Asthma is a chronic inflammatory disorder caused by a dysregulated immune response that results in a Thelper (TH2) pattern of persistent inflammation, airway narrowing, and hyperresponsiveness. There has been an exponential increase in the prevalence of asthma over the past decade that has been partly attributed to growing exposure to environmental insults including oxidant and infectious agents. Lung host defense against these insults is mediated by the pulmonary innate immune system which involves leukocytes and soluble mediators such as surfactant. Surfactant protein A (SP-A), the major protein constituent of surfactant, has multifunctional roles in mediating the lung host response to inflammatory and infectious agents. The hypothesis to be tested is that SP-A plays an important role in linking innate and adaptive immune responses to pulmonary challenges that cause or exacerbate asthma and that deficiencies in SP-A or its activity due to allelic variation lead to enhanced susceptibility to asthma and skewing toward a TH2 cytokine response. We will use a model system that combines an infectious challenge, M. pneumoniae, and allergic sensitization with ovalbumin to investigate the role of SP-A in allergic and infectious inflammation. The atypical bacteria M. pneumoniae has been linked to asthma exacerbation and is present in the airways of patients with chronic, stable, asthma at a greater frequency compared to normal healthy controls. Our preliminary studies show that SP-A regulates immune cell responses to M. pneumoniae and that SP-A null mice have elevated inflammatory responses when challenged with either M. pneumoniae or the model allergen, ovalbumin.
Specific Aim 1 is to define the mechanism by which SP-A protects against M. pneumoniae inflammation and infection in vitro and in vivo and to determine if allelic variants of SP-A have an abrogated ability to modulate the host response.
Specific Aim 2 is to evaluate the role of SP-A in modulating the host response to M. pneumoniae infection in the context of ovalbumin allergen-induced airway reactivity and pulmonary inflammation.
This project will link closely with Project 1 which will provide allelic variants of SP-A and evaluate SP-A regulation of human macrophage and epithelial cell functions and with Project 3, which will evaluate the role of SP-A and its variants in mediating the host response to ozone. Together, the projects will enhance our understanding of the role of SP-A in asthma.
|Kaushik, S Sivaram; Robertson, Scott H; Freeman, Matthew S et al. (2016) Single-breath clinical imaging of hyperpolarized (129)Xe in the airspaces, barrier, and red blood cells using an interleaved 3D radial 1-point Dixon acquisition. Magn Reson Med 75:1434-43|
|Frush, Benjamin W; Li, Zhuowei; Stiles, Jane V et al. (2016) Ozone primes alveolar macrophage-derived innate immunity in healthy human subjects. J Allergy Clin Immunol 138:1213-1215.e1|
|Ledford, Julie G; Voelker, Dennis R; Addison, Kenneth J et al. (2015) Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses. J Immunol 194:6123-32|
|Kaushik, S Sivaram; Freeman, Matthew S; Yoon, Suk W et al. (2014) Measuring diffusion limitation with a perfusion-limited gas--hyperpolarized 129Xe gas-transfer spectroscopy in patients with idiopathic pulmonary fibrosis. J Appl Physiol (1985) 117:577-85|
|Foster, Matthew W; Thompson, J Will; Ledford, Julie G et al. (2014) Identification and Quantitation of Coding Variants and Isoforms of Pulmonary Surfactant Protein A. J Proteome Res 13:3722-32|
|Ogawa, Hirohisa; Ledford, Julie G; Mukherjee, Sambuddho et al. (2014) Surfactant protein D attenuates sub-epithelial fibrosis in allergic airways disease through TGF-Î². Respir Res 15:143|
|Mitsuhashi, Atsushi; Goto, Hisatsugu; Kuramoto, Takuya et al. (2013) Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages. Am J Pathol 182:1843-53|
|Kaushik, S Sivaram; Freeman, Matthew S; Cleveland, Zackary I et al. (2013) Probing the regional distribution of pulmonary gas exchange through single-breath gas- and dissolved-phase 129Xe MR imaging. J Appl Physiol (1985) 115:850-60|
|Horr, Samuel; Roberson, Russell; Hollingsworth, John W (2013) Pseudohypoxemia in a patient with chronic lymphocytic leukemia. Respir Care 58:e31-3|
|Murphy, Susan K; Hollingsworth, John W (2013) Stress: a possible link between genetics, epigenetics, and childhood asthma. Am J Respir Crit Care Med 187:563-4|
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