Abstract
The aim of this study was to further explore the possible mechanisms of montelukast on oral mice ovalbumin-induced eosinophilic gastroenteritis in a mouse model. The results indicated that montelukast could prevent levels of eotaxin-1 and interleukin-5 in intestinal mucosa homogenate when compared with model group. Interestingly, the increase of major basic protein expression in jejunal tissue also was attenuated by treated with montelukast.
We have used a mouse model of oral mice ovalbumin (OVA) allergen-induced eosinophilic gastroenteritis (EG) inflammation, suggesting that montelukast could inhibit intestinal eosinophilic inflammation. This study was designed as previous studyCitation1 to clarify the possible mechanisms of montelukast on animal model of EG disease. At the end of experiment, mice were sacrificed, and a part of jejunal tissue was homogenized for ELISA analysis [eotaxin-1 and interleukin-5 (IL-5)]. Another portion of jejunal tissue was fixed with 4% paraformaldehyde for major basic protein (MBP) immunohistochemistry. Values were presented as mean ± SD. One-way ANOVA was used for statistical analysis of the differences between groups. p < 0.05 was considered statistically significant.
The results indicated that repetitive OVA challenge in BALB/c mice induced a significant increase in the levels of IL-5 and eotaxin-1 (IL-5, 162.59 ± 17.93; eotaxin-1, 468.92 ± 59.97. ng/g) when compared with non-OVA-challenged animals (IL-5, 103.90 ± 12.48; otaxin-1, 291.77 ±50.77. ng/g. all p < 0.01). However, chronic continuous treatment with montelukast (3 mg/kg) could significantly improved these parameters (IL-5, 136.20 ± 25.50; otaxin-1, 394.99 ± 30.00. ng/g. all p < 0.01). These results suggested that montelukast could ameliorate gastrointestinal pathological lesions in a rat model of OVA-induced intestinal eosinophilic inflammation, and this perfect ability might be attribute to the inhibition of intestinal IL-5 and eotaxin-1 levels. Immunohistochemical staining with specific antibodies was performed to detect the functional expression level of MBP, and the results indicated that MBP expression was increased in OVA-challenged BALB/c mice when compare to control group (non-OVA-challenged animals). However, continues treatment with montelukast at dose of 3 mg/kg significantly blocked this pathological change. The expression of MBP increased up to 11.6-fold in OVA-challenged mice (p < 0.01), and montelukast treatment decreased the enhanced expression of MBP by 2.5-fold (p < 0.01).
IL-5 (also known as eosinophil differentiation factor) is the most specific to the eosinophil lineageCitation2. Of the mediators implicated in modulating eosinophil accumulation, only IL-5 and the recently described subfamily of eotaxin chemokines (eotaxin-1) are relatively specific for eosinophilsCitation3. Moreover, eotaxin-1 play a key role in the modulation of eosinophil accumulation in the gastrointestinal tract and that its effect is primarily tissue specificCitation4. For example, eotaxin-1-deficient mice have a defect in eosinophil trafficking to the gastrointestinal tract and are protected from experimental oral antigen-induced gastrointestinal pathology. Furthermore, overproduction of IL-5 through a variety of approaches results in profound eosinophilia and deletion of the IL5 gene causes a marked reduction of eosinophils in gastrointestinal tract after allergen challengeCitation5. These studies have identified IL-5 is a critical eosinophil growth factor and the eotaxins is critical tissue recruitment factors in EG. MBP, eosinophil cationic protein, triggers eosinophils through engagement of receptors for complement and cytokines can lead to the generation of a wide range of eosinophil-active chemokines (such as IL-5 and eotaxin-1), indicating that it has the potential to modulate multiple aspects of the immune response. Epidemiological studies also have shown that the presence of significant extracellular MBP deposition in tissues from patients with eosinophilic gastroenteritis compared with controls is in accord with several prior investigationsCitation6, and extracellular deposition of MBP has been used as an indicator of eosinophil degranulation in these diseases. Based on these observations, it has been hypothesized that inhibiting high-output IL-5 and eotaxin-1 production, and reducing MBP expression in surrounding gastrointestinal tract, may play a very important role in preventing the development of EG.
Based on the previous research worksCitation2, this study investigated for the first time that montelukast could attenuate intestinal eotaxin-1 and IL-5 levels in a mouse model of OVA-induced intestinal eosinophilic inflammation. Furthermore, these activities appeared to be mediated by inhibiting the expression of MBP, eosinophil cationic protein, and thus regulating the inflammation response. Practically, the results would provide a scientific rationale for the use of montelukast in the treatment of EG. Further studies on the detailed mechanisms is now in progress.
Declaration of interest
The authors declare that there are no conflicts of interest.
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