Ozone, a major constituent of photochemical pollution or smog, affects nearly 70 million people in the U.S. O3, a potent oxidant, reacts with proteins and lipids. This leads to lung inflammation and epithelial damage, and contributes to lung injury and surfactant derangement. Surfactant protein A (SP-A), the product of two genes (SP-A1 and SP-A2) in humans, is oxidized by O3, contributing to surfactant dysfunction. However, SP-A also plays a role in innate host defense, including the regulation of proinflammatory cytokine expression by macrophages. Therefore, SP-A oxidation by O3 may play a role in disturbances of host defense in the O3-exposed lung, including inflammation and susceptibility to infection with certain pathogens. With all of these O3-related responses, there is great variability among individuals. Many genetic variants of SP-A have been characterized and an association between low levels of SP-A mRNA and a particular genotype have been made, explaining the high variability in SP-A mRNA levels that have been reported. The central hypothesis of this proposal is that some SP-A variants are more susceptible to oxidation by O3 than others and that this variability results in the marked response heterogeneity of different individuals to O3. This hypothesis will be tested by exposing SP-A variants comprised of both gene products to O3 and studying their ability to modulate cytokine expression in the macrophage-like THP-1 cell line (Aim 1). The ability of the O3-exposed SP-A variants to bind mannose will be tested, as will the effect or this binding on the recognition of bacteria by SP-A and their subsequent phagocytosis by THP-1 cells (Aim 2). These endpoints will also be tested with SP-A variants comprised of a single gene product (Aim 3). Then the role of the specific amino adds responsible for the 03-induced changes in SP-A function will be studied by site-specific mutagenesis (Aim 4). The proposed studies will help elucidate the properties of different SP-A variants and the differential response of these to O3 exposure. The knowledge from these studies will add to our understanding of the basis of the high individual variability to O3 exposure, help us identify individuals at risk for 03-induced lung pathology, and suggest therapeutic strategies to prevent problems due to 03 exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009882-03
Application #
6382302
Study Section
Special Emphasis Panel (ZES1-JPM-B (01))
Program Officer
Mastin, Patrick
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2001-05-01
Budget End
2003-04-30
Support Year
3
Fiscal Year
2001
Total Cost
$236,138
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
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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
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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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