Inflammation Research

, Volume 61, Issue 8, pp 863–873 | Cite as

Chronic aspiration shifts the immune response from adaptive immunity to innate immunity in a murine model of asthma

  • Kuei-Ying Su
  • Anitra D. Thomas
  • Jui-Chih Chang
  • Jason H. Leung
  • Sean M. Lee
  • Zoie E. Holzknecht
  • Mary Lou Everett
  • W. Michael Foster
  • Monica Kraft
  • William Parker
  • R. Duane Davis
  • Shu S. Lin
Original Research Paper
  • 141 Downloads

Abstract

Objective and design

The hypothesis that aspiration of gastric fluid drives the anti-ovalbumin response toward a Th2 reaction even in animals not prone to Th2 responses was evaluated.

Subjects

Forty-eight male C57BL/6 mice were used.

Methods

Mice were sensitized and challenged with ovalbumin starting 5 weeks prior to the initiation of weekly aspirations of either gastric fluid or normal saline as a control. Weekly aspiration continued during the course of exposure to ovalbumin.

Treatment

Aspiration consisted of 50 μl of gastric fluid with 50 μl of 0.9 % normal saline used as a control. Antigen exposure consisted of sensitization to ovalbumin via intraperitoneal injection on days 0 and 14 and challenge on day 21 with aerosolized antigen for 30 min.

Results

No evidence of a shift toward a Th2 response as a result of gastric fluid aspiration was seen in the Th1-prone strain utilized, although a profound down-regulation of a broad array of T cell-associated cytokines and chemokines and up-regulation of macrophage-associated markers was observed as a result of aspiration.

Conclusions

These data provide support for the hypothesis that the clinical association between asthma and gastroesophageal reflux disease (GERD) does not involve an exacerbation of asthma by GERD-associated aspiration of gastric fluid, but may cause immune reactions unrelated to the asthma pathology.

Keywords

Gastroesophageal reflux Aspiration Asthma Innate immunity Adaptive immunity 

Notes

Acknowledgments

This work was supported by the 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 and Julie Fuller for their technical assistance.

Conflict of interest

The authors have no competing interests to declare.

References

  1. 1.
    Delaney BC. Review article: prevalence and epidemiology of gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2004;20(Suppl 8):2–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Spechler SJ. Epidemiology and natural history of gastro-oesophageal reflux disease. Digestion. 1992;51(Suppl 1):24–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Kase JS, Pici M, Visintainer P. Risks for common medical conditions experienced by former preterm infants during toddler years. J Perinat Med. 2009;37:103–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol. 2006;101:1900–20.PubMedCrossRefGoogle Scholar
  5. 5.
    Osler W. The principles and practice of medicine. New York: D. Appleton; 1892. p. 497–503.Google Scholar
  6. 6.
    Machado Mda M, Cardoso PF, Ribeiro IO, Zamin Júnior I, Eilers RJ. Esophageal manometry and 24-h esophageal pH-metry in a large sample of patients with respiratory symptoms. J Bras Pneumol. 2008;34:1040–8.Google Scholar
  7. 7.
    Ahmed T, Vaezi MF. The role of pH monitoring in extraesophageal gastroesophageal reflux disease. Gastrointest Endosc Clin N Am. 2005;15:319–31.PubMedCrossRefGoogle Scholar
  8. 8.
    Meier JH, McNally PR, Punja M, Freeman SR, Sudduth RH, Stocker N, Perry M, Spaulding HS. Does omeprazole (Prilosec) improve respiratory function in asthmatics with gastroesophageal reflux? Dig Dis Sci. 1994;39:2127–33.PubMedCrossRefGoogle Scholar
  9. 9.
    Leggett JJ, Johnston BT, Mills M, Gamble J, Heaney LG. Prevalence of gastroesophageal reflux in difficult asthma. Chest. 2005;127:1227–31.PubMedCrossRefGoogle Scholar
  10. 10.
    Frye JW, Vaezi MF. Extraesophageal GERD. Gastroenterol Clin N Am. 2008;37:845–58.CrossRefGoogle Scholar
  11. 11.
    Gaude G. Pulmonary manifestations of gastroesophageal reflux disease: report. Ann Thorac Med. 2009;4:115–23.PubMedCrossRefGoogle Scholar
  12. 12.
    Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux disease and asthma: a systematic review. Gut. 2007;56:1654–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Hanania NA, Sockrider M, Giraldo L, Valdez R, Flores E, Reibman J, DiMango E, Rogers L, Cammarata C, Carapetyan K, Sormillon J, Simpson E, Williams L, Sundy J, Dudek G, Newton R, Dugdale A, Teague WG, Fitzpatrick A, Khatri S, Patel R, Peabody J, Hunter E, Whitlock D, Smith L, Moy J, Naureckas E, Olopade CS, Hixon J, Brees A, Rivera G, Sietsema S, Zagaja V, Busk M, Williams C, Puntenney P, Busk N, Leone F, Hayes-Hampton M, Summer WR, Meyaski G, Wenzel S, Katial R, Lopez L, Lima J, Blake K, Santos A, Vega K, Lambiase L, Langford T, Schaeffer D, Lang J, McRae M, Karpel J, Cohen R, Ramdeo R, Irvin CG, Dixon AE, Kaminsky DA, Colletti R, Burns SM, Bourassa LM, Lang SE, Griffes LV, Pratt R, Nakos KB, Girard KJ, Mastronarde J, McCoy K, Parsons J, Drake J, Compton R, Raterman L, Cosmar D, Gerald LB, Bailey WC, Erwin S, Kelley A, Laken D, Wanner A, Lockey R, Mendes E, McCullough S, Fimbel B, Grandstaff M, Blumenthal MN, Brottman G, Hagen J, Decker A, Lascewski D, Kelleher S, Bachman K, Quintard C, Sherry C, Salzman G, Pyszczynski D, Haney P, Castro M, Bacharier L, Sumino K, Scheipeter ME, Tarsi J, Wasserman S, Ramsdell J, Vitin J, Tucker T, Anthonisen N, Wise R, Holbrook J, Brown E, Amend-Libercci D, Barry K, Daniel M, Lears A, Leatherman G, Levine C, Masih R, Modak S, Nowakowski D, Prusakowski N, Shade D, Shiflett C, Sugar E, Richter J, Lancet E, Taggart V, Edelman N, Hanania N, Teague G, Summer W, Blumenthal M, Irvin C, Dozor A, Gerald L, Lazarus S, Calhoun W, Kahrilas P, McWilliams B, Rogatko A, Sorkness C, Vento R, Rappaport S, Pezza G, Weinmann G, Snider G, Fish J, Ingbar D, Jenkinson S, Mannino D, Perlstadt H, Rosenwasser L, Samet J, Schraufnagel D, Smith J, Standiford T, Weaver T. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360:1487–99.CrossRefGoogle Scholar
  14. 14.
    Mishra NC, Rir-sima-ah J, Langley RJ, Singh SP, Pena-Philippides JC, Koga T, Razani-Boroujerdi S, Hutt J, Campen M, Kim KC, Tesfaigzi Y, Sopori ML. Nicotine primarily suppresses lung Th2 but not goblet cell and muscle cell responses to allergens. J Immunol. 2008;180:7655–63.PubMedGoogle Scholar
  15. 15.
    Thomas A, Su K-Y, Chang J-C, Leung J, Lee S, Holzknecht Z, Everett M, Parker W, Davis R, Lin S. Gastroesophageal reflux-associated aspiration alters the immune response in asthma. Surg Endosc. 2010;24:1066–74.PubMedCrossRefGoogle Scholar
  16. 16.
    Barbas AS, Downing TE, Balsara KR, Tan HE, Rubinstein GJ, Holzknecht ZE, Collins BH, Parker W, Davis RD, Lin SS. Chronic aspiration shifts the immune response from Th1 to Th2 in a murine model of asthma. Eur J Clin Invest. 2008;38:596–602.PubMedCrossRefGoogle Scholar
  17. 17.
    Nemzek JA, Kim J. Pulmonary inflammation and airway hyperresponsiveness in a mouse model of asthma complicated by acid aspiration. Comp Med. 2009;59:321–30.PubMedGoogle Scholar
  18. 18.
    Downing TE, Sporn TA, Bollinger RR, Davis RD, Parker W, Lin SS. Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity. Exp Biol Med (Maywood). 2008;233:1202–12.CrossRefGoogle Scholar
  19. 19.
    Brewer JP, Kisselgof AB, Martin TR. Genetic Variability in Pulmonary Physiological, Cellular, and Antibody Responses to Antigen in Mice. Am J Respir Crit Care Med. 1999;160:1150–6.PubMedGoogle Scholar
  20. 20.
    Whitehead GS, Walker JKL, Berman KG, Foster WM, Schwartz DA. Allergen-induced airway disease is mouse strain dependent. Am J Physiol Lung Cell Mol Physiol. 2003;285:L32–42.PubMedGoogle Scholar
  21. 21.
    Shinagawa K, Kojima M. Mouse Model of Airway remodeling: strain differences. Am J Respir Crit Care Med. 2003;168:959–67.PubMedCrossRefGoogle Scholar
  22. 22.
    Ackerman KG, Huang H, Grasemann H, Puma C, Singer JB, Hill AE, Lander E, Nadeau JH, Churchill GA, Drazen JM, Beier DR. Interacting genetic loci cause airway hyperresponsiveness. Physiol Genom. 2005;21:105–11.CrossRefGoogle Scholar
  23. 23.
    Zosky GR, Larcombe AN, White OJ, Burchell JT, von Garnier C, Holt PG, Turner DJ, Wikstrom ME, Sly PD, Stumbles PA. Airway hyperresponsiveness is associated with activated CD4+ T cells in the airways. Am J Physiol Lung Cell Mol Physiol. 2009;297:L373–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Tumes DJ, Cormie J, Calvert MG, Stewart K, Nassenstein C, Braun A, Foster PS, Dent LA. Strain-dependent resistance to allergen-induced lung pathophysiology in mice correlates with rate of apoptosis of lung-derived eosinophils. J Leukoc Biol. 2007;81:1362–73.PubMedCrossRefGoogle Scholar
  25. 25.
    Gueders M, Paulissen G, Crahay C, Quesada-Calvo F, Hacha J, Van Hove C, Tournoy K, Louis R, Foidart J-M, Noël A, Cataldo D. Mouse models of asthma: a comparison between C57BL/6 and BALB/c strains regarding bronchial responsiveness, inflammation, and cytokine production. Inflamm Res. 2009;58:845–54.PubMedCrossRefGoogle Scholar
  26. 26.
    Chimenti L, Morici G, Paterno A, Bonanno A, Siena L, Licciardi A, Veca M, Guccione W, Macaluso F, Bonsignore G, Bonsignore MR. Endurance training damages small airway epithelium in mice. Am J Respir Crit Care Med. 2007;175:442–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Lozewicz S, Wells C, Gomez E, Ferguson H, Richman P, Devalia J, Davies RJ. Morphological integrity of the bronchial epithelium in mild asthma. Thorax. 1990;45:12–5.PubMedCrossRefGoogle Scholar
  28. 28.
    Feng NH, Hacker A, Effros RM. Solute exchange between the plasma and epithelial lining fluid of rat lungs. J Appl Physiol. 1992;72:1081–9.PubMedGoogle Scholar
  29. 29.
    Wilson MS, Pesce JT, Ramalingam TR, Thompson RW, Cheever A, Wynn TA. Suppression of murine allergic airway disease by IL-2: anti-IL-2 monoclonal antibody-induced regulatory T cells. J Immunol. 2008;181:6942–54.PubMedGoogle Scholar
  30. 30.
    Neveu WA, Allard JB, Dienz O, Wargo MJ, Ciliberto G, Whittaker LA, Rincon M. IL-6 Is required for airway mucus production induced by inhaled fungal allergens. J Immunol. 2009;183:1732–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Hashimoto T, Kobayashi N, Kajiyama Y, Kaminuma O, Suko M, Mori A. IL-2-induced IL-13 production by allergen-specific human helper T cell clones. Int Arch Allergy Immunol. 2006;140:51–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Downing TE, Sporn TA, Bollinger RR, Davis RD, Parker W, Lin SS. Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity. Exp Biol Med (Maywood). 2008;233:1202–12.CrossRefGoogle Scholar
  33. 33.
    Cheng CM, Hsieh CC, Lin CS, Dai ZK, Shih PK, Everett ML, Thomas AD, Parker W, Davis RD, Lin SS. Macrophage activation by gastric fluid suggests MMP involvement in aspiration-induced lung disease. Immunobiology. 2010;215:173–81.PubMedCrossRefGoogle Scholar
  34. 34.
    Schaumann F, Muller M, Braun A, Luettig B, Peden DB, Hohlfeld JM, Krug N. Endotoxin augments myeloid dendritic cell influx into the airways in patients with allergic asthma. Am J Respir Crit Care Med. 2008;177:1307–13.PubMedCrossRefGoogle Scholar
  35. 35.
    The American Lung Association Asthma Clinical Research Centers. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360:1487–99.CrossRefGoogle Scholar
  36. 36.
    Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole 40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2010;181:1042–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Perng DW, Chang KT, Su KC, Wu YC, Wu MT, Hsu WH, Tsai CM, Lee YC. Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation. Chest. 2007;132:1548–56.PubMedCrossRefGoogle Scholar
  38. 38.
    Oue K, Mukaisho K, Higo T, Araki Y, Nishikawa M, Hattori T, Yamamoto G, Sugihara H. Histological examination of the relationship between respiratory disorders and repetitive microaspiration using a rat gastro-duodenal contents reflux model. Exp Anim. 2011;60:141–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Wright RA, Miller SA, Corsello BF. Acid-induced esophagobronchial-cardiac reflexes in humans. Gastroenterology. 1990;99:71–3.PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2012

Authors and Affiliations

  • Kuei-Ying Su
    • 1
    • 2
    • 5
  • Anitra D. Thomas
    • 1
  • Jui-Chih Chang
    • 1
    • 3
    • 6
  • Jason H. Leung
    • 1
  • Sean M. Lee
    • 1
  • Zoie E. Holzknecht
    • 1
  • Mary Lou Everett
    • 1
  • W. Michael Foster
    • 4
  • Monica Kraft
    • 4
  • William Parker
    • 1
  • R. Duane Davis
    • 1
  • Shu S. Lin
    • 1
    • 5
    • 6
  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 Pulmonary and Critical Care MedicineDuke University Medical CenterDurhamUSA
  5. 5.Department of ImmunologyDuke University Medical CenterDurhamUSA
  6. 6.Department of PathologyDuke University Medical CenterDurhamUSA

Personalised recommendations