title: Biosignature for airway inflammation in a house dust mite-challenged murine model of allergic asthma.
abstract: House dust mite (HDM) challenge is commonly used in murine models of allergic asthma for preclinical pathophysiological studies. However, few studies define objective readouts or biomarkers in this model. In this study we characterized immune responses and defined molecular markers that are specifically altered after HDM challenge. In this murine model, we used repeated HDM challenge for two weeks which induced hallmarks of allergic asthma seen in humans, including airway hyper-responsiveness (AHR) and elevated levels of circulating total and HDM-specific IgE and IgG1. Kinetic studies showed that at least 24 h after last HDM challenge results in significant AHR along with eosinophil infiltration in the lungs. Histologic assessment of lung revealed increased epithelial thickness and goblet cell hyperplasia, in the absence of airway wall collagen deposition, suggesting ongoing tissue repair concomitant with acute allergic lung inflammation. Thus, this model may be suitable to delineate airway inflammation processes that precede airway remodeling and development of fixed airway obstruction. We observed that a panel of cytokines e.g. IFN-γ, IL-1β, IL-4, IL-5, IL-6, KC, TNF-α, IL-13, IL-33, MDC and TARC were elevated in lung tissue and bronchoalveolar fluid, indicating local lung inflammation. However, levels of these cytokines remained unchanged in serum, reflecting lack of systemic inflammation in this model. Based on these findings, we further monitored the expression of 84 selected genes in lung tissues by quantitative real-time PCR array, and identified 31 mRNAs that were significantly up-regulated in lung tissue from HDM-challenged mice. These included genes associated with human asthma (e.g. clca3, ear11, il-13, il-13ra2, il-10, il-21, arg1 and chia1) and leukocyte recruitment in the lungs (e.g. ccl11, ccl12 and ccl24). This study describes a biosignature to enable broad and systematic interrogation of molecular mechanisms and intervention strategies for airway inflammation pertinent to allergic asthma that precedes and possibly potentiates airway remodeling and fibrosis.
authors.affiliation: Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada Department of Immunology, University of Manitoba, Winnipeg, Manitoba, R3E 0T5, Canada.
authors.forename: Hadeesha
authors.initials: H
authors.lastname: Piyadasa
authors.affiliation: Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada Department of Immunology, University of Manitoba, Winnipeg, Manitoba, R3E 0T5, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Altieri
authors.affiliation: Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada.
authors.forename: Sujata
authors.initials: S
authors.lastname: Basu
authors.affiliation: Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada.
authors.forename: Jacquie
authors.initials: J
authors.lastname: Schwartz
authors.affiliation: Department of Immunology, University of Manitoba, Winnipeg, Manitoba, R3E 0T5, Canada Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, R3E 0J9, Canada Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada Canadian Respiratory Research Network.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Manitoba Centre for Proteomics and Systems Biology, University of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada Department of Immunology, University of Manitoba, Winnipeg, Manitoba, R3E 0T5, Canada Biology of Breathing Group, Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, R3E 3P4, Canada Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, R3T 2N2, Canada Canadian Respiratory Research Network neeloffer.mookherjee@umanitoba.ca.
authors.forename: Neeloffer
authors.initials: N
authors.lastname: Mookherjee
keywords: Airway hyper-responsiveness; Allergy; Asthma; Biomarkers; Biosignature; House dust mite; Inflammation