Thursday, April 18, 2024
4/18/2024
Ozone (O3) causes lung injury, exacerbates chronic pulmonary diseases, and increases susceptibility to respiratory infections. Epidemiological studies strongly associate air pollution exposures and incidence of respiratory infections, which is important since more than 1/3 of the United States population lives in areas exceeding the current O3 regulatory standards. Though O3 exposure clearly impairs pulmonary host defense, the specific molecular mechanisms enhancing respiratory pathogen susceptibility remain poorly understood. Defining these mechanisms requires linking molecular pathways modified by environmental pollutants to those critical to host- pathogen interactions. The scavenger receptor families are such a molecular pathway. In this proposal, we plan to study the scavenger receptor CD163 in O3-induced alterations of pulmonary immunity. CD163 is a class B scavenger receptor, expressed on monocytes and macrophages, which exists in both membrane-bound and soluble (sCD163) forms. Membrane CD163 clears cell-free hemoglobin (CFH) by recognizing and internalizing hemoglobin-haptoglobin complexes. Once recognized by CD163, the complex is degraded by heme-oxygenase-1 into anti-inflammatory byproducts. Delayed CFH clearance augments inflammatory responses, exacerbates lung diseases, and modifies macrophage phagocytosis and apoptotic cell clearance (efferocytosis) resulting in persistent inflammation and defective pathogen clearance. Defining the role of CD163 in O3-mediated macrophage functions could uncover a novel mechanism mediating O3-induced adverse health effects. Our preliminary studies indicate that CD163 expression is upregulated in bronchoalveolar lavage (BAL) macrophages from human subjects undergoing acute laboratory O3 exposure. Supporting the human data, mice exposed to O3 have increased BAL macrophage CD163 expression and BALF CFH. O3-exposed CD163 deficient mice demonstrate increased lung injury, neutrophilia and frequency of airspace apoptotic neutrophils. On the basis of these observations, we hypothesize that macrophage-dependent clearance of CFH is mediated by CD163, a mechanism that limits acute lung injury after O3, and maintains effective efferocytosis and pathogen phagocytosis. The studies proposed will define: 1) how CD163 limits pulmonary inflammation by promoting efferocytosis; and 2) how CD163 clearance of CFH maintains macrophage phagocytosis of pathogens. These studies are translational; integrating murine and human samples/observations. Completion of these studies would define a novel molecular pathway for O3-induced health effects and define a specific mechanism by which ambient pollutants mediate critical macrophage functions. Furthermore, studies with sCD163 could identify a therapeutic to mitigate O3-induced susceptibility to pulmonary infections.
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