The Problem: The main initial defense against inhaled particles is the alveolar macrophage. The first contact of the alveolar macrophage with inhaled particles is through """"""""scavenger type"""""""" receptors on the alveolar macrophage surface which bind various environmental particles with remarkable avidity. Defining the nature and function of these receptors is critical to understanding particle health effects, but progress has been stymied by the lack of specific mechanistic probes. The investigators have developed specific blocking monoclonal antibodies that overcome this obstacle. Hypothesis: The investigators draw upon prior studies and preliminary data to formulate the central hypothesis to be tested: 1) class A scavenger receptors (i.e. SRA I/II and MARCO) are the dominant mediators of alveolar macrophage binding of environmental particles in vitro and in vivo; 2) alveolar macrophage SRAs mediate """"""""down-regulation"""""""" of alveolar macrophage pro-inflammatory and microbial responses, an effect which may contribute to health problems from particulate air pollution. Experimental Plan:
Aim 1 will determine the expression and function of SRAs on normal and activated human alveolar macrophages by using specific monoclonal antibodies to measure receptor expression and to block particle binding assessed by flow cytometry). The studies will use a panel of surrogate or """"""""real world"""""""" particles (e.g. TiO2, latex beads, ambient particles) to establish the relative importance of these receptors in human alveolar macrophages in vitro.
Aim 2 will determine the in vivo function of SRAs using knockout mice with genetic deletions of SRA I/II or MARCO or cross-bread """"""""double-knockouts"""""""" of both receptors. After particle delivery into the lungs, the PI will measure particle uptake by the alveolar macrophages and assess inflammatory effects by bronchoalveolar lavage, cytokine measurements and pathologic evaluation of the lungs.
Aim 3 will test the hypothesis that SRAs deliver signals for down-regulation of alveolar macrophages, by evaluating functional responses (bacterial killing, chemokine production) and signaling events (Ca++ flux, phosphorylation) in response to ligation of SRAs by receptor-specific antibodies or particles. Gene array analysis will be used to expand characterization of signal transduction pathways triggered by SRAs. Significance: This research is relevant to the public health question of how inhaled particles cause pulmonary health effects and to the pathophysiology of lung host defense against environmental agents.
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