Surgical Endoscopy

, Volume 24, Issue 5, pp 1066–1074 | Cite as

Gastroesophageal reflux-associated aspiration alters the immune response in asthma

  • Anitra D. Thomas
  • Kuei-Ying Su
  • Jui-Chih Chang
  • Jason H. Leung
  • Sean M. Lee
  • Zoie E. Holzknecht
  • Mary Lou Everett
  • William Parker
  • R. Duane Davis
  • Shu S. Lin



A large number of studies point toward chronic aspiration associated with gastroesophageal reflux disease (GERD) as an important factor involved in the development of asthma, the incidence of which has increased dramatically in industrially developed countries. Recent work suggests that medical intervention aimed at acid blockade is not sufficient to relieve the effects of chronic aspiration on asthma pathology, leaving surgical treatment of the disease as one of the few remaining options. This study examined the effect of chronic aspiration on the airway-associated immune response to allergens using a model of experimentally induced airway hypersensitivity in Balb/c mice.


The mice received aspiration of gastric fluid on days 1, 8, 15, 22, 29, 36, 43, and 50 and were sensitized to ovalbumin by intraperitoneal (IP) injection on days 33 and 47, challenged with aerosolized ovalbumin on day 54, and killed on day 56. Control mice received sham gastric fluid aspirations, sham induction of airway hypersensitivity, or both.


Chronic aspiration of 50 μl murine gastric fluid once per week for 8 weeks had a profound effect on the immune system in the lung, with upregulation of the macrophage/monocyte-associated cytokines tumor necrosis factor-α (TNF-α) and interleukin-12 (IL-12) and profound downregulation of a broad array of T-cell-associated cytokines including interleukins 2, 4, 5, 6, 10, 13, and 23, as well as interferon-γ. The aspiration-induced depression of IL-5 production in particular was found only in mice with airway hypersensitivity and not in control mice without airway hypersensitivity.


The results indicate that chronic aspiration of gastric fluid has a profound effect on the nature of the allergic response to aerosolized allergens, suggesting that the aspiration may be an important factor affecting the pathogenesis of asthma.


Aspiration Asthma Experimental model Gastroesophageal reflux 



This work was supported by a Society of American Gastrointestinal Endoscopic Surgeons research grant, and in part by the Parks Protocol Memorial Fund, the American Association for Thoracic Surgery Second Dwight Harken Research Scholarship, the American College of Surgeons Faculty Research Fellowship Award, the Duke Heart Center Career Development Award, and the Fannie E. Rippel Foundation. We thank Roxanne Wilson for her technical assistance.


Anitra D. Thomas, Kuei-Ying Su, Jui-Chih Chang, Jason H. Leung, Sean M. Lee, Zoie E. Holzknecht, Mary Lou Everett, William Parker, R. Duane Davis, and Shu S. Lin have no conflicts of interest or financial ties to disclose.


  1. 1.
    Romagnani S (2004) The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? Immunology 112:352–363CrossRefPubMedGoogle Scholar
  2. 2.
    Spechler SJ (1992) Epidemiology and natural history of gastro-oesophageal reflux disease. Digestion 51(Suppl 1):24–29CrossRefPubMedGoogle Scholar
  3. 3.
    Theodoropoulos DS, Pecoraro DL, Efstratiadis SE (2002) The association of gastroesophageal reflux disease with asthma and chronic cough in the adult. Am J Respir Med 1:133–146PubMedGoogle Scholar
  4. 4.
    Henderson RD, Woolfe CR (1978) Aspiration and gastroesophageal reflux. Can J Surg 21:352–354PubMedGoogle Scholar
  5. 5.
    Havemann BD, Henderson CA, El-Serag HB (2007) The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut 56:1654–1664CrossRefPubMedGoogle Scholar
  6. 6.
    Perng DW, Chang KT, Su KC, Wu YC, Wu MT, Hsu WH, Tsai CM, Lee YC (2007) Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation. Chest 132:1548–1556CrossRefPubMedGoogle Scholar
  7. 7.
    Teixeira BC, Norton RC, Penna FJ, Camargos PA, Lasmar LM, Macedo AV (2007) Gastroesophageal reflux and asthma in childhood: a study on their relationship using esophageal PH monitoring. J Pediatr 83:535–540CrossRefGoogle Scholar
  8. 8.
    Mays EE (1976) Intrinsic asthma in adults: association with gastroesophageal reflux. JAMA 236:2626–2628CrossRefPubMedGoogle Scholar
  9. 9.
    Jain S (2005) Proton pump inhibitor therapy for gastroesophageal reflux disease: does it treat the asthma? Chest 127:1097–1098CrossRefPubMedGoogle Scholar
  10. 10.
    Delaney BC (2004) Review article: prevalence and epidemiology of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 20(Suppl 8):2–4CrossRefPubMedGoogle Scholar
  11. 11.
    Ruigomez A, Rodriguez LA, Wallander MA, Johansson S, Thomas M, Price D (2005) Gastroesophageal reflux disease and asthma: a longitudinal study in UK general practice. Chest 128:85–93CrossRefPubMedGoogle Scholar
  12. 12.
    Asilsoy S, Babayigit A, Olmez D, Uzuner N, Karaman O, Oren O, Turgut CS, Tezcan D (2007) Helicobacter pylori infection and gastroesophageal reflux in asthmatic children. J Trop Pediatr 54:129–132CrossRefPubMedGoogle Scholar
  13. 13.
    Saha C, Riner ME, Liu G (2005) Individual and neighborhood-level factors in predicting asthma. Arch Pediatr Adolesc Med 159:759–763CrossRefPubMedGoogle Scholar
  14. 14.
    Farcau D, Dreghiciu D, Chereches-Panta P, Popa M, Farcau M, Nanulescu M (2004) Gastroesophageal reflux in asthmatic children: prevalence and pathogenic role. Pneumologia 53:127–131PubMedGoogle Scholar
  15. 15.
    Eagan TM, Brogger JC, Eide GE, Bakke PS (2005) The incidence of adult asthma: a review. Int J Tuberc Lung Dis 9:603–612PubMedGoogle Scholar
  16. 16.
    Jiang SP, Huang LW (2005) Role of gastroesophageal reflux disease in asthmatic patients. Eur Rev Med Pharmacol Sci 9:151–160PubMedGoogle Scholar
  17. 17.
    Barbas AS, Downing TE, Balsara KR, Tan HE, Rubinstein GJ, Holzknecht ZE, Collins BH, Parker W, Davis RD, Lin SS (2008) Chronic aspiration shifts the immune response from Th1 to Th2 in a murine model of asthma. Eur J Clin Invest 38:596–602CrossRefPubMedGoogle Scholar
  18. 18.
    Whitehead GS, Walker JK, Berman KG, Foster WM, Schwartz DA (2003) Allergen-induced airway disease is mouse strain dependent (see comment). Am J Physiol Lung Cell Mol Physiol 285:32–42Google Scholar
  19. 19.
    Shen HH, Ochkur SI, McGarry MP, Crosby JR, Hines EM, Borchers MT, Wang H, Biechelle TL, O’Neill KR, Ansay TL, Colbert DC, Cormier SA, Justice JP, Lee NA, Lee JJ (2003) A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse. J Immunol 170:3296–3305PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Anitra D. Thomas
    • 1
  • Kuei-Ying Su
    • 1
    • 2
  • Jui-Chih Chang
    • 1
    • 3
  • Jason H. Leung
    • 1
  • Sean M. Lee
    • 1
  • Zoie E. Holzknecht
    • 1
  • Mary Lou Everett
    • 1
  • William Parker
    • 1
  • R. Duane Davis
    • 1
  • Shu S. Lin
    • 1
    • 4
  1. 1.Department of SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Section of Allergy, Immunology, and RheumatologyBuddhist Tzu Chi General HospitalHualienTaiwan
  3. 3.Division of Thoracic and Cardiovascular SurgeryBuddhist Tzu Chi General HospitalHualienTaiwan
  4. 4.Department of ImmunologyDuke University Medical CenterDurhamUSA

Personalised recommendations