|Year : 2017 | Volume
| Issue : 1 | Page : 17-22
Effect of histone deacytylase inhibitors on allergic airway inflammation in mouse model anesthetized with ketamine
Mohamed Gamal Eldin Elsakkar1, Nagwa Mahmoud Nour El-Din Hassan1, Reham Abd El-Halem Abo El-Wafa2, Rania G Mohamed3, Esraa Saeed Shaban Habiba MBBCh 4
1 Department of Clinical Pharmacology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
3 Department of Pathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
4 Department of Clinical Pharmacology, Faculty of Medicine, University of Alexandria, Alexandria; Wageh basha, Ganakls, Alexandria, Egypt
|Date of Submission||12-Jan-2016|
|Date of Acceptance||24-May-2016|
|Date of Web Publication||22-Mar-2017|
Esraa Saeed Shaban Habiba
5A Wagehbasha, Ganakles, 1straml, Alexandria, 21532
Source of Support: None, Conflict of Interest: None
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment.
The present study was designed to examine the modulatory effects of the histone deacytelase inhibitor [valproic acid (VPA)] on ovalbumin (OVA)-induced airway inflammation in mice.
Airway inflammation was induced by means of intraperitoneal injection of 83.33 μg of OVA in 2.92 mg of alum on days 1, 11, and 14 and then challenged with 1% w/v OVA aerosol in PBS on days 15–18. However, normal control mice received PBS instead. The animals were then divided into three groups: the normal group, the untreated asthmatic group, and the VPA-treated group, which received 300 mg/kg of VPA on days 15–18 1 h before each nebulization. At the end of the experimental period (day 19), each animal was anesthetized with 80 mg/kg of ketamine intraperitoneally and then bronchoalveolar lavage fluid was collected and centrifuged. The collected supernatants of bronchoalveolar lavage were used to assess interleukin-4, whereas the cell pellets were collected and resuspended for cytological examination.
Treatment with VPA resulted in a significant reduction in interleukin-4 level, total cell count, and neutrophil percentage in bronchoalveolar lavage fluid (P<0.05). The mean±SD was 16.55±1.07, 38.93±6.46, and 30.32±4.61 in the VPA-treated group versus 24.86±3.06, 99.03±6.67, and 70.40±8.30 in the untreated asthmatic group, respectively.
The treatment with VPA reduces inflammatory cellular infiltration, mainly neutrophils, in a mouse model of asthma.
Keywords: airway inflammation, interleukin-4, neutrophils, valproic acid
|How to cite this article:|
Eldin Elsakkar MG, El-Din Hassan NN, Abo El-Wafa RE, Mohamed RG, Shaban Habiba ES. Effect of histone deacytylase inhibitors on allergic airway inflammation in mouse model anesthetized with ketamine. Res Opin Anesth Intensive Care 2017;4:17-22
|How to cite this URL:|
Eldin Elsakkar MG, El-Din Hassan NN, Abo El-Wafa RE, Mohamed RG, Shaban Habiba ES. Effect of histone deacytylase inhibitors on allergic airway inflammation in mouse model anesthetized with ketamine. Res Opin Anesth Intensive Care [serial online] 2017 [cited 2020 May 31];4:17-22. Available from: http://www.roaic.eg.net/text.asp?2017/4/1/17/202694
| Introduction|| |
Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyper-responsiveness (AHR) that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with variable airflow obstruction within the lung that is often reversible either spontaneously or with treatment .
Bronchial asthma is the most common chronic disease of the respiratory system among children and adolescents. It has become a major public health problem because of its high and increasing morbidity and mortality worldwide and its associated healthcare costs . Asthma affects ∼300 million people worldwide, with 250 000 annual deaths . Asthma prevalence was 4.8% in Egypt . The prevalence of asthma among Egyptian children between 3 and 15 years of age was estimated to be 8.2% . Among children between 11 and 15 years of age in schools, the overall prevalence of wheeze ever, wheeze during the last year, and physician-diagnosed asthma was 26.5, 14.7, and 9.4%, respectively . Up to one in four children with asthma is unable to attend school regularly because of poor asthma control .
Airway inflammation is a dominant feature that leads to clinical symptoms of asthma. The inflammatory response in the asthmatic airways involves a complex interplay of the respiratory epithelium, innate immune system, and adaptive immunity that initiates and drives a chronic inflammatory response . The development of allergic asthma is initiated by sensitization to an environmental allergen . Allergens are taken up and processed by antigen-presenting cells such as dendritic cells that present allergen to allergen-specific CD4+ T-cells that subsequently differentiate ,. CD4+ T helper cells can be induced to differentiate toward T helper 1 (Th1), Th2, Th17, and regulatory (Treg) phenotypes according to the local cytokine milieu. T-lymphocytes and the cytokines produced by T-cells play a crucial role in the development of asthma . Th1 cells result in a neutrophil-predominant inflammatory response through interferon-γ and tumor necrosis factor-α . Th2-type cells produce interleukin (IL)-4, IL-9, IL-13, and IL-5 ,. IL-4 promotes growth of mast cells, basophils, and eosinophils ,. IL-4 and IL-13 stimulate allergen-specific B-cells to proliferate and switch to production of immunoglobulin E (IgE) . In addition, IL-9 and IL-13 have been shown to contribute to AHR  and are involved in goblet cell hyperplasia and mucus hypersecretion . IL-5 secretion by Th2 cells is critical for eosinophil differentiation and maturation. Th2 cells result in eosinophilic-predominant inflammatory response . Th17 cells, through IL-17, promote neutrophil recruitment, which is involved in the pathogenesis of asthma . Treg cells are crucial immunoregulatory cells, capable of suppressing Th1, Th2, and Th17-mediated adaptive immune responses and redress coexistence of Th1/Th2 and Th17/Treg imbalances ,.
Valproic acid (VPA) is an histone deacetylase inhibitors (HDAC) inhibitor of class I as well as class II histone deacetylases . VPA has developed into one of the most frequently used antiepileptic drugs worldwide. HDAC inhibitors have a number of properties that may be useful in treating airway remodeling in asthma. They have anti-inflammatory properties, antifibrotic effects, and antiangiogenic effects. The use of VPA increases Treg numbers and activity, which has an anti-inflammatory action, indicating a potential role in the treatment of asthma .
| Methods|| |
Male CD1 mice of body weight ranging from 20 to 25 g were purchased from the animal center in Alexandria Faculty of Medicine. Animal care and use were carried out in accordance with the Animal Ethics Committee of the Alexandria Faculty of Medicine.
Drugs and chemicals
VPA, (Depakine; Sanofi Aventis, France (Paris)), Ovalbumin (OVA) (Bio Basic, Canada), aluminum hydroxide (Oxford, UK), and PBS (El Nasr, Egypt) were used in this study.
The animals were randomly divided into three groups of eight mice each.
The normal control group received intraperitoneal injections of PBS on days 1, 11, and 14 then nebulized with PBS aerosol every day on days 15–18 .
The untreated asthmatic group was sensitized with 83.33 μg of OVA in 2.92 mg of alum intraperitoneally on days 1, 11, and 14 of the study and then challenged with 1% w/v OVA aerosol in PBS on days 15–18 .
The VPA-treated asthmatic group was sensitized and challenged with OVA as previously described plus treated with 300 mg/kg of VPA intraperitoneally for 4 successive days (days 15–18) .
By the end of the experimental period (day 19) each animal was anesthetized with 80 mg/kg of ketamine intraperitoneally .
Bronchoalveolar lavage fluid (BALF) was then collected. The collected BALF was centrifuged at 1000 rpm for 10 minand the supernatant was collected. The collected supernatants of bronchoalveolar lavage (BAL) were used to assess IL-4 level, and the cell pellets were collected and resuspended for cytological examination .
Data analysis was performed using the Statistical Package of Social Science, version 20 software package (SPSS Inc., Chicago, Illinois, USA). The variables for each group were analyzed by calculating mean and SD. Statistical analysis for data using the analysis of variance one-way test was carried out for comparing mean between more than two groups when the values normally distributed and the post-hoc test (Duncan’s new multiple range test) was used for comparing mean of two independent groups after a significant analysis of variance. A level of P less than 0.05 was defined as being statistically significant.
| Results|| |
Effect of VPA therapy on IL-4 level in BALF
The administration of OVA for induction of asthma was associated with a statistically significant increase in IL-4 level in BALF, with a mean value of 24.86±3.06 in the untreated group versus 0.15±0.04 in the normal control group ([Table 1]). Likewise, VPA treatment resulted in a statistically significant decrease in IL-4 level in BALF, with a mean value of 16.55±1.07 in the VPA-treated group versus 24.86±3.06 in the untreated asthmatic group.
|Table 1 Effect of VPA therapy on IL-4 level, total cell count, and neutrophils percentage in BALF in murine model of asthma|
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Effect of VPA therapy on total cell count in BALF
The induction of asthma was associated with marked recruitment of inflammatory cells in BALF, which was significantly different relative to the number of cells that could be harvested from BALF of normal control mice. Treatment with VPA was associated with a statistically significant decrease in the total cell count in BALF, with mean values of 38.93±6.46 in the VPA-treated group versus 99.03±6.67 in the untreated asthmatic group ([Table 1]).
Effect of VPA therapy on neutrophil percentage in BALF
Induction of asthma resulted in a significant increase in neutrophilic cell percentage in the untreated asthmatic group versus the control group. VPA treatment was associated with a statistically significant decrease in neutrophil percentage in BALF, with a mean value of 30.32±4.61 in the VPA-treated group versus 70.40±8.30 in the untreated asthmatic group ([Table 1]).
| Discussion|| |
Asthma is a complex highly prevalent and potentially serious chronic inflammatory disease . The prevalence of asthma has been continuing to increase, with tremendous socioeconomic impact in developing countries .
Airway inflammation is a dominant feature that leads to clinical symptoms of asthma. The inflammatory response in the asthmatic airways involves a complex interplay of the respiratory epithelium, innate immune system, and adaptive immunity that initiates and drives a chronic inflammatory response . The development of allergic asthma is initiated by sensitization to an environmental allergen . For allergic sensitization, allergens are taken up and processed by antigen-presenting cells such as dendritic cells that present allergen to allergen-specific CD4+ T-cells that subsequently differentiate ,. CD4+ T helper cells can be induced to differentiate toward Th1, Th2, Th17, and Treg phenotypes according to the local cytokine milieu. T-lymphocytes and the cytokines produced by T-cells play a crucial role in the development of asthma .
Several animal models have been utilized to induce allergic airway inflammation, the one mostly used being acute models to OVA. OVA derived from chicken egg is a more frequently used allergen as it induces a robust allergic bronchial inflammation, particularly where acute allergic response is concerned. It comprises a sensitization step in the presence of aluminum hydroxide as an adjuvant and is known to promote the development of a Th2 phenotype of the immune system exposed to an antigen, and a second step in which the mice are challenged, with the allergen introduced directly into the airways by aerosol to induce the modeled asthma features .
From the results of the present study, it is obvious that sensitization and challenge with OVA-induced biochemical and cytological alterations characteristic of allergic airway inflammation.
The increased level of IL-4 cytokines in BALF observed in current study indicates that, after exposure to allergens, Th2 cells secrete cytokines, such as IL-4, IL-5, and IL-13, which promote AHR, IgE production, and infiltration of inflammatory cells. IL-4 facilitates the differentiation and proliferation of Th2 cells, the switching of B-cells to secrete IgE . In addition to the lymphocytic source of IL-4 by activated CD4− Th2 cells, there is a nonlymphocytic source for IL-4, such as mast cells, eosinophils, basophils, and activated alveolar macrophages, which also release substantial amounts of IL-4. In addition, type-2 CD8+ T-cells and invariant natural killer T-cells have been reported to produce IL-4, but Th2 is the main source of IL-4 . This is in accordance with the results of study by Yang et al. , which stated that the pathophysiology of asthma is extremely complicated, involving the network of Th2 cells and its cytokines.
As regards inflammatory infiltrate in BAL, it is significantly increased in total number with predominance of neutrophilic infiltrate with complete absence of eosinophils in OVA-sensitized mice.
Neutrophils are one of the important inflammatory cells and play a crucial role in severe asthma. Neutrophilic activities are modulated by specific regulatory molecules. Cytokines such as tumor necrosis factor-α, interleukin (IL)-1β, granulocyte-colony stimulating factor, and granulocyte–macrophage colony stimulating factor and chemokines such as IL-8 have profound effects on neutrophils. They amplify several responses such as adhesion and respiratory burst. Neutrophils are not only the target of mediators, but are also a source of various cytokines and chemokines .
The increased numbers of neutrophils are in accordance with the study by Zuoren et al. . However, it is contradictory to the study by Yang et al. , who showed mixed inflammatory infiltration of eosinophils and neutrophils.
The increased level of neutrophils is explained through different mechanisms. Animals such as guinea pigs, rats, and mice are used for examining mechanisms of asthma, the activity of a variety of genes and cellular pathways, prediction of safety of new drugs or chemicals, and advances in the understanding of the pathophysiology of asthma as an allergic airway disease. The mouse is the most widely used species, mainly because of the availability of transgenic animals and because of the wide array of specific reagents that are available for analysis of the cellular and mediator response . Various strains of mouse are available among them; BALB/c and C57BL/6 mice are the most widely used ones due to their well-characterized immunological responses .
BALB/c mice typically mount Th2-dominated immune responses, and the induction of parameters of allergic responses such as allergen-specific IgE, AHR, and eosinophilic airway inflammation are robust. Conversely, C57BL/6 mice exhibit Th1-dominated immune responses and have limitations in the development of allergic airway responses compared with BALB/c mice, especially in the development of allergen-specific IgE responses and airway responsiveness to inhaled methcholine .
In current study, CD1 mice is the available strain of mice used in our model. On reviewing the previous literature, the only available data on CD1 was from study by Abdel-Aziz et al. , who showed increased inflammatory cell infiltrate in BAL in mouse model of asthma, but the type of infiltrate and type of Th cell dominance was not clear.
In addition to strain difference, timing of challenge explains neutrophilic infiltrate. Nabe et al.  reported that during challenge of mice, the first through third challenges are responsible for establishing the airway inflammation that is characterized by infiltrations of eosinophils and CD4+ T-cells. Subsequently, the fourth challenge induces neutrophil infiltration into the airway, which contributes importantly to the induction of the late airway response. In present study, mice were killed 24 h after fourth challenge.
Moreover, lipopolysaccharide (LPS) that contaminates most preparations of OVA may contribute to neutrophilia ,,. Moon et al.  reported that airway exposure to LPS-containing allergens induces stimulation of Th17 that secrete IL-17, which produce neutrophilic airway inflammation. Whitehead et al.  demonstrated effect of different doses of LPS through using OVA together with very low doses (≤10–3 µg) of LPS displayed, which produced modest amounts of Th2 cytokines, with associated airway eosinophilia. When the higher dose of 10–1 µg LPS was used, mice initially displayed similar Th2 responses, as well as Th17-associated neutrophilia.
Other T-cell subtypes play a role in neutrophilic airway inflammation, including the balance of the IL-17-producing Th17 cells and Treg. Th17 cells are associated with neutrophilic inflammation and have been shown to contribute to severe asthma and relative corticosteroid insensitivity  through their ability to recruit and activate neutrophil granulocytes and augment Th2-mediated eosinophilic inflammation, either directly through IL-8 production  or indirectly by inducing the production of colony stimulatory factors and CXCL8 by tissue resident cells .
Unfortunately, 5–10% of patients present severe neutrophilic asthma, which remains uncontrolled despite high doses of inhaled corticosteroid combined with long-acting β-agonists . Therefore, novel, and effective treatment regimens are required, and, recently, increasing attention has been focused on interfering with the inflammatory process, as well as on treating steroid-insensitive asthma .
In the present study, a significant decrease in BALF total cell number and neutrophilic percent were observed with VPA treatment of OVA-sensitized mice.
Studies exploring the effects of VPA on neutrophilic airway inflammation are limited. The only available studies are study by Banerjee et al. , which explored the effect of tricosatin A, another HDAC inhibitor, in murine model using female C57/BL6 mice with different timing and dose of OVA sensitization and challenge, resulting in a decrease in inflammatory infiltrate of eosinophils and neutrophils. The other study by Kankaanranta et al.  explained that decreased neutrophilis by accumulation, activation, and delayed death of neutrophils at the inflamed site has been implicated in the pathogenesis of severe asthma and asthma exacerbations. HDAC inhibitors decrease neutrophils through antagonizing granulocyte–macrophage colony stimulating factor-afforded neutrophil survival by inducing apoptosis.
Another mechanism explains a decrease in neutrophils; Treg cells have been found to inhibit neutrophil function and promote their apoptosis. Moreover, Treg cells are recognized as a major subset of immune cells possessing potent suppressive properties directed at T effector cells. Treg cells mediate its suppressive action by promoting the generation of IL-10 and TGF-β1, inhibit IL-6 production by polymorphonuclear leukocytes, and induce the expression of heme oxygenase-1 and the suppressor of cytokine signaling-3 molecule .
HDAC inhibitors have potent anti-inflammatory effects by suppressing Th1, Th2, and Th17 responses, through the activation of Tregs. The suppression of Th2 leads to a decrease in the level of both IL-4 and IL-13, which promotes IgE production in B-cells ,.
In present study, IL-4 level is significantly decreased with VPA treatment. These results are in accordance with the study by Royce et al. , who investigated the protective effect of VPA against AHR and remodeling in mouse model of allergic inflammation. Choi et al.  investigated the effect of tricostatin A, which is HDAC inhibitor, on murine model of asthma explained the decrease in IL-4 by increased number and activity of Treg cells, which suppress the release of inflammatory cytokines.
Finally, we concluded that the application of VPA on OVA-induced airway inflammation resulted in a significant reduction in inflammatory cellular infiltration mainly for neutrophils.
Financial support and sponsorship
Conflicts of interest
The use of sodium valproate is effective anti-inflammatory drug for attenuation of neutrophilic airway inflammation induced by OVA.
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