OZONE EFFECTS ON FUNCTION OF SURFACTANT PROTEIN VARIANTS

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date5/1/994/30/00

Funding

  • National Institute of Environmental Health Sciences

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