• 上海交通大學(xué)附屬第一人民醫(yī)院( 上海 200080)通訊作者: 金先橋, E-mail: jinxianqiao@ 126. com#現(xiàn)在山東濰坊醫(yī)學(xué)院附屬醫(yī)院呼吸科工作;

目的  探討慢性煙曲霉暴露對哮喘大鼠氣道上皮細胞損傷及表皮生長因子受體( EGFR) 表達的影響。方法  56 只雄性Wistar 大鼠隨機分為7 組( 每組8 只) : 慢性哮喘組( A 組) , 慢性哮喘+ 煙曲霉孢子吸入1 周( B 組) 、3 周( C 組) 和5 周( D 組) 組, 慢性哮喘+ 生理鹽水吸入組( E 組) , 卵白蛋白( OVA) 致敏生理鹽水激發(fā)組( F 組) , OVA 致敏生理鹽水激發(fā)+ 煙曲霉孢子吸入組( G 組) 。測定大鼠基礎(chǔ)氣道阻力和氣道阻力變化率, ELISA 法測定BALF 中表皮生長因子( EGF) 及轉(zhuǎn)化生長因子α( TGF-α) 濃度, 肺組織切片HE 染色觀察氣道上皮細胞損傷脫落程度, 過碘酸雪夫染色( PAS) 觀察氣道上皮杯狀細胞增生程度, 免疫組化染色測定氣道上皮細胞EGFR 表達強度, 免疫印跡測定肺組織EGFR 蛋白表達。結(jié)果  B、C、D 組大鼠BALF 中EGF[ ( 51. 72 ±8. 54) 、( 68. 12 ±7. 85) 、( 86. 24 ±9. 12) pg/mL] 、TGF-α[ ( 55. 26 ±9. 30) 、( 75. 58 ±11. 56) 、( 96. 75 ±14. 66) pg/mL] 、脫落上皮/ 氣道上皮[ ( 11. 25 ±3. 12) % 、( 26. 45 ±5. 56) % 、( 28. 50 ±7. 50) % ] 、杯狀細胞/ 上皮細胞面積比值[ ( 16. 42 ±5. 24) %、( 22. 64 ±6. 82) % 、( 36. 38 ±9. 21) % ] 、氣道上皮細胞EGFR 陽性信號累積光密度( IOD) 值( 82 ±15、120 ±19、165 ±21) 、肺組織EGFR 蛋白表達IOD 值( 0. 91 ±0. 26、1. 61 ±0. 52、2. 52 ±0. 78) 均高于A、E、F 及G 組( P  lt;0. 05 或 lt;0. 01) 。C 和D 組大鼠氣道阻力變化率[ ( 61. 91 ±5. 26) % 、( 84. 69 ±6. 38) % ] 均高于A、E、F 及G 組( P 值分別 lt; 0. 05 或 lt; 0. 01) 。氣道上皮細胞EGFR 表達IOD 值與脫落上皮/ 氣道上皮( % ) 及杯狀細胞/ 上皮細胞面積比值( % ) 呈正相關(guān)( r =0. 692, P  lt;0. 01; r = 0. 657, P  lt; 0. 01) 。結(jié)論  慢性煙曲霉暴露加重哮喘大鼠氣道上皮細胞損傷, 上調(diào)哮喘大鼠氣道上皮細胞EGFR 表達, 促進杯狀細胞增生, 加重氣道高反應(yīng)性。

引用本文： 高福生,金先橋,喬建甌,張軼. 慢性煙曲霉暴露對哮喘大鼠氣道上皮細胞損傷及表皮生長因子受體表達的影響. 中國呼吸與危重監(jiān)護雜志, 2010, 9(2): 115-121. doi: 復(fù)制

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1. Burgel PR，Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax，2004，59：992-996.
2. Puddicombe SM，Polosa R，Richter A，et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J，2000，14：1362-1374.
3. Denning DW，O’Driscoll BR，Hogaboam CM，et al. The link between fungi and severe asthma：a summary of the evidence. Eur Respir J，2006，27：615-626.
4. Gao FS，Qiao JO，Zhang Y，Jin XQ. Chronic intranasal administration of Aspergillus fumigatus spores leads to aggravation of airway inflammation and remodeling in asthmatic rats. Respirology，2009，14：360-370.
5. Palmans E，Kips JC，Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats. Am J Respir Crit Care Med，2000，161：627-635.
6. 高福生，龍飛，祁卉卉，等. 反復(fù)吸入煙曲霉孢子對慢性阻塞性肺疾病大鼠氣道炎癥和重構(gòu)的影響. 中國呼吸和危重監(jiān)護雜志，2008，7：205-209.
7. Glaab T，Mitzner W，Braun A，et al. Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice. J Appl Physiol，2004，97：1104-1111.
8. Sumi Y，F(xiàn)oley S，Daigle S，et al. Structural changes and airway remodelling in occupational asthma at a mean interval of 14 years after cessation of exposure. Clin Exp Allergy，2007，37：1781-178.
9. Snibson KJ，Bischof RJ，Slocombe RF，et al. Airway remodelling and inflammation in sheep lungs after chronic airway challenge with house dust mite. Clin Exp Allergy，2005，35：146-152.
10. Leigh R，Ellis R，Wattie J，et al. Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation. Am J Respir Cell Mol Biol，2002，27：526-535.
11. Ou XM，F(xiàn)eng YL，Wen FQ，et al. Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-?B. Respirology，2008，13：63-72.
12. Engelhart S，Hanfland J，Glasmacher A，et al. Impact of portable air filtration units on exposure of haematology-oncology patients to airborne Aspergillus fumigatus spores under field conditions. J Hosp Infect，2003，54：300-304.
13. Rivera A，Hohl T，Pamer EG. Immune response to Aspergillus fumigatus infections. Biol Blood Marrow Transplant，2006，12：47-49.
14. Holgate ST，Lackie P，Wilson S，et al. Bronchial epithelium as a key regulator of airway allergen sensitization and remodeling in asthma. Am J Respir Crit Care Med，2000，162：S113-S117.
15. Holgate ST. The airway epithelium is central to the pathogenesis of asthma. Allergol Int，2008，57：1-10.
16. Kauffman HF，Tomee JF，van de Riet MA，et al. Protease-dependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production. J Allergy Clin Immunol，2000，105：1185-1193.
17. Kohri K，Ueki IF，Shim JJ，et al. Pseudomonas aeruginosa induces MUC5AC production via epidermal growth factor receptor. Eur Respir J，2002，20：1263-1270.
18. Shao MX，Ueki IF，Nadel JA. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA，2003，100：11618-11623.
19. Takeyama K，Jung B，Shim JJ，et al. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol，2001，280：L165-172.
20. Takeyama K，Dabbagh K，Jeong Shim J，et al. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor：role of neutrophils. J Immunol，2000，164：1546-1552.
21. Shim JJ，Dabbagh K，Ueki IF，et al. IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am J Physiol Lung Cell Mol Physiol，2001，280：L134-140.
22. Thai P，Loukoianov A，Wachi S，et al. Regulation of airway mucin gene expression. Annu Rev Physiol，2008，70：405-429.
23. Takeyama K，Tamaoki J，Kondo M，et al. Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clin Exp Allergy，2008，38：857-865.
  1. 1. Burgel PR，Nadel JA. Roles of epidermal growth factor receptor activation in epithelial cell repair and mucin production in airway epithelium. Thorax，2004，59：992-996.
  2. 2. Puddicombe SM，Polosa R，Richter A，et al. Involvement of the epidermal growth factor receptor in epithelial repair in asthma. FASEB J，2000，14：1362-1374.
  3. 3. Denning DW，O’Driscoll BR，Hogaboam CM，et al. The link between fungi and severe asthma：a summary of the evidence. Eur Respir J，2006，27：615-626.
  4. 4. Gao FS，Qiao JO，Zhang Y，Jin XQ. Chronic intranasal administration of Aspergillus fumigatus spores leads to aggravation of airway inflammation and remodeling in asthmatic rats. Respirology，2009，14：360-370.
  5. 5. Palmans E，Kips JC，Pauwels RA. Prolonged allergen exposure induces structural airway changes in sensitized rats. Am J Respir Crit Care Med，2000，161：627-635.
  6. 6. 高福生，龍飛，祁卉卉，等. 反復(fù)吸入煙曲霉孢子對慢性阻塞性肺疾病大鼠氣道炎癥和重構(gòu)的影響. 中國呼吸和危重監(jiān)護雜志，2008，7：205-209.
  7. 7. Glaab T，Mitzner W，Braun A，et al. Repetitive measurements of pulmonary mechanics to inhaled cholinergic challenge in spontaneously breathing mice. J Appl Physiol，2004，97：1104-1111.
  8. 8. Sumi Y，F(xiàn)oley S，Daigle S，et al. Structural changes and airway remodelling in occupational asthma at a mean interval of 14 years after cessation of exposure. Clin Exp Allergy，2007，37：1781-178.
  9. 9. Snibson KJ，Bischof RJ，Slocombe RF，et al. Airway remodelling and inflammation in sheep lungs after chronic airway challenge with house dust mite. Clin Exp Allergy，2005，35：146-152.
  10. 10. Leigh R，Ellis R，Wattie J，et al. Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation. Am J Respir Cell Mol Biol，2002，27：526-535.
  11. 11. Ou XM，F(xiàn)eng YL，Wen FQ，et al. Macrolides attenuate mucus hypersecretion in rat airways through inactivation of NF-?B. Respirology，2008，13：63-72.
  12. 12. Engelhart S，Hanfland J，Glasmacher A，et al. Impact of portable air filtration units on exposure of haematology-oncology patients to airborne Aspergillus fumigatus spores under field conditions. J Hosp Infect，2003，54：300-304.
  13. 13. Rivera A，Hohl T，Pamer EG. Immune response to Aspergillus fumigatus infections. Biol Blood Marrow Transplant，2006，12：47-49.
  14. 14. Holgate ST，Lackie P，Wilson S，et al. Bronchial epithelium as a key regulator of airway allergen sensitization and remodeling in asthma. Am J Respir Crit Care Med，2000，162：S113-S117.
  15. 15. Holgate ST. The airway epithelium is central to the pathogenesis of asthma. Allergol Int，2008，57：1-10.
  16. 16. Kauffman HF，Tomee JF，van de Riet MA，et al. Protease-dependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production. J Allergy Clin Immunol，2000，105：1185-1193.
  17. 17. Kohri K，Ueki IF，Shim JJ，et al. Pseudomonas aeruginosa induces MUC5AC production via epidermal growth factor receptor. Eur Respir J，2002，20：1263-1270.
  18. 18. Shao MX，Ueki IF，Nadel JA. Tumor necrosis factor alpha-converting enzyme mediates MUC5AC mucin expression in cultured human airway epithelial cells. Proc Natl Acad Sci USA，2003，100：11618-11623.
  19. 19. Takeyama K，Jung B，Shim JJ，et al. Activation of epidermal growth factor receptors is responsible for mucin synthesis induced by cigarette smoke. Am J Physiol Lung Cell Mol Physiol，2001，280：L165-172.
  20. 20. Takeyama K，Dabbagh K，Jeong Shim J，et al. Oxidative stress causes mucin synthesis via transactivation of epidermal growth factor receptor：role of neutrophils. J Immunol，2000，164：1546-1552.
  21. 21. Shim JJ，Dabbagh K，Ueki IF，et al. IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. Am J Physiol Lung Cell Mol Physiol，2001，280：L134-140.
  22. 22. Thai P，Loukoianov A，Wachi S，et al. Regulation of airway mucin gene expression. Annu Rev Physiol，2008，70：405-429.
  23. 23. Takeyama K，Tamaoki J，Kondo M，et al. Role of epidermal growth factor receptor in maintaining airway goblet cell hyperplasia in rats sensitized to allergen. Clin Exp Allergy，2008，38：857-865.