Temporal regulation of cytokine mRNA expression in equine recurrent airway obstruction

Department of Veterinary Science, Maxwell Gluck Equine Research Center, University of Kentucky, Lexington, KY 40546-0099, USA.
Veterinary Immunology and Immunopathology (Impact Factor: 1.54). 11/2005; 108(1-2):237-45. DOI: 10.1016/j.vetimm.2005.07.013
Source: PubMed


Acute and chronic inflammation of the airway remains an important health problem for equids. "Heaves" or recurrent airway obstruction (RAO) remains one of the most commonly diagnosed conditions affecting the lung of older horses in Europe and the United States. The typical clinical signs of RAO include non-productive coughing, serous nasal discharge, labored expiratory effort, and flaring of the nostrils. Auscultation of the lungs of the affected horse often reveals abnormal respiratory sounds, described as crackles and wheezes, throughout the area of the lung field. These clinical signs occur secondary to an inflammatory response that results in bronchospasm, excessive mucus production and airway obstruction. This inflammatory response is characterized by the presence of excessive mucus and inflammatory cells, primarily neutrophils, in the small airways. Most evidence suggests that RAO is the result of a pulmonary hypersensitivity to inhaled antigens. Exposure of affected horses to hay dust, pollens, and mold spores leads to neutrophil accumulation in the lung and bronchospasm. The identification of allergen-specific IgE in bronchoalveolar lavage (BAL) fluid and sera of affected horses supports the involvement of a late phase, IgE-mediated, hypersensitivity reaction in the pathogenesis of equine RAO. The production of IgE antibodies is regulated by the cytokines IL-4 and IL-13. Using a quantitative PCR method we have reported that horses with RAO exhibit a modified Type 2 cytokine response characterized by the production of IL-4 and IL-13 mRNA, but not IL-5 mRNA in BAL cells. Interferon-gamma mRNA was also elevated, suggesting a mixed response. While these results are consistent with equine RAO being the result of an aberrant Type 2 cytokine response to inhaled allergens, others have failed to find any evidence of elevated Type 2 cytokine mRNA in BAL from horses with "heaves". It is likely that these disparate results could be the result of differences in the clinical stage of the affected animals or the timing of sample collection. Here, we report a diverse pattern of cytokine gene expression when sampling a group of affected horses over a period of time.

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Available from: Ralph E Beadle, Sep 21, 2014
    • "C, controls; CR, cribbers; IL, interleukin; mRNA, messenger RNA; TNF, tumor necrosis factor; W, weavers. (Liburt et al., 2010) and pathological conditions (Horohov et al., 2005; McFarlane and Holbrook, 2008; Hughes et al., 2011) but none have examined their expression in individuals exhibiting abnormal behaviors. "
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    ABSTRACT: In animals, recent studies have shown a dynamic interaction between neuroendocrine-immune systems and consequent behaviors, resulting in adaptive responses to different stimuli. Stereotypic oral and locomotor behaviors are common among intensively managed horses; however, little is known about how or whether immune responses affect such abnormal repetitive behaviors. Cytokines can be classified as proinflammatory or anti-inflammatory and they can affect brain development, neurogenesis, and synaptic plasticity. In humans and rodents, there is some evidence that cytokines can impair behavior. Our study compared leukocyte gene expression of cytokines of horses with stereotypic behavior with those exhibiting normal behavior. Blood samples were collected from 22 horses: 8 non-stereotypic controls (group C), 8 cribbers (group CR), and 6 weavers (group W). Leukocyte counts were obtained using an automated cell counter. Expression of some proinflammatory [interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-a] and anti-inflammatory (IL-4 and IL-10) cytokines was determined by quantitative polymerase chain reaction. No differences in body temperature, heart rate, respiratory rate, total proteins in serum, or leukocyte counts were found. A significant effect of group was found for IL-4, IL-10 messenger RNA (mRNA), and TNF-a mRNA. Group CR and group W showed a similar profile of cytokines expression. The results of this study show that there are differences in cytokine mRNA expression between non-stereotypic and stereotypic horses which could be related to a different activation of the immune system.
    No preview · Article · Sep 2015 · Journal of Veterinary Behavior Clinical Applications and Research
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    • "S. Hansen et al. / Veterinary Immunology and Immunopathology 158 (2014) 238–243 239 cytokines including interferon (IL)-4, IL-5 and IL-13, and a concomitant decrease in Th1 associated cytokines namely interferon gamma (IFN-␥) (Cordeau et al., 2004; Kleiber et al., 2005; Lavoie et al., 2001). Conflicting results have been reported with an increase in Th1 associated cytokines alone, or in combination with Th2 associated cytokines (Ainsworth et al., 2003; Beadle et al., 2002; Giguere et al., 2002; Horohov et al., 2005). Also, other studies have suggested a Th17 pathway (Ainsworth et al., 2006; Debrue et al., 2005). "
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    ABSTRACT: An imbalance in various cytokine mRNA expression in bronchoalveolar lavage (BAL) and peripheral blood mononuclear cells (PBMC) in horses suffering from recurrent airway obstruction (RAO) has been demonstrated; however, the natural variation of cytokine expression in healthy horses has yet to be described. The objectives of this study were to: 1) identify age-related differences in the expression of pro-inflammatory cytokines in BAL and PBMC, 2) compare the expression of pro-inflammatory cytokines between BAL and PBMC, 3) evaluate the relationship between BAL pro-inflammatory cytokine expression and BAL cytology. Cells from BAL and PBMC were collected from 66 horses and stimulated with LPS and PGN. The expression of IL-1β, IL-6, IL-8, TNF-α and TLR-4 were measured using qPCR. A significant age-related decrease for IL-1β and IL-8 in BAL, significant difference in cytokine mRNA expressions between BAL and PBMC and a significant relationship between TLR-4, IL-8 in LPS stimulated BAL samples and the percentage of neutrophils in BAL cytology were found. In conclusion, the natural age-related decrease in pro-inflammatory cytokine expression in BAL is new knowledge; this in contrast to other age-related findings associated with PBMC, where pro-inflammatory cytokines are known to increase with age in both horses and humans, the phenomenon known as ‘inflamm-aging’
    Full-text · Article · Apr 2014 · Veterinary Immunology and Immunopathology
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    • "The pathogenesis of RAO is complex; environmental antigens induce airway inflammation, migration of PMN cells to the bronchioalveolar space and a Th2 adaptive immune response with production of IgE and IgG antibodies . Whereas IgE is known to be responsible for triggering type I hypersensitivity in affected airways (Eder et al., 2000; Halliwell et al., 1993; Horohov et al., 2005; Moran et al., 2012), IgG triggers a type III hypersensitivity response that activates the production of proinflammatory factors such as C–X–C chemokines that stimulate PMN migration into the affected area (Lavoie-Lamoureux et al., 2010; Lavoie et al., 2001). One of the most common allergens responsible for RAO in horses is A. fumigatus, which is known to damage epithelial structures via the production of elastase, protease, catalase, dismutase, and cytotoxic ribonuclease (Purkayastha et al., 2000). "
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    ABSTRACT: Recurrent airway obstruction (RAO) is an equine immune-mediated disease with a high incidence worldwide. The aim of this work was to contribute to the understanding of RAO pathogenesis by studying T cells bearing regulatory markers in peripheral blood (PB) and in bronchoalveolar lavage fluid (BALF) recovered from the same group of susceptible horses before and after exposure tomouldy hay, which has been shown to induce RAO signology in our horse herd. With this purpose, mononuclear cells were obtained from the BALF and PB from horses before and after antigenic challenge and were stained with fluorochrome-conjugated antibodies against CD4, CD25 and Foxp3 and subsequently analyzed by flow cytometry. The results indicated that the percentage of CD4+, Foxp3+ cells clearly increased in PB and BALF obtained from horses with RAO. In addition, the percentage of CD4+, CD25high cells was greatly augmented in BALF of RAO positive horses compared with a baseline. No changes were observed in the PB compartment. The percentage of CD4+, CD25high, Foxp3+ cells in BALF increased in horses with active disease compared to horses in remission; this cell population also does not show changes in the PB compartment when RAO positive and RAO negative horses were compared. On the other hand, when the percentage of CD4, Foxp3 positive cells were compared with the percentage of CD4+, CD25high cells, the numbers were very similar. This observation was true for PB and BALF cells from non exposed horses as well as horses exposed to antigen. In all the experimental situations studied, the population expressing all of the markers CD4+, CD25high, Foxp3+ represent only a minor percentage of CD4+, CD25high or CD4+, Foxp3 subpopulations; therefore, an significant number of CD4+, CD25high, Foxp3- and CD4+, CD25null, Foxp3+ cells must exist. Finally, we conclude that horses with RAO show an airway accumulation of T cells bearing regulatory markers that probably are modulating the course of this disease, and that these T cells may be involved in the resolution of immune-mediated bronchial inflammation.
    Full-text · Article · Jan 2014 · Veterinary Immunology and Immunopathology
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