Aspirin enhances sensitization to the egg-white allergen ovalbumin in rats

Autoři: Takahiro Fukushima aff001;  Tomoharu Yokooji aff001;  Taiki Hirano aff001;  Yuta Kataoka aff001;  Takanori Taogoshi aff001;  Hiroaki Matsuo aff001
Působiště autorů: Department of Pharmaceutical Services, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan aff001;  Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan aff002
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0226165


Enhancement of oral absorption of food allergens by non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, is considered an exacerbating factor in the development of food allergies. In this study, we examined the effect of aspirin on oral sensitization to and absorption of the egg-white allergen ovalbumin (OVA) in rats. The absorption of OVA was evaluated by measuring the plasma concentration of OVA after oral administration by gavage. To evaluate oral sensitization to OVA, plasma levels of immunoglobulin (Ig) E and IgG1 antibodies (Abs) specific to OVA were determined by enzyme-linked immunosorbent assay after initiation of sensitization. High-dose aspirin (30 mg/kg) increased oral OVA absorption and plasma levels of OVA-specific IgE and IgG1 Abs compared with those observed in vehicle-treated rats. In contrast, low-dose aspirin (3 mg/kg) exerted no changes in either absorption or sensitization. Spermine, an absorption enhancer, increased the oral absorption of OVA to nearly the same extent as high-dose aspirin, whereas the plasma levels of OVA-specific IgE and IgG1 Abs exhibited no significant differences between spermine- and vehicle-treated rats. Among the NSAIDs, diclofenac and indomethacin increased sensitization to OVA, similar to high-dose aspirin, but meloxicam exerted no effects on Ab levels. In conclusion, we showed that high-dose aspirin enhanced oral sensitization to OVA. Our study suggests that enhanced oral sensitization to OVA cannot be ascribed to increased absorption of OVA from the intestinal tract. Although the mechanisms underlying this enhancement of sensitization are still controversial, our study suggests that modification of cytokine production due to impairment of the intestinal barrier function and inhibition of cyclooxygenase-1 activity by aspirin may be involved.

Klíčová slova:

Allergens – Blood plasma – Drug absorption – Enzyme-linked immunoassays – Gastrointestinal tract – NSAIDs – Oral administration – Food allergies


1. Matsuo H, Yokooji T, Taogoshi T. Common food allergens and their IgE-binding epitopes. Allergol Int. 2015;64:332–43. doi: 10.1016/j.alit.2015.06.009 26433529

2. Ebisawa M, Ito K, Fujisawa T.; Committee for Japanese Pediatric Guideline for Food Allergy, The Japanese Society of Pediatric Allergy and Clinical Immunology, The Japanese Society of Allergology. Japanese guidelines for food allergy 2017. Allergol Int. 2017;66:248–264. doi: 10.1016/j.alit.2017.02.001 28285847

3. Kawai S. Cyclooxygenase selectivity and the risk of gastro-intestinal complications of various non-steroidal anti-inflammatory drugs: A clinical consideration. Inflamm Res. 1998;47 Suppl 2:S102–6. doi: 10.1007/s000110050291 9831331

4. Yokooji T, Hamura K, Matsuo H. Intestinal absorption of lysozyme, an egg-white allergen, in rats: kinetics and effect of NSAIDs. Biochem Biophys Res Commun. 2013;438:61–5. doi: 10.1016/j.bbrc.2013.07.024 23872145

5. Yokooji T, Nouma H, Matsuo H. Characterization of ovalbumin absorption pathways in the rat intestine, including the effects of aspirin. Biol Pharm Bull. 2014;37:1359–65. doi: 10.1248/bpb.b14-00290 25087958

6. Yokooji T, Fukushima T, Hamura K, Ninomiya N, Ohashi R, Taogoshi T, et al. Intestinal absorption of the wheat allergen gliadin in rats. Allergol Int. 2019;68:247–253. doi: 10.1016/j.alit.2018.11.005 30559050

7. Matsuo H, Morimoto K, Akaki T, Kaneko S, Kusatake K, Kuroda T, et al. Exercise and aspirin increase levels of circulating gliadin peptides in patients with wheat-dependent exercise-induced anaphylaxis. Clin Exp Allergy. 2005;35:461–6. doi: 10.1111/j.1365-2222.2005.02213.x 15836754

8. Matsuo H, Kaneko S, Tsujino Y, Honda S, Kohno K, Takahashi H, et al. Effects of non-steroidal anti-inflammatory drugs (NSAIDs) on serum allergen levels after wheat ingestion. J Dermatol Sci. 2009;53:241–3. doi: 10.1016/j.jdermsci.2008.09.004 18947983

9. Yokooji T, Matsuo H. Sodium cromoglycate prevents exacerbation of IgE-mediated food-allergic reaction induced by aspirin in a rat model of egg allergy. Int Arch Allergy Immunol. 2015;167:193–202. doi: 10.1159/000437328 26329011

10. Proust B, Astier C, Jacquenet S, Ogier V, Magueur E, Roitel O, et al. A single oral sensiuzauon to peanut without adjuvant leads to anaphylaxis in mice. Int Arch Allergy Immunol. 2008;146:212–8. doi: 10.1159/000115889 18268389

11. Brockow K, Kneissl D, Valentini L, Zelger O, Grosber M, Kugler C, et al. Using a gluten oral food challenge protocol to improve diagnosis of wheat-dependent exercise-induced anaphylaxis. J Allergy Clin Immunol. 2015;135:977–84.e4. doi: 10.1016/j.jaci.2014.08.024 25269870

12. Food and Drug Administration. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Center for Drug Evaluation and Research (CDER) 2005. doi: 10.1089/blr.2006.25.697

13. Lee M, Feldman M. Age-related reductions in gastric mucosal prostaglandin levels increase susceptibility to aspirin-induced injury in rats. Gastroenterology. 1994;107: 1746–50. doi: 10.1016/0016-5085(94)90816-8 7958687

14. Naito Y, Yoshikawa T, Yagi N, Matsuyama K, Yoshida N, Seto K, et al. Effects of polaprezinc on lipid peroxidation, neutrophil accumulation, and TNF-alpha expression in rats with aspirin-induced gastric mucosal injury. Dig Dis Sci. 2001;46: 845–51. doi: 10.1023/a:1010716804594 11330422

15. Suzuki T, Yoshida N, Nakabe N, Isozaki Y, Kajikawa H, Takagi T, et al. Prophylactic effect of rebamipide on aspirin-induced gastric lesions and disruption of tight junctional protein zonula occludens-1 distribution. J Pharmacol Sci. 2008;106:469–77. doi: 10.1254/jphs.fp0071422 18360096

16. Oshima T, Miwa H, Joh T. Aspirin induces gastric epithelial barrier dysfunction by activating p38 MAPK via claudin-7. Am J Physiol Cell Physiol. 2008;295:C800–6. doi: 10.1152/ajpcell.00157.2008 18667601

17. Louis E, Franchimont D, Deprez M, Lamproye A, Schaaf N, Mahieu P, et al. Decrease in systemic tolerance to fed ovalbumin in indomethacin-treated mice. Int Arch Allergy Immunol. 1996;109:21–6. doi: 10.1159/000237227 8527946

18. Isobe N, Suzuki M, Oda M, Tanabe S. Enzyme-modified cheese exerts inhibitory effects on allergen permeation in rats suffering from indomethacin-induced intestinal inflammation. Biosci Biotechnol Biochem. 2008;72:1740–5. doi: 10.1271/bbb.80042 18603772

19. Sugita Y, Takao K, Toyama Y, Shirahata A. Enhancement of intestinal absorption of macromolecules by spermine in rats. Amino Acids. 2007;33: 253–260. doi: 10.1007/s00726-007-0532-1 17653818

20. Sugita Y, Takao K, Sugino Y, Kuwabara R, Shirahata A. Enhancement of gastrointestinal absorption of ovalbumin caused by spermine induces an increase in plasma histamine levels in mice sensitized to ovalbumin. Biol Pharm Bull. 2011;34:415–9. doi: 10.1248/bpb.34.415 21372394

21. Dhuban KB, d’Hennezel E, Ben-Shoshan M, McCusker C, Clarke A, Fiset P, et al. Altered T helper 17 responses in children with food allergy. Int Arch Allergy Immunol. 2013;162:318–22. doi: 10.1159/000354028 24193199

22. Moon HG, Kang CS, Choi JP, Choi DS, Choi HI, Choi YW, et al. Acetyl salicylic acid inhibits Th17 airway inflammation via blockade of IL-6 and IL-17 positive feedback. Exp Mol Med. 2013;45:e6. doi: 10.1038/emm.2013.10 23306703

23. Moon HG, Tae YM, Kim YS, Gyu Jeon S, Oh SY, Song Gho Y, et al. Conversion of Th17-type into Th2-type inflammation by acetyl salicylic acid via the adenosine and uric acid pathway in the lung. Allergy. 2010;65:1093–103. doi: 10.1111/j.1398-9995.2010.02352.x 20337611

24. Boniface K, Bak-Jensen KS, Li Y, Blumenschein WM, McGeachy MJ, McClanahan TK, et al. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling. J Exp Med. 2009; 206:535–48. doi: 10.1084/jem.20082293 19273625

25. Demehri S, Morimoto M, Holtzman MJ, Kopan R. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol. 2009;7:e1000067. doi: 10.1371/journal.pbio.1000067 19557146

26. Jang S, Morris S, Lukacs NW. TSLP promotes induction of Th2 differentiation but is not necessary during established allergen-induced pulmonary disease. PLoS One. 2013;8:e56433. doi: 10.1371/journal.pone.0056433 23437132

27. Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 2005;6:1047–53. doi: 10.1038/ni1247 16142237

28. Berraïes A, Hamdi B, Ammar J, Hamzaoui K, Hamzaoui A. Increased expression of thymic stromal lymphopoietin in induced sputum from asthmatic children. Immunol Lett. 2016;178:85–91. doi: 10.1016/j.imlet.2016.08.004 27528425

29. Cultrone A, de Wouters T, Lakhdari O, Kelly D, Mulder I, Logan E, et al. The NF-κB binding site located in the proximal region of the TSLP promoter is critical for TSLP modulation in human intestinal epithelial cells. Eur J Immunol. 2013;43:1053–62. doi: 10.1002/eji.201142340 23310954

30. Paplińska-Goryca M, Nejman-Gryz P, Proboszcz M, Krenke R. The effect of 1,25-dihydroxyvitamin D3 on TSLP, IL-33 and IL-25 expression in respiratory epithelium. Eur Cytokine Netw. 2016;27:54–62. doi: 10.1684/ecn.2016.0377 27478079

31. Yu HS, Angkasekwinai P, Chang SH, Chung Y, Dong C. Protease allergens induce the expression of IL-25 via Erk and p38 MAPK pathway. J Korean Med Sci. 2010; 25:829–34. doi: 10.3346/jkms.2010.25.6.829 20514301

32. Varricchi G, Pecoraro A, Marone G, Criscuolo G, Spadaro G, Genovese A, et al. Thymic Stromal Lymphopoietin Isoforms, Inflammatory Disorders, and Cancer. Front Immunol. 2018;9:1595. doi: 10.3389/fimmu.2018.01595 30057581

33. Lund SJ, Portillo A, Cavagnero K, Baum RE, Naji LH, Badrani JH, et al. Leukotriene C4 Potentiates IL-33-Induced Group 2 Innate Lymphoid Cell Activation and Lung Inflammation. J Immunol. 2017; 199:1096–1104. doi: 10.4049/jimmunol.1601569 28667163

34. Xiong Y, Cui X, Li W, Lv J, Du L, Mi W, et al. BLT1 signaling in epithelial cells mediates allergic sensitization via promotion of IL-33 production. Allergy. 2019; 74:495–506. doi: 10.1111/all.13656 30390302

Článok vyšiel v časopise


2019 Číslo 12