# CXCL10/CXCR3 regulation of ozone-induced epithelial permeability

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $605,420

## Abstract

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.

## Key facts

- **NIH application ID:** 9831087
- **Project number:** 5R01ES027574-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Robert Matthew Tighe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $605,420
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9831087

## Citation

> US National Institutes of Health, RePORTER application 9831087, CXCL10/CXCR3 regulation of ozone-induced epithelial permeability (5R01ES027574-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9831087. Licensed CC0.

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