Browsing by Author "Thorne, Peter S."

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    Preventing asthma in high risk kids (PARK) with omalizumab: Design, rationale, methods, lessons learned and adaptation
    (Elsevier, 2021-01) Phipatanakul, Wanda; Mauger, David T.; Guilbert, Theresa W.; Bacharier, Leonard B.; Durrani, Sandy; Jackson, Daniel J.; Martinez, Fernando D.; Fitzpatrick, Anne M.; Cunningham, Amparito; Kunselman, Susan; Wheatley, Lisa M.; Bauer, Cindy; Davis, Carla M.; Geng, Bob; Kloepfer, Kirsten M.; Lapin, Craig; Liu, Andrew H.; Pongracic, Jacqueline A.; Teach, Stephen J.; Chmiel, James; Gaffin, Jonathan M.; Greenhawt, Matthew; Gupta, Meera R.; Lai, Peggy S.; Lemanske, Robert F.; Morgan, Wayne J.; Sheehan, William J.; Stokes, Jeffrey; Thorne, Peter S.; Oettgen, Hans C.; Israel, Elliot; Pediatrics, School of Medicine
    Asthma remains one of the most important challenges to pediatric public health in the US. A large majority of children with persistent and chronic asthma demonstrate aeroallergen sensitization, which remains a pivotal risk factor associated with the development of persistent, progressive asthma throughout life. In individuals with a tendency toward Type 2 inflammation, sensitization and exposure to high concentrations of offending allergens is associated with increased risk for development of, and impairment from, asthma. The cascade of biological responses to allergens is primarily mediated through IgE antibodies and their production is further stimulated by IgE responses to antigen exposure. In addition, circulating IgE impairs innate anti-viral immune responses. The latter effect could magnify the effects of another early life exposure associated with increased risk of the development of asthma – viral infections. Omalizumab binds to circulating IgE and thus ablates antigen signaling through IgE-related mechanisms. Further, it has been shown restore IFN-α response to rhinovirus and to reduce asthma exacerbations during the viral season. We therefore hypothesized that early blockade of IgE and IgE mediated responses with omalizumab would prevent the development and reduce the severity of asthma in those at high risk for developing asthma. Herein, we describe a double-blind, placebo-controlled trial of omalizumab in 2–3 year old children at high risk for development of asthma to prevent the development and reduce the severity of asthma. We describe the rationale, methods, and lessons learned in implementing this potentially transformative trial aimed at prevention of asthma.
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    Submucosal Gland Myoepithelial Cells Are Reserve Stem Cells That Can Regenerate Mouse Tracheal Epithelium
    (Elsevier, 2018-05-03) Lynch, Thomas J.; Anderson, Preston J.; Rotti, Pavana G.; Tyler, Scott R.; Crooke, Adrianne K.; Choi, Soon H.; Montoro, Daniel T.; Silverman, Carolyn L.; Shahin, Weam; Zhao, Rui; Jensen-Cody, Chandler; Adamcakova-Dodd, Andrea; Evans, T. Idil Apak; Xie, Weiliang; Zhang, Yulong; Mou, Hongmei; Herring, B. Paul; Thorne, Peter S.; Rajagopal, Jayaraj; Yeaman, Charles; Parekh, Kalpaj R.; Engelhardt, John F.; Cellular and Integrative Physiology, School of Medicine
    The mouse trachea is thought to contain two distinct stem cell compartments that contribute to airway repair-basal cells in the surface airway epithelium (SAE) and an unknown submucosal gland (SMG) cell type. Whether a lineage relationship exists between these two stem cell compartments remains unclear. Using lineage tracing of glandular myoepithelial cells (MECs), we demonstrate that MECs can give rise to seven cell types of the SAE and SMGs following severe airway injury. MECs progressively adopted a basal cell phenotype on the SAE and established lasting progenitors capable of further regeneration following reinjury. MECs activate Wnt-regulated transcription factors (Lef-1/TCF7) following injury and Lef-1 induction in cultured MECs promoted transition to a basal cell phenotype. Surprisingly, dose-dependent MEC conditional activation of Lef-1 in vivo promoted self-limited airway regeneration in the absence of injury. Thus, modulating the Lef-1 transcriptional program in MEC-derived progenitors may have regenerative medicine applications for lung diseases.