Environmental agents, including the atypical bacteria, Mycoplasma pneumoniae, and ozone are known to contribute to the exacerbation of asthma. A first line of defense against inhaled challenges is the pulmonary innate immune system, which includes the surfactant proteins. We have demonstrated that SP-A binds to lipids and proteins on M. pneumoniae, a TLR2 agonist, attenuating its pathogenicity. This line of defense may be particularly important in asthma, as studies have shown that SP-A inhibits allergen-induced lymphocyte proliferation and histamine release by immune cells from asthmatic children. SP-A null mice exhibit increased susceptibility to infection and inflammation caused by bacteria and viruses, and exhibit enhanced allergic inflammation. SP-A alleles have been associated with a variety of lung diseases including oxidant injury associated with ozone exposure and a recent association with increased risk for asthma. These data imply that disease susceptibility may be associated with variants of SP-A that have altered host defense functions and offer reduced protection in the setting of environmental insults. Therefore, surfactant proteins may have multiple roles in attenuating infection and inflammation. We hypothesize that in asthma, dysfunction of SP-A, due to quantitative and functional deficiencies in the protein, is associated with reduced ability to modulate inflammation. This dysfunction results in increased allergic inflammation in asthma. We propose that the basis of dysfunction is both genetic and structural.
In Aim 1, we will determine the relationship between the genotypes at the SP-A loci and the actual proteins expressed in the bronchoalveolar compartments of normal and asthmatic individuals employing a proteonomics approach.
In aim 2, we will determine the activity of SP-A isolated from normal and asthmatic subjects and specific SP-A allelic variants in the recognition of Mycoplasma pneumoniae, and the modulation of the innate immune response of human macrophages.
In specific aim 3, we will determine the activity of specific SP-A allelic variants and SP-A isolated from normal and asthmatic subjects in modulation of the immune response by airway epithelial cells to the environmental insults M. pneumoniae and ozone exposure, respectively.
This project is an integral part of the global goal of this program: to determine how SP-A modulates response to environmental insults that result in allergic airway inflammation. Project 1 will interface closely with Project 2 (Dr. Wright), as these concepts will be investigated in human and animal models of disease. Project 1 will also interface closely with Project 3 (Dr. Foster) as bronchoalveolar lavage (BAL) obtained from subjects recruited in Project 3 will be studied in Dr. Kraft's laboratory in Project 1. All projects will share a Clinical and Laboratory Core, which Drs. Sundy, Voelker and Kraft will co-direct.
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|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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