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Principal Investigator: Tighe, Robert Matthew
Institute Receiving Award Duke University
Location Durham, NC
Grant Number R01ES027574
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Dec 2017 to 30 Nov 2023
DESCRIPTION (provided by applicant): ABSTRACT: Ozone (O3), a highly recognized cause of environmental lung injury, contributes to exacerbations of chronic pulmonary diseases and overall mortality. Despite efforts to reduce ambient O3 levels, these are expected to rise with global warming. Addressing this public health concern requires focus on pulmonary mechanism(s) of O3-induced host-responses to identify candidate pathways that can be targeted with precision in susceptible individuals. O3 inhalation is known to compromise barrier integrity of respiratory epithelial surfaces, an initial step in pulmonary injury. Although frequently overlooked, a compromised epithelium compounds susceptibility to subsequent exposures with airborne infectious and/or toxic agents. Epithelial barrier preservation requires coordinated signaling between the epithelium and resident immune cells, principally macrophages. Identifying the specific cellular mechanisms critical to this interaction would identify individuals with heightened susceptibility to O3 inhalation and potential targets for intervention. In controlled exposures of healthy human subjects to O3, the expression of the interferon-γ (IFN-γ) inducible chemokines CXCL9, CXCL10 and CXCL11 in bronchoalveolar lavage (BAL) macrophages are increased and this expression is associated with increased BAL albumin, a marker of epithelial permeability. Consistent with the human data, mice deficient in the receptor for the IFN-γ inducible chemokines (CXCR3-/-) are protected from O3-induced increases in epithelial permeability and demonstrate altered expression of epithelial barrier proteins. To translate the CXCR3-/- finding, a common human polymorphism of CXCR3 exists wherein individuals with the minor allele have reduced CXCR3 gene expression/function. Therefore, this polymorphism may identify individuals with decreased susceptibility to O3-derived health effects. Based on these findings, we hypothesize that O3 induces the production and release of IFN-γ inducible chemokines by airway macrophages, activating CXCR3 on epithelial cells, which leads to O3-induced permeability via modulation of epithelial barrier proteins. Our Specific Aims are: Aim 1: To define the requirements for and mechanisms of CXCR3 signaling in O3-induced epithelial permeability at the cellular level; Aim 2: To define the impact of CXCL10-CXCR3 signaling on O3-induced epithelial barrier dysfunction in vivo; and Aim 3: To define if a human intronic CXCR3 polymorphism that reduces CXCR3 functionality defines genetic susceptibility to O3-derived alterations in airway inflammation, and epithelial permeability. These studies will clearly determine the extent to which the CXCL10/CXCR3 axis mediates increased O3-induced airway epithelial permeability and whether a functional CXCR3 polymorphism is associated with O3 susceptibility. Furthermore, it provides a means to identify O3- susceptible individuals and define novel therapeutics to limit O3-induced epithelial permeability.
Science Code(s)/Area of Science(s) Primary: 69 - Respiratory
Secondary: -
Publications See publications associated with this Grant.
Program Officer Srikanth Nadadur
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