Abstract
BackgroundIL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma. The house dust mite (HDM) sheep asthma model displays many features of the human condition and is an ideal model to further elucidate the involvement of these critical Th2 cytokines. We hypothesized that airway exposure to HDM allergen would induce or elevate the expression profile of IL-4 and IL-13 during the allergic airway response in this large animal model of asthma.MethodsBronchoalveolar lavage (BAL) samples were collected from saline- and house dust mite (HDM)- challenged lung lobes of sensitized sheep from 0 to 48 h post-challenge. BAL cytokines (IL-4, IL-13, IL-6, IL-10, TNF-α) were each measured by ELISA. IL-4 and IL-13 expression was assessed in BAL leukocytes by flow cytometry and in airway tissue sections by immunohistology.ResultsIL-4 and IL-13 were increased in BAL samples following airway allergen challenge. HDM challenge resulted in a significant increase in BAL IL-4 levels at 4 h compared to saline-challenged airways, while BAL IL-13 levels were elevated at all time-points after allergen challenge. IL-6 levels were maintained following HDM challenge but declined after saline challenge, while HDM administration resulted in an acute elevation in IL-10 at 4 h but no change in TNF-α levels over time. Lymphocytes were the main early source of IL-4, with IL-4 release by alveolar macrophages (AMs) prominent from 24 h post-allergen challenge. IL-13 producing AMs were increased at 4 and 24 h following HDM compared to saline challenge, and tissue staining provided evidence of IL-13 expression in airway epithelium as well as immune cells in airway tissue.ConclusionIn a sheep model of allergic asthma, airway inflammation is accompanied by the temporal release of key cytokines following allergen exposure that primarily reflects the Th2-driven nature of the immune response in asthma. The present study demonstrates for the first time the involvement of IL-4 and IL-13 in a relevant large animal model of allergic airways disease.
Highlights
IL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma
The current study aimed to investigate the expression of IL-4 and IL-13, as well as IL-6, IL-10 and TNF-α, in the sheep model of asthma following allergen challenge of the airways
While macrophages were the major cell component in Bronchoalveolar lavage (BAL), there was an initial decline in numbers at 4 h after saline or house dust mite (HDM) challenge, followed by a return to similar baseline levels within 48 h post-challenge (Fig. 3a)
Summary
IL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma. Asthma is a chronic inflammatory disease of the lungs characterized by inflammation, airway hyperresponsiveness (AHR) and airway wall remodelling. The Th2 cytokines, including interleukin (IL)-4, IL-5, IL9, IL-13 and IL-25, together promote key pathophysiological features of asthma including allergen-specific IgE, airway inflammation (characterized by activated lymphocytes, eosinophils, mast cells and macrophages), damage to the airway epithelium, mucus gland hyperplasia and structural remodelling of the airway wall [2,3,4]. There is strong evidence that IL-4 and IL-13 play a crucial role in orchestrating the recruitment and activation of the effector cells of the asthmatic response. IL-4 and IL-13 act on bronchial epithelial, endothelial and airway smooth muscle cells, collectively leading to many of the pathophysiological features of asthma [3, 7]
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