Problem: The health effects of inhaled environmental exposures are determined in large part by the 'first responded cell of the lung, the alveolar macrophage (AM). The important initial contact of AMs with inhaled agents is through members of the 'scavenger1 receptor class A family (SRA), especially MARCO and SRAI/II. The role of these pattern-recognition receptors in lung defense against inhaled oxidants and how they function for clearance and signaling are important but unanswered questions. Pilot Data: 2 novel and surprising observations spark our proposed research. First, despite being considered as passive 'molecular flypaper1, our data show distinct signaling and modulatory effects of the SRAs on macrophage behavior. Second, SRA-deficient mice show markedly increased inflammation in response to both an inhaled oxidant gas (ozone) and the soluble fraction of particulate air pollution (in addition to known SRA interactions with solid particles). We draw upon our pilot studies and the available literature to formulate our central hypothesis: AM scavenger receptors protect the lung directly by clearance of pathogenic particles and indirectly by removal of the pro-inflammatory oxidized lipids generated within alveolar lining fluid.
Specific Aims :
Aim 1 :
This aim will test the hypothesis that SRA deficient mice will show increased lung inflammation and injury in response to oxidant challenges in all 3 physical forms: solid particles (e.g. concentrated ambient air particles, CAPs), liquid (the soluble fraction of CAPs), and gaseous (e.g. ozone).
Aim 2 :
This aim will test the hypothesis that AMs from SRA-deficient mice will show diminished uptake of oxidized lipids generated in lung lining fluid and altered responses (cytokine release, toxicity) compared to wild-type AMs in vitro. Co-culture experiments with lung epithelial cells will test the prediction that diminished clearance of oxidized lipids by SRA-deficient AMs will reveal inflammatory and toxic responses in epithelium.
Aim 3 :
This aim will characterize signaling mechanisms for SRA-mediated particle phagocytosis and AM modulation, including identification of co-receptors and signals for particle internalization, and expression profiling of genetic programs triggered by SRA ligation. Significance: This research will identify novel mechanisms for lung defense against inhaled oxidants and illuminate basic mechanisms for phagocytic clearance of inhaled particles. ? ? ?
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