• Users Online: 426
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 17-22

Effect of histone deacytylase inhibitors on allergic airway inflammation in mouse model anesthetized with ketamine


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 Submission12-Jan-2016
Date of Acceptance24-May-2016
Date of Web Publication22-Mar-2017

Correspondence Address:
Esraa Saeed Shaban Habiba
5A Wagehbasha, Ganakles, 1straml, Alexandria, 21532
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.202694

Rights and Permissions
  Abstract 

Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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 Top


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 [1].

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 [2]. Asthma affects ∼300 million people worldwide, with 250 000 annual deaths [3]. Asthma prevalence was 4.8% in Egypt [4]. The prevalence of asthma among Egyptian children between 3 and 15 years of age was estimated to be 8.2% [5]. 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 [6]. Up to one in four children with asthma is unable to attend school regularly because of poor asthma control [7].

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 [8]. The development of allergic asthma is initiated by sensitization to an environmental allergen [9]. 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 [10],[11]. 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 [12]. Th1 cells result in a neutrophil-predominant inflammatory response through interferon-γ and tumor necrosis factor-α [13]. Th2-type cells produce interleukin (IL)-4, IL-9, IL-13, and IL-5 [14],[15]. IL-4 promotes growth of mast cells, basophils, and eosinophils [16],[17]. IL-4 and IL-13 stimulate allergen-specific B-cells to proliferate and switch to production of immunoglobulin E (IgE) [11]. In addition, IL-9 and IL-13 have been shown to contribute to AHR [18] and are involved in goblet cell hyperplasia and mucus hypersecretion [19]. IL-5 secretion by Th2 cells is critical for eosinophil differentiation and maturation. Th2 cells result in eosinophilic-predominant inflammatory response [20]. Th17 cells, through IL-17, promote neutrophil recruitment, which is involved in the pathogenesis of asthma [21]. 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 [12],[22].

Valproic acid (VPA) is an histone deacetylase inhibitors (HDAC) inhibitor of class I as well as class II histone deacetylases [23]. 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 [24].


  Methods Top


Experimental animals

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.

Experimental design

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 [25].

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 [25].

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) [24].

Experimental procedures

By the end of the experimental period (day 19) each animal was anesthetized with 80 mg/kg of ketamine intraperitoneally [26].

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 [27].

Statistical methods

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 Top


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

Click here to view


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 Top


Asthma is a complex highly prevalent and potentially serious chronic inflammatory disease [28]. The prevalence of asthma has been continuing to increase, with tremendous socioeconomic impact in developing countries [29].

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 [8]. The development of allergic asthma is initiated by sensitization to an environmental allergen [9]. 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 [10],[11]. 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 [12].

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 [30].

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 [31]. 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 [32]. This is in accordance with the results of study by Yang et al. [31], 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 [33].

The increased numbers of neutrophils are in accordance with the study by Zuoren et al. [34]. However, it is contradictory to the study by Yang et al. [31], 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 [35]. 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 [36].

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 [36].

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. [37], 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. [38] 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 [39],[40],[41]. Moon et al. [42] reported that airway exposure to LPS-containing allergens induces stimulation of Th17 that secrete IL-17, which produce neutrophilic airway inflammation. Whitehead et al. [43] 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 [44] through their ability to recruit and activate neutrophil granulocytes and augment Th2-mediated eosinophilic inflammation, either directly through IL-8 production [45] or indirectly by inducing the production of colony stimulatory factors and CXCL8 by tissue resident cells [46].

Unfortunately, 5–10% of patients present severe neutrophilic asthma, which remains uncontrolled despite high doses of inhaled corticosteroid combined with long-acting β-agonists [28]. 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 [47].

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. [48], 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. [49] 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 [50].

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 [51],[52].

In present study, IL-4 level is significantly decreased with VPA treatment. These results are in accordance with the study by Royce et al. [24], who investigated the protective effect of VPA against AHR and remodeling in mouse model of allergic inflammation. Choi et al. [53] 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

Nil.

Conflicts of interest

The use of sodium valproate is effective anti-inflammatory drug for attenuation of neutrophilic airway inflammation induced by OVA.

 
  References Top

1.
National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda, MD: National Heart, Lung, and Blood Institute; 2007.  Back to cited text no. 1
    
2.
Wang T, Zhong XG, Li YH, Jia X, Zhang SJ, Gao YS et al. Protective effect of emodin against airway inflammation in the ovalbumin-induced mouse model. Chin J Integr Med 2015; 21:431–437.  Back to cited text no. 2
    
3.
Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy 2009; 39:193–202.  Back to cited text no. 3
    
4.
Khallaf N, el-Ansary S, Hassan M. Acute respiratory infections: sentinel survey in Egypt. World Health Forum 1996; 17:297–300.  Back to cited text no. 4
    
5.
Pearce N, Aït-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E, Robertson C et al. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 2007; 62:758–766.  Back to cited text no. 5
    
6.
Georgy V, Fahim HI, El-Gaafary M, Walters S. Prevalence and socioeconomic associations of asthma and allergic rhinitis in northern [corrected] Africa. Eur Respir J 2006; 28:756–762.  Back to cited text no. 6
    
7.
Bassili A, Zaki A, Zaher S. Quality of care of children with chronic disease in Alexandria, Egypt: the models of asthma, type 1 diabetes, epilepsy, and rheumatic heart disease. Egyptian-Italian Collaborative Group on Pediatric Chronic Diseases. Pediatrics 2000; 106:E12.  Back to cited text no. 7
    
8.
Rajajendram R, Tham CL, Akhtar MN, Sulaiman MR, Israf DA. Inhibition of epithelial CC-family chemokine synthesis by the synthetic chalcone DMPF-1 via disruption of NF-κB nuclear translocation and suppression of experimental asthma in mice. Mediators Inflamm 2015; 2015:176926.  Back to cited text no. 8
    
9.
Holt PG, Thomas WR. Sensitization to airborne environmental allergens: unresolved issues. Nat Immunol 2005; 6:957–960.  Back to cited text no. 9
    
10.
Lambrecht BN, Hammad H. Biology of lung dendritic cells at the origin of asthma. Immunity 2009; 31:412–424.  Back to cited text no. 10
    
11.
Del Prete G, Maggi E, Parronchi P, Chrétien I, Tiri A, Macchia D et al. IL-4 is an essential factor for the IgE synthesis induced in vitro by human T cell clones and their supernatants. J Immunol 1988; 140:4193–4198.  Back to cited text no. 11
    
12.
Liu F, Yu J, Bai L, Xue Z, Zhang X. Pingchuan formula improves asthma via restoration of the Th17/Treg balance in a mouse model. BMC Complement Altern Med 2015; 15:234.  Back to cited text no. 12
    
13.
Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, Maselli R. Cellular mechanisms underlying eosinophilic and neutrophilic airway inflammation in asthma. Mediators Inflamm 2015; 2015:879783.  Back to cited text no. 13
    
14.
Romagnani S. The Th1/Th2 paradigm. Immunol Today 1997; 18:263–266.  Back to cited text no. 14
    
15.
Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136:2348–2357.  Back to cited text no. 15
    
16.
Swain SL, Weinberg AD, English M, Huston G. IL-4 directs the development of Th2-like helper effectors. J Immunol 1990; 145:3796–3806.  Back to cited text no. 16
    
17.
Coyle AJ, Le Gros G, Bertrand C, Tsuyuki S, Heusser CH, Kopf M, Anderson GP. Interleukin-4 is required for the induction of lung Th2 mucosal immunity. Am J Respir Cell Mol Biol 1995; 13:54–59.  Back to cited text no. 17
    
18.
Bao Z, Lim S, Liao W, Lin Y, Thiemermann C, Leung BP, Wong WS. Glycogen synthase kinase-3beta inhibition attenuates asthma in mice. Am J Respir Crit Care Med 2007; 176:431–438.  Back to cited text no. 18
    
19.
Tanabe T, Kanoh S, Tsushima K, Yamazaki Y, Kubo K, Rubin BK. Clarithromycin inhibits interleukin-13-induced goblet cell hyperplasia in human airway cells. Am J Respir Cell Mol Biol 2011; 45:1075–1083.  Back to cited text no. 19
    
20.
Ray A, Cohn L. Th2 cells and GATA-3 in asthma: new insights into the regulation of airway inflammation. J Clin Invest 1999; 104:985–993.  Back to cited text no. 20
    
21.
Cosmi L, Liotta F, Maggi E, Romagnani S, Annunziato F. Th17 cells: new players in asthma pathogenesis. Allergy 2011; 66:989–998.  Back to cited text no. 21
    
22.
Robinson DS. The role of the T cell in asthma. J Allergy Clin Immunol 2010; 126:1081–1091.  Back to cited text no. 22
    
23.
Cetinkaya M, Cansev M, Cekmez F, Tayman C, Canpolat FE, Kafa IM et al. Protective effects of valproic acid, a histone deacetylase inhibitor, against hyperoxic lung injury in a neonatal rat model. PLoS One 2015; 10:e0126028.  Back to cited text no. 23
    
24.
Royce SG, Dang W, Ververis K, De Sampayo N, El-Osta A, Tang ML, Karagiannis TC. Protective effects of valproic acid against airway hyperresponsiveness and airway remodeling in a mouse model of allergic airways disease. Epigenetics 2011; 6:1463–1470.  Back to cited text no. 24
    
25.
You H, Chen S, Mao L, Li B, Yuan Y, Li R, Yang X. The adjuvant effect induced by di-(2-ethylhexyl) phthalate (DEHP) is mediated through oxidative stress in a mouse model of asthma. Food Chem Toxicol 2014; 71:272–281.  Back to cited text no. 25
    
26.
Verma M, Chattopadhyay BD, Paul BN. Epigenetic regulation of DNMT1 gene in mouse model of asthma disease. Mol Biol Rep 2013; 40:2357–2368.  Back to cited text no. 26
    
27.
Pouliot P, Camateros P, Radzioch D, Lambrecht BN, Olivier M. Protein tyrosine phosphatases regulate asthma development in a murine asthma model. J Immunol 2009; 182:1334–1340.  Back to cited text no. 27
    
28.
Bonamichi-Santos R, Aun MV, Agondi RC, Kalil J, Giavina-Bianchi P. Microbiome and asthma: what have experimental models already taught us?. J Immunol Res 2015; 2015:614758.  Back to cited text no. 28
    
29.
Shaik FB, Panati K, Narasimha VR, Narala VR. Chenodeoxycholic acid attenuates ovalbumin-induced airway inflammation in murine model of asthma by inhibiting the T(H)2 cytokines. Biochem Biophys Res Commun 2015; 463:600–605.  Back to cited text no. 29
    
30.
Daubeuf F, Frossard N. Acute asthma models to ovalbumin in the mouse. Curr Protoc Mouse Biol 2013; 3:31–37.  Back to cited text no. 30
    
31.
Yang SH, Kao TI, Chiang BL, Chen HY, Chen KH, Chen JL. Immune-modulatory effects of bu-zhong-yi-qi-tang in ovalbumin-induced murine model of allergic asthma. PLoS One 2015; 10:e0127636.  Back to cited text no. 31
    
32.
Williams CM, Rahman S, Hubeau C, Ma HL. Cytokine pathways in allergic disease. Toxicol Pathol 2012; 40:205–215.  Back to cited text no. 32
    
33.
Saffar AS, Ashdown H, Gounni AS. The molecular mechanisms of glucocorticoids-mediated neutrophil survival. Curr Drug Targets 2011; 12:556–562.  Back to cited text no. 33
    
34.
Zuoren Z, Pinhua P, Hongyi T, Yongbin H, Chengping H. Effects of chitin micro-particles on airway inflammation in a mouse neutrophilic asthmatic model. Zhonghua Jie He He Hu Xi Za Zhi 2015; 38:185–190.  Back to cited text no. 34
    
35.
Nials AT, Uddin S. Mouse models of allergic asthma: acute and chronic allergen challenge. Dis Model Mech 2008; 1:213–220.  Back to cited text no. 35
    
36.
Shin YS, Takeda K, Gelfand EW. Understanding asthma using animal models. Allergy Asthma Immunol Res 2009; 1:10–18.  Back to cited text no. 36
    
37.
Abdel-Aziz M, Abass A, Zalata K, Abd Al-Galel T, Allam U, Karrouf G. Effect of dexamethasone and Nigella sativa on inducible nitric oxide synthase in the lungs of a murine model of allergic Asthma. Iran J Allergy Asthma Immunol 2014; 13:324–334.  Back to cited text no. 37
    
38.
Nabe T, Hosokawa F, Matsuya K, Morishita T, Ikedo A, Fujii M et al. Important role of neutrophils in the late asthmatic response in mice. Life Sci 2011; 88:1127–1135.  Back to cited text no. 38
    
39.
Schwartz DA. Does inhalation of endotoxin cause asthma? Am J Respir Crit Care Med 2001; 163:305–306.  Back to cited text no. 39
    
40.
Reed CE, Milton DK. Endotoxin-stimulated innate immunity: a contributing factor for asthma. J Allergy Clin Immunol 2001; 108:157–166.  Back to cited text no. 40
    
41.
Jung YW, Schoeb TR, Weaver CT, Chaplin DD. Antigen and lipopolysaccharide play synergistic roles in the effector phase of airway inflammation in mice. Am J Pathol 2006; 168:1425–1434.  Back to cited text no. 41
    
42.
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.  Back to cited text no. 42
    
43.
Whitehead GS, Thomas SY, Cook DN. Modulation of distinct asthmatic phenotypes in mice by dose-dependent inhalation of microbial products. Environ Health Perspect 2014; 122:34–42.  Back to cited text no. 43
    
44.
Brook PO, Perry MM, Adcock IM, Durham AL. Epigenome-modifying tools in asthma. Epigenomics 2015; 7:1017–1032.  Back to cited text no. 44
    
45.
Pelletier M, Maggi L, Micheletti A, Lazzeri E, Tamassia N, Costantini C et al. Evidence for a cross-talk between human neutrophils and Th17 cells. Blood 2010; 115:335–343.  Back to cited text no. 45
    
46.
Newcomb DC, Peebles RJ Jr. Th17-mediated inflammation in asthma. Curr Opin Immunol 2013; 25:755–760.  Back to cited text no. 46
    
47.
Lei Y, Boinapally V, Zoltowska A, Adner M, Hellman L, Nilsson G. Vaccination against IL-33 inhibits airway hyperresponsiveness and inflammation in a house dust mite model of asthma. PLoS One 2015; 10:e0133774.  Back to cited text no. 47
    
48.
Banerjee A, Trivedi CM, Damera G, Jiang M, Jester W, Hoshi T et al. Trichostatin A abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 2012; 46:132–138.  Back to cited text no. 48
    
49.
Kankaanranta H, Janka-Junttila M, Ilmarinen-Salo P, Ito K, Jalonen U, Ito M et al. Histone deacetylase inhibitors induce apoptosis in human eosinophils and neutrophils. J Inflamm (Lond) 2010; 7:9.  Back to cited text no. 49
    
50.
Lewkowicz N, Klink M, Mycko MP, Lewkowicz P. Neutrophil − CD4+CD25+ T regulatory cell interactions: a possible new mechanism of infectious tolerance. Immunobiology 2013; 218:455–464.  Back to cited text no. 50
    
51.
Doñas C, Fritz M, Manríquez V, Tejón G, Bono MR, Loyola A, Rosemblatt M. Trichostatin A promotes the generation and suppressive functions of regulatory T cells. Clin Dev Immunol 2013; 2013:679804.  Back to cited text no. 51
    
52.
Cho JS, Kang JH, Han IH, Um JY, Park IH, Lee SH, Lee HM. Antiallergic effects of trichostatin A in a murine model of allergic rhinitis. Clin Exp Otorhinolaryngol 2015; 8:243–249.  Back to cited text no. 52
    
53.
Choi JH, Oh SW, Kang MS, Kwon HJ, Oh GT, Kim DY. Trichostatin A attenuates airway inflammation in mouse asthma model. Clin Exp Allergy 2005; 35:89–96.  Back to cited text no. 53
    



 
 
    Tables

  [Table 1]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Methods
Results
Discussion
References
Article Tables

 Article Access Statistics
    Viewed977    
    Printed22    
    Emailed0    
    PDF Downloaded78    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]