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: Two 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: AMscavenger 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) comparedto 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 intemalization, 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES011008-10
Application #
7992419
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Nadadur, Srikanth
Project Start
2001-08-01
Project End
2011-11-30
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
10
Fiscal Year
2011
Total Cost
$354,424
Indirect Cost
Name
Harvard University
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115
MacLeod, Daniel T; Nakatsuji, Teruaki; Yamasaki, Kenshi et al. (2013) HSV-1 exploits the innate immune scavenger receptor MARCO to enhance epithelial adsorption and infection. Nat Commun 4:1963
Józefowski, Szczepan; Yang, Zhiping; Marcinkiewicz, Janusz et al. (2012) Scavenger receptors and β-glucan receptors participate in the recognition of yeasts by murine macrophages. Inflamm Res 61:113-26
Sever-Chroneos, Zvjezdana; Krupa, Agnieszka; Davis, Jeremy et al. (2011) Surfactant protein A (SP-A)-mediated clearance of Staphylococcus aureus involves binding of SP-A to the staphylococcal adhesin eap and the macrophage receptors SP-A receptor 210 and scavenger receptor class A. J Biol Chem 286:4854-70
Ghosh, Sanjukta; Gregory, David; Smith, Alexia et al. (2011) MARCO regulates early inflammatory responses against influenza: a useful macrophage function with adverse outcome. Am J Respir Cell Mol Biol 45:1036-44
Thelen, Tennille; Hao, Yibai; Medeiros, Alexandra I et al. (2010) The class A scavenger receptor, macrophage receptor with collagenous structure, is the major phagocytic receptor for Clostridium sordellii expressed by human decidual macrophages. J Immunol 185:4328-35
DeLoid, Glen M; Sulahian, Timothy H; Imrich, Amy et al. (2009) Heterogeneity in macrophage phagocytosis of Staphylococcus aureus strains: high-throughput scanning cytometry-based analysis. PLoS One 4:e6209
Sulahian, Timothy H; Imrich, Amy; Deloid, Glen et al. (2008) Signaling pathways required for macrophage scavenger receptor-mediated phagocytosis: analysis by scanning cytometry. Respir Res 9:59
Arredouani, Mohamed S; Franco, Francesca; Imrich, Amy et al. (2007) Scavenger Receptors SR-AI/II and MARCO limit pulmonary dendritic cell migration and allergic airway inflammation. J Immunol 178:5912-20
Zhou, Hongwei; Kobzik, Lester (2007) Effect of concentrated ambient particles on macrophage phagocytosis and killing of Streptococcus pneumoniae. Am J Respir Cell Mol Biol 36:460-5
Dahl, Morten; Bauer, Alison K; Arredouani, Mohamed et al. (2007) Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II. J Clin Invest 117:757-64

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