• 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(duì)哮喘大鼠氣道上皮細(xì)胞損傷及表皮生長(zhǎng)因子受體( EGFR) 表達(dá)的影響。方法  56 只雄性Wistar 大鼠隨機(jī)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(cè)定大鼠基礎(chǔ)氣道阻力和氣道阻力變化率, ELISA 法測(cè)定BALF 中表皮生長(zhǎng)因子( EGF) 及轉(zhuǎn)化生長(zhǎng)因子α( TGF-α) 濃度, 肺組織切片HE 染色觀察氣道上皮細(xì)胞損傷脫落程度, 過(guò)碘酸雪夫染色( PAS) 觀察氣道上皮杯狀細(xì)胞增生程度, 免疫組化染色測(cè)定氣道上皮細(xì)胞EGFR 表達(dá)強(qiáng)度, 免疫印跡測(cè)定肺組織EGFR 蛋白表達(dá)。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(xì)胞/ 上皮細(xì)胞面積比值[ ( 16. 42 ±5. 24) %、( 22. 64 ±6. 82) % 、( 36. 38 ±9. 21) % ] 、氣道上皮細(xì)胞EGFR 陽(yáng)性信號(hào)累積光密度( IOD) 值( 82 ±15、120 ±19、165 ±21) 、肺組織EGFR 蛋白表達(dá)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(xì)胞EGFR 表達(dá)IOD 值與脫落上皮/ 氣道上皮( % ) 及杯狀細(xì)胞/ 上皮細(xì)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(xì)胞損傷, 上調(diào)哮喘大鼠氣道上皮細(xì)胞EGFR 表達(dá), 促進(jìn)杯狀細(xì)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(duì)哮喘大鼠氣道上皮細(xì)胞損傷及表皮生長(zhǎng)因子受體表達(dá)的影響. 中國(guó)呼吸與危重監(jiān)護(hù)雜志, 2010, 9(2): 115-121. doi: 復(fù)制

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(duì)慢性阻塞性肺疾病大鼠氣道炎癥和重構(gòu)的影響. 中國(guó)呼吸和危重監(jiān)護(hù)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(duì)慢性阻塞性肺疾病大鼠氣道炎癥和重構(gòu)的影響. 中國(guó)呼吸和危重監(jiān)護(hù)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.