Effect of Prostaglandin E1 Analog Misoprostol in an Ovalbumin- Induced Allergic Rhinitis Model

Eurasian J Med 2019; 51(1): 75-9 Original Article

Effect of Prostaglandin E1 Analog Misoprostol in An Ovalbumin- Induced Allergic Rhinitis Model

Zulkuf Kaya1 , Muhammed Yayla2 , Arzu Bilen3 , Nihal Efe Atilla4 , Sevilay Ozmen5 , Irfan Cinar2 , Zafer Bayraktutan6 , Vahit Mutlu1 , Harun Un7, Erdem Toktay8

ABSTRACT Objective: The aim of the present study was to demonstrate the effects of misoprostol in ovalbumin- induced allergic rhinitis (AR). The second purpose was to compare the effect profile of the combination of an antihistamine with misoprostol during treatment of AR. Materials and Methods: Twenty-five adult male rats were used and were randomly classified into five groups (n=5): healthy+saline, AR, AR and desloratadine (D)-treated group, AR and misoprostol (M)-treated group, and AR and combined-treated group. Results: Desloratadine administration had significantly lower nasal symptoms than the AR group, but nasal symptoms in the AR+M group were better than those in the AR+D group. The best improvement in serum IgE levels was seen in the misoprostol alone and combination treatment groups. Conclusion: We suggest that prostaglandins should be considered in the treatment of AR, and that the effects of these types of drugs should be tested clinically in patients. Cite this article as: Kaya Z, Yayla M, Bilen A, et al. Keywords: Allergy, desloratadine, misoprostol, rat, rhinitis Effect of Prostaglandin E1 Analog Misoprostol in An Ovalbumin-Induced Allergic Rhinitis Model. Eurasian J Med 2019; 51(1): 75-9. ORCID IDs of the authors: Introduction Z.K: 0000-0002-9378-1672 M.Y: 0000-0002-0659-3084 Allergic rhinitis (AR) is defined as the presence of at least one of the following: nasal discharge, A.B: 0000-0001-9017-8344 sneezing, nasal itchiness, and nasal congestion [1]. Patients with AR may also be disturbed by N.E.A: 0000-0002-3239-4142 S.O: 0000-0003-4092-8260 sleep disorders, mood disorders, impaired daily activities, and deterioration in social relationships I.C: 0000-0002-9826-2556 Z.B: 0000-0002-4324-5943 [2]. Concurrently, it is stated that AR causes significant morbidity and has a significant effect on V.M: 0000-0002-2803-3328 E.T: 0000-0002-0715-2707 the quality of life. According to epidemiological evidence, the prevalence of AR, as well as all This study was an oral presentation at Turkish Society atopic diseases, is increasing worldwide [3]. AR is a common disease that affects 10%-40% of the of Anaesthesiology and Reanimation 51st National Congress 2017. world’s population [4]. 1Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, Ataturk University, Erzurum, Turkey Allergic rhinitis (AR) treatment consists of allergen prevention, patient education, pharmaco- 2Department of Pharmacology, Kafkas University logical treatment, and allergen immunotherapy. Preventing contact between the allergen and School of Medicine, Kars, Turkey 3Department of Internal Medicine, Ataturk the nasal mucosa is the main prevention method, but in most cases, this is insufficient, and -ap University School of Medicine, Erzurum/Turkey 4Department of Otorhinolaryngology, Head and propriate drug treatment for symptom control is also required. Currently, the most commonly Neck Surgery, Erzurum Training and Research Hospital, Erzurum, Turkey used treatment agents are nasal steroids, antihistamines, leukotriene receptor antagonists, and 5Department of Pathology, Ataturk University School of Medicine, Erzurum, Turkey immunotherapy. The aim of the treatment is to increase the patient’s quality of life and adapta- 6Department of Biochemistry, Ataturk University School of Medicine Erzurum, Turkey tion to their current life by controlling the symptoms [5, 6]. However, because of the frequency 7Department of Biochemistry, Agri Ibrahim Cecen University School of Pharmacy, Ağrı, Turkey of side effects and the chronic use of the drugs used in the treatment of AR, most patients stop 8Department of Histology and Embriology, Ataturk University School of Medicine, Erzurum, Turkey using the drugs and cannot be treated. Therefore, the production of drugs that are more effective, especially those with fewer central side effects, plays an important role in increasing patient Received: January 29, 2019 Accepted: February 11, 2019 compliance. Correspondence to: Muhammed Yayla E-mail: [email protected] Prostaglandin E (PGE) is a metabolite of the arachidonic acid produced by the cyclooxygenase DOI 10.5152/eurasianjmed.2019.19025 enzyme, which is known to prevent inflammation developed in the airways [7]. PGE performs its physiological function through four PGE receptors (EP1-4), which play a pharmacologi- cally important role [7]. Studies have shown that PGE receptors mediate many physiological Content of this journal is licensed under a Creative events, such as pain, fever, platelet aggregation, gastric cytoprotection, airway protection, Commons ovulation, fertilization, bronchodilation, vasodilatation, angiogenesis, cytokine, and chemokine Attribution 4.0 International License. modulation. PGE is synthesized in the body in two forms, PGE1 and PGE2, but it is also among 76 • Kaya et al. Role of Misoprostol on Alerjic Rhinitis in Rat Eurasian J Med 2019; 51(1): 75-9 the most important prostaglandins, having li- Materials and Methods group were given a saline solution alone accord- gands at four different receptors. However, ing to the same schedule. while endogenous PGE2 acts as an inflamma- Animals tory, PGE1 acts as an anti-inflammatory agent Male Sprague-Dawley rats were supplied by Evaluation of nasal symptoms [8, 9]. Studies of our subject have shown that the Ataturk University’s Experimental Medical On day 21 of the study, rats were placed in an the EP1, 2, 3, and 4 receptor analogs may have and Research Center. The study was approved observation cage for approximately 10 min for beneficial effects on antigen-induced hyper- by the Ataturk University National Animal Eth- acclimatization before the experiment started. sensitivity and mucus secretion in the nasal ics Committee (2018/207). Rats were housed After nasal instillation of 20 mL 10% OVA into epithelium [10]. It is shown here that the EP2 in standard plastic cages with sawdust bedding. the bilateral nasal cavities, the animals were and 3 analogs prevent mucus production, and The cages were placed in an air-conditioned placed in observation cages (one animal/cage), and the numbers of sneezes and nasal rub- the EP3 analog prevents neutrophil migration, room at 22 °C under lighting controls (14 h bing movements were counted for 30 min by thus reducing inflammation in the airways. light/10 h dark cycle). All rats had free access to four blinded observers who were unaware of However, the selective EP1 analog has been standard rat food and tap water. Rats were fed the sample’s identity. Thereafter, blood samples shown to have no effect. Additionally, the EP4 a standard rat diet. were collected from each rat via cardiac punc- analog has been shown to affect the effector ture under anesthesia using isoflurane; the rats phase of the antigen. In a clinical study, it has A total of 25 adult male Sprague-Dawley rats (220-250 g) were used. Rats were randomly were then killed. Serum was prepared and fro- been shown that the local administration of zen at -80 °C prior to biochemical analysis. Nasal PGE1 and PGE2 analogs is beneficial for AR classified into five groups (n=5): healthy+saline, AR, AR and desloratadine (D)-treated group, tissue and submandibular glands were immedi- and improves symptoms [11]. However, the AR and misoprostol (M)-treated group, and AR ately removed from all the rats at the end of the local use of PGE1 has been reported to cause and combined-treated group. study for histopathological changes. nasal irritation. Immunoglobulin E measurements in serum Preparation of OVA-induced AR rat model Misoprostol is a PGE1 analog drug used in the OVA-specific IgE levels in serum were measured The AR model was established according to treatment of peptic ulcers due to nonsteroidal in duplicate using a highly sensitive enzyme- literature-based standard protocols [15, 16]. anti-inflammatory drugs’ resistance to destruc- linked immunosorbent assay (Sunred, China) ac- Specifically, 20 rats belonging to the AR, AR+D, tive enzymes, such as aspirin [12]. The effect of cording to the manufacturer’s instructions (201- AR+M, and AR+DM groups were sensitized misoprostol on prostaglandin EP2 receptors is 11-4050) for kits designed specifically for rats. with a 1 mL intraperitoneal injection of 30 mg Al attributed to the prostaglandin EP3 receptor (OH) and 0.3 mg OVA (Sigma, USA) solutions 3 Histopathological examination and prostaglandin EP4 receptors. However, it once every other day over a period of 14 days The tissues reserved for histopathological ex- has no effect on the prostaglandin EP1 receptor (total of seven injections). Then, sensitization amination were rapidly fixed in a 10% buffered [13]. In 1992, misoprostol was patented to treat continued via nasal challenge (by putting drops formalin solution for 24 h. After fixation, a tissue allergic diseases in the late phase, but its effect in bilateral nasal cavities) with 20 mL 10% OVA sample was routinely processed and embedded on AR was not directly demonstrated [14]. once a day from day 15 to day 21. All rats in the in paraffin. For routine histological examina- AR+D group received 10 mg/kg desloratadine tion, 5 μm-thick sections were cut as paraffin- Therefore, the aim of the present study was to orally (dissolved in saline solution), the AR+M embedded tissue samples. After 5 μm-thick sec- demonstrate the effects of misoprostol in oval- group received 100 μg/kg misoprostol admin- tions of the tissue were mounted onto positively bumin (OVA)-induced AR. The second purpose istered orally (dissolved in saline solution), and charged slides and then underwent deparaf- of the study was to compare the effect profile the AR+DM group received combined therapy finization and rehydration, two sections of each of the combination of an antihistamine with with the nasal challenge once every 7 days at the rat were stained with Mayer’s hematoxylin and misoprostol during treatment of AR. same schedule. The healthy group and the AR eosin and Toluidine blue. All sections were ex- amined and photographed using a light photomi- Table 1. Demonstration of serum IgE levels and nasal symptom scores croscope (Nikon Eclipse E600; USA). Mean SD Min Max p IgE H 96.77 12.09 77.30 113.37 0.000 Statistical analysis The Statistical Package for the Social Sciences AR 241.01 12.63 222.83 263.39 (SPSS), version 20.0 software (IBM Corp., Armonk, AR+D 173.67 14.25 149.11 199.50 NY, USA) was used for molecular analysis. The re- AR+M 158.61 12.44 138.03 176.85 sults are presented as mean±standard deviation. AR+DM 149.33 14.25 118.79 172.18 Between-group comparisons for biochemical anal- yses and nasal symptoms were performed using a Nasal symptoms H 29.80 8.93 19.00 40.00 0.000 one-way ANOVA and Tukey’s multiple comparison AR 303.60 15.63 285.00 322.00 tests. A p<0.05 was considered significant. AR+D 144.20 7.60 133.00 151.00 AR+M 125.60 7.92 118.00 138.00 Results AR+DM 105.60 3.65 101.00 110.00 Nasal symptom findings p<0.05 significant, test: post hoc Tukey. In AR studies, the gold standard that is closest to H: healthy; AR: allergic rhinitis; D: desloratadine; M: misoprostol. the clinic is the evaluation of nasal symptoms. As Eurasian J Med 2019; 51(1): 75-9 Kaya et al. Role of Misoprostol on Alerjic Rhinitis in Rat • 77 shown in Table 1 and Figure 1, nasal symptoms healthy group, the nasal septum epithelium and ure 3-E2). In the nasal septum of the AR group, were significantly higher in the AR group than in connective tissue were normal, and no histo- intense inflammatory cell areas in the epithelium the healthy group (p=0.04). Desloratadine ad- pathological findings were found (Figure 3-E3). and connective tissue, edema areas within the ministration had significantly lower nasal symp- Serous and mucous sinuses were histologically connective tissue, and a significant thickness in- toms than the AR group, but nasal symptoms in normal in the submandibular gland (Figure 3-E1). crease in the connective tissue were observed the AR+M group were better than those in the No mast cells were observed in this group (Fig- (Figure 3-A3). In the submandibular glands, AR+D group (p=0.026). In our study, if we eval- uate the nasal symptoms in the AR+D group, Table 2. Histopathological scoring the best improvement is seen after combined Groups AA E EA V PN MC treatment (p=0.000). In this case, misoprostol Healthy 0 0 0 0 0 0 significantly inhibits the symptoms both alone and when combined with an antihistamine. AR 3 2 3 0 3 3 AR+desloratadine 2 1 2 0 2 2 Serum IgE results AR+misoprostol 1 0 1 1 2 0 Since AR is IgE dependent, it is important to show serum IgE levels. In Figure 2, the level of AR+desloratadine+misoprostol 0 0 1 1 1 0 IgE is significantly higher in the AR group than in E: edema; AA: acinar atrophy; EA: inflammation area; V: vacuolization; PN: pyknotic nucleus; MC: mast cell. Scoring: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). the healthy group (p=0.001). Desloratadine significantly improved serum IgE levels when compared with the AR group. However, the best improvement was seen in the misoprostol alone and combination treatment groups (p=0.000).

Histopathological results Finally, we evaluated the nasal septum and submandibular gland histopathologically. In the

400 e 300

200 d c b 100 a Nasal Symptom scores Nasal Symptom 0 H AR AR+D AR+M AR+DM

Figure 1. Nasal symptom scores after OVA- induced allergic rhinitis model. The same letters in the columns were not statistically significant. Different letters in the columns were statistically significant (p<0.05). H: healthy; AR: allergic rhinitis; D: desloratadine; M: misoprostol.

300 c

200 c b b a 100 Serum IgE levels kU/L 0 H AR AR+D AR+M AR+DM

Figure 2. Serum IgE levels of the groups. The Figure 3. Light photomicroscope results of the submandibular gland and nasal septum. First column same letters in the columns were not statistically (1) is hematoxylin and eosin staining of the submandibular gland. Second column (2) is Toluidine blue significant. Different letters in the columns were staining of the submandibular gland. Third column (3) is hematoxylin and eosin staining of the nasal statistically significant (p<0.05). septum. H: healthy; AR: allergic rhinitis; D: desloratadine; M: misoprostol. E: healthy; A: allergic rhinitis; B: AR+desloratadine; C: AR+misoprostol; D: AR+DM groups. 78 • Kaya et al. Role of Misoprostol on Alerjic Rhinitis in Rat Eurasian J Med 2019; 51(1): 75-9 changes in the atrophic sinuses, from serous aci- levels were significantly higher after AR, and se- compared with misoprostol and desloratadine. nus and pyknotic nuclei, were significant in some rum IgE levels approached normal levels [20]. In This suggests that misoprostol may play an im- gland epithelial cells. However, it has been ob- the present study, serum IgE levels were signifi- portant role in the treatment of AR, which is served that they had lost their prominent limits cantly higher in the AR group than in the healthy another important finding in combination with (Figure 3-A1). Mast cell increase was observed group, thus supporting the appropriateness of existing antihistamine therapy. Previous studies (Figure 3-A2). In the AR+D group, inflamma- our model. have shown that misoprostol decreases IgE de- tory cell areas were observed in the nasal sep- pendent histamine release, supporting our find- tum connective tissue, whereas the connective The inflammatory process in AR begins when ings [29]. Furthermore, EP1, 2, 3, and 4 analogs tissue increase was relatively lower than in the the nasal mucosa meets the allergen and con- have been shown to have beneficial effects on AR group (Table 1, Figure 3-B3). In the subman- tinues with inflammatory cell infiltration. IgE antigen-induced hypersensitivity and mucus se- dibular gland, the serous acinus was normal, but production occurs as a result of complex inter- cretion in the nasal epithelium [10]. It is shown atrophic acinus and pyknotic nuclei were partly actions between B cells, T cells, mast cells, and here that EP2 and EP3 analogs prevent mucus found in epithelial cells (Figure 3-B1). However, basophils [21]. In this process, cytokines, such production, and EP3 analog also reduces neu- fewer mast cells were observed than in the as interleukin (IL)-4, IL-13, and IL-18, as well as trophil migration and inflammation in the air- AR group (Figure 3-B2). There were markedly surface and adhesion molecules, which provide ways. However, the selective EP1 analog had no higher inflammatory cell areas in the epithelial a physical interaction between T and B cells, effect. Furthermore, the EP4 analog was shown and connective tissues in the nasal septum of the also play an important role [22]. T helper cell to act on the effector phase of the antigen. A AR+M group than those of the AR group, but type 2-type cytokines induce allergen-specific clinical study also showed that the local adminis- no edema areas were observed (Table 1, Fig- IgE production by inducing an IgE isotype shift tration of PGE1 and PGE2 analogs was benefi- ure 3-C3). In the submandibular glands, serous in IL-4 and IL-13 B cells and lead to the matura- cial in AR and improved symptoms [11]. In our and mucous membranes were similar to that tion and aggregation of cells, such as eosino- study, misoprostol showed a significant effect of healthy tissues. However, some vacuoliza- phils, basophils, and mast cells [23]. Allergens on both the AR group and the AR+D group. tion and pyknotic nuclei were observed (Figure associated with bridging to IgEs after allergen However, the combination of desloratadine and 3-C2). No further mast cells were observed exposure cause the release of histamine; leu- misoprostol has been more effective in relieving (Figure 3-C2). In the AR+DM group, relatively kotrienes C4, D4, and E4; prostaglandin D2; the symptoms. fewer inflammatory cell areas were seen in the and cytokines from mast cells and basophils, nasal septum epithelium and connective tissue, causing early and late phase inflammation [24, In our study, nasal septum and submandibu- but edema areas were not observed. However, 25]. However, the pathophysiology of AR is still lar glands were evaluated histopathologically. the increase of goblet secretion cells in the epi- not fully resolved. Therefore, the development Pathological changes in the nasal tissue due to thelium was noteworthy (Table 2, Figure 3-D3). of new treatment strategies and the clarifica- AR are usually as follows: thickening of the na- Serous and mucous acini were the most similar tion of physiopathology are still up for discus- sal respiratory epithelium, edema, and degen- healthy tissue in the submandibular gland. How- sion. eration of the mucous membrane, mast cell ever, rarely, pyknotic nucleus gland epithelium increase, and vascular congestion [16, 18]. In and vacuation were seen (Figure 3-D1). No Prostaglandin E (PGE) is a metabolite of the addition, significant histopathological changes mast cells were observed in this group (Figure arachidonic acid produced by the cyclooxygen- occur in the salivary glands of patients with AR. 3-D2). ase enzyme and is known to have a physiologi- Significant changes, such as reduction of salivary cal effect in the prevention of inflammation in secretion, decreased contents, and number of Discussion the airways [7]. It dilates the bronchi, inhibits secretory cells, have been recorded [15]. It is In our study, we have shown that misoprostol the proliferation of lymphocytes, and inhibits thought that the acinar cells did not recover may have beneficial effects alone and in combi- the production of important inflammatory cy- despite treatment with vacuolization, apoptosis, nation in the OVA-induced allergic model. tokines, such as tumor necrosis factor-α, IL-1β, and irradiation, and this situation is associated IL-8, and IL-12, and the production of important with decreased salivation [30]. In our study, in- Allergic rhinitis (AR) is characterized by nasal chemokines released from macrophages, neu- tense inflammatory cell areas in the AR group mucosal inflammation that develops because trophils, and dendritic cells, such as chemokine and edema areas within the connective tissue, as of an IgE-mediated reaction. Cells, mediators, ligand (CCL) 3 and CCL4 [26-28]. It performs well as a significant thickness increase in the con- cytokines, chemokines, neuropeptides, and its physiological effects with four types of re- nective tissue, were observed, whereas atrophic various adhesion molecules involved in inflam- ceptors (EP1-4), which are also pharmacologi- acini and some of the gland epithelial cells were mation interact with one another in a complex cally important [7]. PGE receptors have been observed in the serous mucins of the subman- structure and contribute to the emergence of shown to mediate many physiological events, dibular glands. Inflammatory cell areas of the specific symptoms and nonspecific nasal -hy such as pain, fever, platelet aggregation, gastric epithelium and connective tissue were signifi- perreactivity [17]. In experimental AR model cytoprotection, bone health, airway protection, cantly lower in the nasal septum of the AR+M studies, nasal symptoms are evaluated clinically. ovulation, fertilization, bronchodilation, vasodi- group than that of the AR+D group. Never- Observable nasal discharge and nasal itching latation, angiogenesis, cytokine, and chemokine theless, some vacuolization and pyknotic nuclei scores were observed to be significantly higher modulation. Endogenous PGE1 acts as anti-in- were observed. In the AR+DM group, relatively in the AR model than in the healthy group [18]. flammatory [8, 9]. Therefore, in our study, we fewer inflammatory cell areas were observed Significant improvements are observed in these evaluated misoprostol, which is the PGE1 analog in the nasal septum epithelium and connective symptoms due to treatment [19]. In our study, and has the effect of binding to prostaglandin tissue, but edema areas were not observed. Se- it was shown that nasal symptoms increased sig- EP2, EP3, and EP4 receptors. In the present rous and mucous acini were determined as the nificantly due to hyperreactivity in the AR group. study, we found the best IgE recovery in the closest group to healthy tissue in submandibular Concurrently, it was reported that serum IgE combination group at serum IgE level when glands. Eurasian J Med 2019; 51(1): 75-9 Kaya et al. Role of Misoprostol on Alerjic Rhinitis in Rat • 79

As a result of our study, we have shown that the (ARIA): achievements in 10 years and future 19. Jung HW, Jung JK, Park YK. Antiallergic effect of pathophysiology of AR, which has become an needs. J Allergy Clin Immunol 2012; 130: 1049- Ostericum koreanum root extract on ovalbu- important disease in modern society, has not yet 62. [CrossRef] min-induced allergic rhinitis mouse model and been clarified. Many cytokines, as well as immu- 7. Shimizu T HR, Shimizu S, Kouzaki H, Majima Y. mast cells. Asian Pac J Allergy Immunol. 2011; 29: nological cells of these cells and systems, can be Role of prostaglandin E2 as a protective media- 338-48. tor for allergic inflammation. Clin Exp Allergy important in products, and we have determined 20. Kim M, Kim KE, Jung HY, et al. Recombinant Rev 2007; 7: 36-40. [CrossRef] erythroid differentiation regulator 1 inhibits that it is important for new treatment methods 8. Murota H, Kotobuki Y, Umegaki N, Tani M, Kata- both inflammation and angiogenesis in a mouse to be taken into consideration. In conclusion, we yama I. New aspect of anti-inflammatory action model of rosacea. Exp Dermatol 2015; 24: 680- suggest that prostaglandins should be consid- of lipo-prostaglandinE1 in the management of 5. [CrossRef] ered in the treatment of AR, and that the ef- collagen diseases-related skin ulcer. Rheumatol 21. Small P, Keith PK, Kim H. Allergic rhinitis. Allergy fects of these types of drugs should be tested Int 2008; 28: 1127-35. [CrossRef] Asthma Clin Immunol 2018; 14: 51. [CrossRef] clinically in patients. 9. Sobota RM, Muller PJ, Heinrich PC, Schaper F. 22. Small P FS, Becker A, Boisvert P, et al. Rhinitis: a Prostaglandin E1 inhibits IL-6-induced MCP-1 practical and comprehensive approach to assess- Ethics Committee Approval: Ethics Committee ap- expression by interfering specifically in IL-6-de- ment and therapy. J Otolaryngol 2007; 36: 5-27. proval was received for this study from the Ethics pendent ERK1/2, but not STAT3, activation. Bio- [CrossRef] Committee of Atatürk University (2018/207). chem J 2008; 412: 65-72. [CrossRef] 23. Campo P, Rondon C, Gould HJ, Barrionuevo E, 10. Hattori R, Shimizu S, Majima Y, Shimizu T. Pros- Gevaert P, Blanca M. Local IgE in non-allergic Informed Consent: N/A. taglandin E2 receptor EP2, EP3, and EP4 agonists rhinitis. Clin Exp Allergy 2015; 45: 872-81. inhibit antigen-induced mucus hypersecretion in [CrossRef] Peer-review: Externally peer-reviewed. the nasal epithelium of sensitized rats. Ann Otol 24. Pullerits T, Praks L, Ristioja V, Lotvall J. Com- Rhinol Laryngol 2009; 118: 536-41. [CrossRef] parison of a nasal glucocorticoid, antileukotriene, 11. Karim SM, Adaikan PG, Kunaratnam N. Effect of Author Contributions: Concept – M.Y., Z.K.; Design and a combination of antileukotriene and antihis- – A.B., N.E.A.; Supervision – H.U., I.C.; Data Collection topical prostaglandins on nasal patency in man. tamine in the treatment of seasonal allergic rhi- and/or Processing – S.O., E.T.; Analysis and /or Inter- Prostaglandins 1978; 15: 457-62. [CrossRef] nitis. J Allergy Clin Immunol 2002; 109: 949-55. pretation – M.Y., V.M.; Literature Search – Z.K., V.M.; 12. Graham DY, White RH, Moreland LW, et al. [CrossRef] Writing – Z.K., M.Y.; Critical Reviews – H.U., Z.K, M.Y. Duodenal and gastric ulcer prevention with 25. Wilson AM, O’Byrne PM, Parameswaran K. Leu- misoprostol in arthritis patients taking NSAIDs. kotriene receptor antagonists for allergic rhinitis: Conflict of Interest: The authors have no conflicts of Misoprostol Study Group. Ann Intern Med 1993; a systematic review and meta-analysis. Am J Med interest to declare. 119: 257-62. [CrossRef] 2004; 116: 338-44. [CrossRef] 13. Moreno JJ. Eicosanoid receptors: Targets for 26. Takayama K G-CG, Sukhova GK, Comander J, Financial Disclosure: The authors declared that this the treatment of disrupted intestinal epithelial Gimbrone MA Jr, Libby P. Prostaglandin E2 sup- study has received no financial support. homeostasis. Eur J Pharmacol 2017; 796: 7-19. presses chemokine production in human macro- [CrossRef] References 14. Rafeul Alam, J. Andrew Grant, inventors. Use of phages through the EP4 receptor. J Biol Chem 2002; 277: 44147-54. [CrossRef] 1. Tran NP, Vickery J, Blaiss MS. Management of misoprostol for the treatment of allergy. US pat- 27. Yamane H, Sugimoto Y, Tanaka S, Ichikawa A. rhinitis: allergic and non-allergic. Allergy Asthma ent WO1993006831A1. 1991. Prostaglandin E(2) receptors, EP2 and EP4, dif- Immunol Res 2011; 3: 148-56. [CrossRef] 15. Tatar A, Parlak SN, Yayla M, Ugan RA, Polat E, ferentially modulate TNF-alpha and IL-6 pro- 2. Bousquet J, Neukirch F, Bousquet PJ, et al. Sever- Halici Z. Effects of allergic rhinitis and deslorata- duction induced by lipopolysaccharide in mouse ity and impairment of allergic rhinitis in patients dine on the submandibular gland in a rat allergy consulting in primary care. J Allergy Clin Immu- model. Int Forum Allergy Rhinol 2015; 5: 1164-9. peritoneal neutrophils. Biochem Biophys Res nol 2006; 117: 158-62. [CrossRef] [CrossRef] Commun 2000; 278: 224-8. [CrossRef] 3. Nathan RA. The burden of allergic rhinitis. Al- 16. Tatar A, Yayla M, Kose D, Halici Z, Yoruk O, Po- 28. Vassiliou E, Jing H, Ganea D. Prostaglandin E2 in- lergy Asthma Proc 2007; 28: 3-9. [CrossRef] lat E. The role of endothelin-1 and endothelin hibits TNF production in murine bone marrow- 4. Bauchau V, Durham SR. Epidemiological char- receptor antagonists in allergic rhinitis inflamma- derived dendritic cells. Cell Immunol 2003; 223: acterization of the intermittent and persistent tion: ovalbumin-induced rat model. Rhinology 120-32. [CrossRef] types of allergic rhinitis. Allergy 2005; 60: 350-3. 2016; 54: 266-72. [CrossRef] 29. Babakhin AA, Nolte H, DuBuske LM. Effect of [CrossRef] 17. Shinmei Y, Yano H, Kagawa Y, et al. Effect of misoprostol on the secretion of histamine from 5. Bousquet J, Arnavielhe S, Bedbrook A, et al. The Brazilian propolis on sneezing and nasal rubbing basophils of whole blood. Ann Allergy Asthma Allergic Rhinitis and its Impact on Asthma (ARIA) in experimental allergic rhinitis of mice. Immu- Immunol 2000; 84: 361-5. [CrossRef] score of allergic rhinitis using mobile technology nopharmacol Immunotoxicol 2009; 31: 688-93. 30. Muhvic-Urek M, Bralic M, Curic S, Pezelj-Ribaric correlates with quality of life: The MASK study. [CrossRef] S, Borcic J, Tomac J. Imbalance between apopto- Allergy 2018; 73: 505-10. [CrossRef] 18. Zhang Y, Feng J, Sun J, et al. H2-Eb1 expression is sis and proliferation causes late radiation damage 6. Bousquet J, Schunemann HJ, Samolinski B, et upregulated in the nasal mucosa of allergic rhinitis. of salivary gland in mouse. Physiol Res 2006; 55: al. Allergic Rhinitis and its Impact on Asthma Asian Pac J Allergy Immunol 2014; 32: 308-15. 89-95.