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Leung J.M.,U.S. National Institutes of Health | Sin D.D.,James Hogg Research Center | Sin D.D.,University of British Columbia
Canadian Respiratory Journal | Year: 2013

The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases. © 2013 Pulsus Group Inc. All rights reserved.

Gold M.J.,University of British Columbia | Hughes M.R.,University of British Columbia | Antignano F.,University of British Columbia | Hirota J.A.,James Hogg Research Center | And 3 more authors.
Journal of Allergy and Clinical Immunology | Year: 2015

Background Inpp5d (Src homology 2 domain-containing inositol-5-phosphatase [Ship1])-deficient mice experience spontaneous airway inflammation and have enhanced sensitivity to allergen-induced airway inflammation. Objective We hypothesized that lineage-specific deletion of Ship1 expression in cells known to be crucial for adaptive TH2 responses would uncover distinct roles that could either positively or negatively regulate susceptibility to allergic airway inflammation (AAI). Methods Ship1 expression was deleted in B cells, T cells, or dendritic cells (DCs), and the resulting Ship1ΔB cell, Ship1ΔT cell, Ship1ΔDC, or Ship1F/F (wild-type) control mice were evaluated in a model of house dust mite (HDM)-induced AAI. Results Unlike germline panhematopoietic Ship1 deletion, deletion of Ship1 selectively in either the B-cell, T-cell, or DC lineages did not result in spontaneous airway inflammation. Strikingly, although loss of Ship1 in the B-cell lineage did not affect HDM-induced AAI, loss of Ship1 in either of the T-cell or DC lineages protected mice from AAI by skewing the typical TH2 immune response toward a TH1 response. Conclusions Although panhematopoietic deletion of Ship1 leads to spontaneous lung inflammation, selective deletion of Ship1 in T cells or DCs impairs the formation of an adaptive TH2 response and protects animals from HDM-induced AAI. © 2015 American Academy of Allergy, Asthma & Immunology.

Kirby M.,Robarts Research Institute | Kirby M.,University of Western Ontario | Pike D.,Robarts Research Institute | Pike D.,University of Western Ontario | And 4 more authors.
Radiology | Year: 2014

Purpose: To evaluate the predictive value of imaging and clinical and physiological measurements of chronic obstructive pulmonary disease (COPD) in patients monitored for more than 5 years for pulmonary exacerbations that required hospitalization.Materials and Methods: Exacerbations requiring hospitalization were monitored over 5 years in 91 subjects who provided written informed consent. Study was local research ethics board and Health Canada approved and HIPAA compliant. Subjects with COPD underwent spirometry, plethysmography, diffusing capacity of carbon monoxide, St George's Respiratory Questionnaire, 6-minute walk test, and imaging. Computed tomographic (CT) wall area and relative area with attenuation values less than 2950 HU (RA950), helium 3 (3He) magnetic resonance (MR) imaging ventilation defect percentage (VDP), and apparent diffusion coefficient were generated. Zero-inflated Poisson model was used to compare number of hospitalizations with lung function and imaging measurements.Results: Twenty-four subjects were hospitalized 58 times and had significantly worse forced expiratory volume in 1 second (FEV1) (P < .0001), CT RA950 (P = .02), and 3He VDP (P < .0001) than values in 67 subjects who were not hospitalized. In mild to moderate COPD, nine hospitalized subjects had significantly worse FEV1 (P = .02) and 3He VDP (P = .02) than values in 52 subjects who were not hospitalized. 3He VDP was quantitatively related to CT airway morphology (r = 0.26, P = .01) and quantitatively (r = 0.61, P < .0001) and spatially related to emphysema; this spatial relationship was significantly greater for hospitalized patients with COPD than unhospitalized patients (P = .0006). For all subjects, number of prior hospitalizations (P , .0001), 6-minute walk test distance (P < .0001), CT RA950 (P = .03), and 3He VDP (P = .002) were significantly related to number of hospitalizations. For 61 subjects with mild to moderate COPD, only 3He VDP was significantly associated with COPD exacerbations (P = .01).Conclusion: 3He MR imaging VDP represents a mixed airways-emphysema phenotype and helps identify subjects with mild to moderate COPD who are at risk for exacerbation that requires hospitalization. © RSNA, 2014.

Gold M.J.,University of British Columbia | Antignano F.,University of British Columbia | Halim T.Y.F.,British Columbia Cancer Agency | Hirota J.A.,James Hogg Research Center | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background Allergic inflammation involves the sensitization of naive CD4+ T cells to allergens, resulting in a TH2-skewed inflammatory response. Although antigen presentation by dendritic cells to T cells in the lymph node is crucial for TH2 cell development, the innate signals that initiate adaptive type 2 inflammation and the role of group 2 innate lymphoid cells (ILC2s) are poorly understood. Objective We sought to investigate the influence of ILC2s and the route of priming on the development of an adaptive type 2 immune response to lung allergens. Methods Wild-type and ILC2-deficient mice were exposed intranasally or systemically to the T H2-inducing antigens house dust mite or ovalbumin in a model of allergic airway inflammation or the TH17-inducing bacterial antigen Saccharopolyspora rectivirgula in a model of hypersensitivity pneumonitis. The formation of an adaptive immune response was evaluated based on serum antibody titers and production of T cell-derived cytokines (IL-4, IL-5, IL-13 and IL-17A). Results We find that lung ILC2s play a critical role in priming the adaptive type 2 immune response to inhaled allergens, including the recruitment of eosinophils, TH2 cytokine production and serum IgE levels. Surprisingly, systemic priming with ovalbumin, with or without adjuvants, circumvents the requirement for ILC2s in inducing TH2-driven lung inflammation. ILC2s were also found to be dispensable for the sensitization to TH1- or TH17-inducing antigens. Conclusion These data highlight a critical role for ILC2s in the development of adaptive type 2 responses to local, but not systemic, antigen exposure. © 2013 American Academy of Allergy, Asthma & Immunology.

Tam A.,University of British Columbia | Wadsworth S.,University of British Columbia | Dorscheid D.,University of British Columbia | Man S.F.P.,University of British Columbia | Sin D.D.,James Hogg Research Center
Therapeutic Advances in Respiratory Disease | Year: 2011

The mammalian airway is lined by a variety of specialized epithelial cells that not only serve as a physical barrier but also respond to environment-induced damage through the release of biologically active factors and constant cellular renewal. The lung epithelium responds to environmental insults such as pathogens, cigarette smoke and pollution by secreting inflammatory mediators and antimicrobial peptides, and by recruiting immune cells to the site of infection or damage. When the epithelium is severely damaged, basal cells and Clara cells that have stem-cell-like properties are capable of self-renewal and proliferation in the affected area, to repair the damage. In order to effectively fight off infections, the epithelium requires the assistance of neutrophils recruited from the peripheral circulation through transendothelial followed by transepithelial migration events. Activated neutrophils migrate across the epithelium through a series of ligand-receptor interactions to the site of injury, where they secrete proteolytic enzymes and oxidative radicals for pathogen destruction. However, chronic activation and recruitment of neutrophils in airway diseases such as chronic obstructive pulmonary disease and asthma has been associated with tissue damage and disease severity. In this paper, we review the current understanding of the airway epithelial response to injury and its interaction with inflammatory cells, in particular the neutrophil. © 2011 The Author(s).

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