Published work points to an important role of surfactant protein A (SP-A) in innate host defense. SP-A modulates a number of host defense processes and exposure to ozone results in functional and structural alterations of SP-A. Two human genes, SP-A1 and SP-A2, and several genetic variants for each SP-A gene have been characterized. In vitro studies show functional, structural, or biochemical differences between the two genes and the gene-specific variants. SP-A levels are altered in a variety of lung diseases, and SP-A genetic variants are associated with risk for several pulmonary diseases. Our central hypothesis is that differences among SP-A variants account for differences in risk to lung disease in response to environmental insults. Our specific hypothesis is that the two human SP-A gene products are not functionally equivalent with regards to their host defense function, and that ozone exposure has a differential impact on this function. To investigate the specific hypothesis, we propose to study the effect of ozone, on pathogen-infected C57BL/6 and SP-A-/- mice (Aim 1) by assessing: a) survival with bacterial infection; b) ability to clear pathogens from their lungs and limit dissemination of infection; c) cytokine production, the in vivo phagocytic index of macrophages, and the in vivo oxidation status of SP-A; as well as, on the ex vivo host defense function of macrophages from wild type and SP-A-/- mice (Aim 2). To generate transgenic mouse lines on the SP-A-/- background that express equivalent levels of human SP-A1 or SP-A2 gene products (Aim 3). To study the impact of ozone on the SP-A1 and SP-A2 transgenic mouse lines by carrying out studies similar to those described for Aim 1 and by studying biochemical characteristics of the transgene products (Aim 4), and the ex vivo host defense function of macrophages from the SP-A1 and SP-A2 mouse lines (Aim 5). Through the proposed work we will generate an animal model to study human SP-A variants, and we will determine, in vivo, and in response to ozone exposure, the role of SP-A in host defense and assess functional host defense differences between the two human SP-A gene products. Knowledge gained may help explain and perhaps link the in vitro data with the human genetic association data, and provide insight in the understanding of the value of the SP-A gene duplication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009882-07
Application #
7265287
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
1999-05-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
7
Fiscal Year
2007
Total Cost
$427,269
Indirect Cost
Name
Pennsylvania State University
Department
Physiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Phelps, David S; Umstead, Todd M; Floros, Joanna (2014) Sex differences in the acute in vivo effects of different human SP-A variants on the mouse alveolar macrophage proteome. J Proteomics 108:427-44
Mikerov, Anatoly N; Phelps, David S; Gan, Xiaozhuang et al. (2014) Effect of ozone exposure and infection on bronchoalveolar lavage: sex differences in response patterns. Toxicol Lett 230:333-344
Phelps, David S; Umstead, Todd M; Silveyra, Patricia et al. (2013) Differences in the alveolar macrophage proteome in transgenic mice expressing human SP-A1 and SP-A2. J Proteom Genom Res 1:2-26
Mikerov, Anatoly N; Hu, Sanmei; Durrani, Faryal et al. (2012) Impact of sex and ozone exposure on the course of pneumonia in wild type and SP-A (-/-) mice. Microb Pathog 52:239-49
Gradov, O V (2012) [Experimental setups for ozonometric microscopy]. Med Tekh :42-7
Durrani, Faryal; Phelps, David S; Weisz, Judith et al. (2011) Gonadal hormones and oxidative stress interaction differentially affects survival of male and female mice after lung Klebsiella pneumoniae infection. Exp Lung Res 38:165-72
Wang, Guirong; Guo, Xiaoxuan; Diangelo, Susan et al. (2010) Humanized SFTPA1 and SFTPA2 transgenic mice reveal functional divergence of SP-A1 and SP-A2: formation of tubular myelin in vivo requires both gene products. J Biol Chem 285:11998-2010
Haque, Rizwanul; Umstead, Todd M; Ahn, Kwangmi et al. (2009) Effect of low doses of lipopolysaccharide prior to ozone exposure on bronchoalveolar lavage: Differences between wild type and surfactant protein A-deficient mice. Pneumon 22:143-155
Floros, Joanna; Wang, Guirong; Mikerov, Anatoly N (2009) Genetic complexity of the human innate host defense molecules, surfactant protein A1 (SP-A1) and SP-A2--impact on function. Crit Rev Eukaryot Gene Expr 19:125-37
Mikerov, Anatoly N; Haque, Rizwanul; Gan, Xiaozhuang et al. (2008) Ablation of SP-A has a negative impact on the susceptibility of mice to Klebsiella pneumoniae infection after ozone exposure: sex differences. Respir Res 9:77

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