PULMONARY SURFACTANT EFFECTS ON MACROPHAGE PHENOTYPE

Project: Research project

Project Details

Description

Inflammation is an important part of normal pulmonary host-defense
processes, but when the control of inflammation is compromised and the
response too exuberant, the consequences for the lung can be deadly.
The alveolar macrophage plays a central role in triggering an regulating
the inflammatory response and we will examine the ability of pulmonary
surfactant to regulate macrophage differentiation and function. This
regulation depends on a delicate balance between the usually dominant
inhibitory effects of surfactant lipids and the stimulatory influence of
SP-A, a protein whose levels increase during many types of lung injury.
We will use the THP-1 monocytic cell line and normal monocytes and
alveolar macrophages to test the hypotheses that surfactant is
responsible for development and maintenance of the distinct phenotype of
the alveolar macrophage and that SP-A and surfactant containing higher
than normal amounts of SP-A can alter macrophage phenotype, promoting
the development of an inflammatory response. Specific Aim 1 will use
flow cytometry to define the effects that surfactant components exert on
the expression of macrophage cell surface molecules and RT-PCR to assess
mRNA levels for these markers. Specific Aim 2 will study the effect of
SP-A on the production of the proinflammatory cytokines (TNF-alpha, IL-
1beta, IL-6 and IL-8) and the modulation of this influence by surfactant
lipids. Cytokines will be measured by ELISA and mRNA by RT-PCR. The
mechanism responsible for these actions will be probed with neutralizing
antibodies and by the addition of exogenous cytokines. Specific Aim 3
will use biochemical techniques to identify proteins on the macrophage
cell surface that serve as ligands for SP-A and the conditions needed
for binding to occur. The results of this work will provide valuable
insight into how the alveolar microenvironment controls the ability of
the alveolar macrophage to initiate and modulate an inflammatory
response in the lung. The information gained will serve as a basis for
the development of new therapeutic modalities to prevent and halt lung
inflammation and reduce the significant morbidity and mortality
associated with it.
StatusFinished
Effective start/end date12/1/9611/30/01

Funding

  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute: $305,477.00

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