyposis. Drugs 2005;65(11):1537-52.
17.董春玲,鲁继荣,王桂芳等,地塞米松对哮喘小鼠肺液清除功能障碍的作用,药学服务与研究,2008 Feb; 8 (1):42-72。
18.蒋媛,俞晨杰,沈晓辉等,伴或不伴变应性鼻炎的鼻息肉组织中水通蛋白5的表达及意义,临床耳鼻咽喉头颈外科杂志, Sep2008,Vol 22,No 18.
1 Preston GM,Carroll TP,Guggino WB , et al . Appearance of water channels in Xenopus occytes expressing red cell CHIP28 protein [J ] .Science,1992 ,256(5055) :385-387.
2马兵,李学军,水通道的生理功能及与疾病的关系,国外医学生理病理科学和临床分册,1998,18(2): 101~104。
3 Yang B. The human aquaporin gene family (review) [J]. Current Genomics, 2000, 1(1): 9l~102.
4 Song Y, Jayaraman S, Yang B, et al. Role of aquaporin water channels in airway fluid transport, humidification, and surface liquid hydration [J]. J Gen Physiol, 2001, 117(6): 573~582.
5 Krane AM, Fortner CN , Hand A , et al . Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation[J ] . Proc Natl Acad Sci USA , 2001 , 98 :14114-14119.
6 Kozono D , Masato Y, King LS , et al . Aquaporin water channels :atomic structure and molecular dynamics meet clinical medicine [J ] . JClin Invest , 2002 , 109 :1395-1399.
7 Krane CM, Towne JE , Menon AG. Cloning and characterization of murine Aqp5 : evidence for a conserved aquaporin gene cluster[J ] . Mamm Genome , 1999 , 10(5) :498-505.
8 K. Tsubota, S. Hirai, L.S. King, P. Agre and N. Ishida, Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjogren's syndrome, 2001(357), 688–689.
9 Hwang SM, Lee RH , Song JM, et al . Expression of aquaporin5 and its regulation in skeletal muscle cells[J ] . Exp Mol Med ,2002 ,34 (1) :69-74.
10 Parvin MN , Tsumura K, Akamatsu T , et al . Expression and localization of AQP5 in the stomach and duodenumof the rat [J ] . Biochim Biophys Acta ,2002 ,1542(1-3) :116-124.
11 Song YL, Verkman AS. Aquaporin-5 dependent fluid secretion in airway submucosal glands. J Biol Chem, 2001, 276: 41288~41292.
12 Kreda SM, Gynn MC, Fenstermacher DA, et al. Expression and localization of epithelial aquaporins in the adult human lung. Am J Respir Cell Mol. Biol, 2001, 24: 224~234.
13李志海,高起学,水通道蛋白-5在人鼻息肉组织中的表达,临床耳鼻咽喉科杂志,2005, 19 ( 4):162-165。
14 Yang B. The human aquaporin gene family (review) [J]. Current Genomics, 2000, 1(1): 9l~102.
15张景熙,AQP5的结构功能及其调节,国外医学生理、病理科学与临床分册,2003, 23 (6):599-601。
16 Yang F , Kawedia JD , Menon AG. Cyclic AMP regulates aquaporin 5 expression at both transcriptional and post-transcriptional levels through a protein kinase A pathway[J ] . J Biol Chem. 2003 , 278(34) : 32173-32180.
17 Smith KJ , Siddiqui AA , Midica LA , et al . Interferon-αupregulates gene expression of Aquaporin-5 in human parotid glands. [J ] J Interfer-on Cytokine Res , 1999 ,19 : 929-935.
18 Rabb H , Wang Z , Nemoto T , et al . Acute renal failure leads to dys-regulation of lung salt and water channels [J ] . Kidney Int . 2003 , 63(2) : 600-606.
19 Ishikawa Y, Skowronski MT , Inoue N , et al . Alpha (1) -adrenocep-tor-induced trafficking of aquaporin-5 to the apical plasma membrane of rat parotid cells[J ] . Biochem Biophys Res Commun , 1999 , 265 (1) :94-100.
20 Christian Müller,Matthias Sendler and Jan-Peter Hildebrandt, Downregulation of aquaporins 1 and 5 in nasal gland by osmotic stress in ducklings,Anas platyrhynchos: implications for the production of hypertonic fluid, THE JOURNAL OF EXPERIMENTAL BIOLOGY,2006,209:4067-4076
21张欣欣,郭永清,张文杰,等. Na+通道与鼻息肉形成关系的初步研究中华耳咽喉科杂志,2000,35 ( 5) :359-362。
22 Pedersen PS ,Braunstein TH ,Jorgensen A , et al . Stimulation of aquaporin5 andtransepithelial water permeability in human airway epithelium by hyperosmotic stress[J ] . Pflugers Arch ,2007 ,453(6) :777-785.
23蒋媛,俞晨杰,沈晓辉等,伴或不伴变应性鼻炎的鼻息肉组织中水通道蛋白5的表达及意义,临床耳鼻咽喉头颈外科杂志, 2008, 22(18):842-845。
24 Boucher RC. Molecular insights into the physiology of the thin film of airway surface liquid. J Physiol, 1999, 516: 631~638.
25雷霏,赵小冬,朱建国,等,实验性变应性鼻炎大鼠鼻黏膜水通道蛋白5的表达及意义[J ] ,中华耳鼻咽喉科杂志,2005,40 (3):172-175。
26 Zhihong Chen, Rong Zhu, Li Bai,et al. Downregulation of aquaporin 5 induced by vector-based short hairpin RNA and its effect on MUC5AC gene expression in human airway submucosal gland cells. Respiratory Physiology & Neurobiology. 2006, 152(2): 197-203.
27 Peter Steen Pedersen, Thomas Hartig Braunstein, Anders J?rgensen, et al. Stimulation of aquaporin-5 and transepithelial water permeability in human airway epithelium by hyperosmotic stress. Pflugers Arch. 2007, 453(6): 777-785.
28 Venkataramana K. Sidhaye, Ali D. Güler, Kelly S. Schweitzer,et al. Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions. Proc Natl Acad Sci USA. 2006, 103(12): 4747–4752.
29 Johji Nomura, Akinori Hisatsune, Takeshi Miyata, et al. The role of CpGmethylation in cell type-specific expression of the aquaporin-5 gene. Biochem Biophys Res Commun. 2007, 353(4): 1017-1022.
30 Marie Skowron-zwarg, Sonja Boland, Nathalie Caruso, et al.Interleukin-13 interferes with CFTR and AQP5 expression and localization during human airway epithelial cell differentiation. Experimental Cell Research, 2007, 313(12): 2695-2702.
2.张欣欣,郭永清,张文杰,等, Na+通道与鼻息肉形成关系的初步研中华耳鼻咽喉科杂志,2000,35 ( 5):359-362。
3. Connolly DL, Shanahan CM,Weissberg PL. The aquaporin1A family of water channel protein. Int J Biochem Cell Biol, 1998, 30: 169-173.
4. Atílio Maximino Fernandes,Fabiana Cardoso Pereira Valera,Wilma T. Anselmo-Lima,Mechanism of action of glucocorticoids in nasal polyposis,Rev Bras Otorrinolaringol,2008,74(2):279-83.
5. Raina S, Preston G M, Guggino W B, et al. Molecular cloning and characterization of an aqquaporin cDNA from salivary, lacrimal, and respiratory tissues[J]. J Biol Chem, 1995, 270: 1908-1912.
6. Yang F, Kawedia J D, Menon A G. Cyclic AMP regulates aquaporin -5 expression at both transcriptional and post-transcriptional levels through a protein kinase A pathaway[J].J Biol Chem, 2003, 278:32173-32180.
7. Ma T, Song Y, Gillespie A, et al. Defective secretion of saliva in trans-genic micelacking aquaporin-5 water channels[J]. J Biol Chem, 1999, 274:20071-20074.
8. Benson M. Pathophysiological effects of glucocorticoids on nasalpolyps: an update. Curr Opin Allergy Clin Immunol 2005;5:31-5.
9. Benitez P, Alobid I, Haro J, Berenguer J, Bernal-Sprekelsen M,Pujols L, Picado C, Mullol J. A short course of oral prednisone followed by intranasal budesonide is an effective treatment of severe nasal polyps. Laryngoscope 2006,116:770-5.
10.中华医学会耳鼻咽喉科学分会,中华耳鼻咽喉科杂志编辑委员会,变应性鼻炎诊断标准及疗效评定标准(1997年修订,海口),中华耳鼻咽喉科杂志,1998,33:134-135。
11. Nielsen S, King LS, Christensen BM, et al. Aquaporins in complex tissues:Ⅱ. Subcellular distribution in respiratory and glandular tissues of rat. Am J Physiol. 1997;273:1549-1561.
12. King LS, Nielsen S, Agre P. Aquaporins in complex tissues:Ⅰ. Developmental patterns in respiratory and glandular tissues of rat. Am J Physiol. 1997;273:1541-1548.
13. Song Y, Verkman AS. Aquauaporin-5 dependent fluid secretion in airway submucosal glands. J Biol Chem, 2001, 276: 41288-41292.
14. Mladina R, Clement P, Lopadin A,Mann W, Passali D. International Consensus on Nasal Polyposis 2002-2004. Eur Arch Otorhinolaryngol 2005;262(6):519-21.
15. Fokkens W,Lund V,Bachert C,Clement P,Hellings P, Holmstrom M et al. EAACI position paper on rhinosinusitis and nasal polyps executive summary. Allergy 2005;60(5):583-601.
16. Bachert C, Watelet, JB,Gevaert P,Cauwenberge,PV.Pharmacological management of nasal polyposis. Drugs 2005;65(11):1537-52.
17.董春玲,鲁继荣,王桂芳等,地塞米松对哮喘小鼠肺液清除功能障碍的作用,药学服务与研究,2008 Feb; 8 (1):42-72。
18.蒋媛,俞晨杰,沈晓辉等,伴或不伴变应性鼻炎的鼻息肉组织中水通蛋白5的表达及意义,临床耳鼻咽喉头颈外科杂志, Sep2008,Vol 22,No 18.
1 Preston GM,Carroll TP,Guggino WB , et al . Appearance of water channels in Xenopus occytes expressing red cell CHIP28 protein [J ] .Science,1992 ,256(5055) :385-387.
2马兵,李学军,水通道的生理功能及与疾病的关系,国外医学生理病理科学和临床分册,1998,18(2): 101~104。
3 Yang B. The human aquaporin gene family (review) [J]. Current Genomics, 2000, 1(1): 9l~102.
4 Song Y, Jayaraman S, Yang B, et al. Role of aquaporin water channels in airway fluid transport, humidification, and surface liquid hydration [J]. J Gen Physiol, 2001, 117(6): 573~582.
5 Krane AM, Fortner CN , Hand A , et al . Aquaporin 5-deficient mouse lungs are hyperresponsive to cholinergic stimulation[J ] . Proc Natl Acad Sci USA , 2001 , 98 :14114-14119.
6 Kozono D , Masato Y, King LS , et al . Aquaporin water channels :atomic structure and molecular dynamics meet clinical medicine [J ] . JClin Invest , 2002 , 109 :1395-1399.
7 Krane CM, Towne JE , Menon AG. Cloning and characterization of murine Aqp5 : evidence for a conserved aquaporin gene cluster[J ] . Mamm Genome , 1999 , 10(5) :498-505.
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