ONES Grant: CXCL10/CXCR3 Regulation of Ozone-Induced Epithelial Permeability

CXCL10/CXCR3 Regulation of Ozone-Induced Epithelial Permeability

The purpose of this research study to understand how environmental and genetic factors may be involved in lung function. Study participants will undergo a 1-day screening that includes a blood draw and breathing testing, return for a two-day series of testing to include blood draw, and brief breathing test before and after an inhaled challenge with either filtered air (FA) or ozone (O3). Participants return the next day for a brief breathing test, a blood draw and a procedure called bronchoscopy to evaluate the lung after the challenge. Participants then return 18 - 20 days later to repeat the two-day series of testing to be challenged with the exposure not received on the first series, (FA or O3). Each visit will take about 3 - 3.5 hours. Follow-up phone calls from the study team will occur at 24 hours after each 2-day test series. Total study duration is about one to one-and a half months.

Study Overview

• Status: Completed
• Conditions: Environmental and Genetic Factors on Lung Function
• Intervention / Treatment: Drug: Ozone; Other: Filtered Air

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke Asthma, Allergy, and Airway Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Prior enrollment in the NIEHS Environmental Polymorphism Registry located in the greater Raleigh-Durham area
• Wild type or homozygous (female)/hemizygous (male - since sex-linked) expression of the CXCR3 polymorphism rs2280964

Exclusion Criteria:

• Current smokers of tobacco products including e-cigarettes or those with previous smoking history within the prior 5 years
• BMI less than 37 kg/m2
• Pregnant women and women who are presently lactating.
• Subjects that have received antibiotic administration or an upper respiratory infection within the previous 4 weeks
• College and graduate students or employees who are under direct supervision by any of the investigators in this protocol
• Alcohol or illicit substance abuse
• Chronic cardio/pulmonary respiratory disorders or other medical conditions as determined by the investigator
• Increased airway hyperresponsiveness at baseline as measured by a positive methacholine challenge response (methacholine PC20 FEV1 < 8 mg/ml)
• Subjects will be requested to refrain from antihistamines, nonsteroidal anti-inflammatory agents, antioxidants (e.g. beta-carotene, selenium, and lutein) and supplemental vitamins (e.g. C and E), for 1 week prior to, and during testing.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ozone	Drug: Ozone; Subjects will perform alternating 15 minutes rest with 15 minutes treadmill walk exercise periods for 135 minutes in while breathing Ozone (O3).
Placebo Comparator: Filtered Air	Other: Filtered Air; Subjects will perform alternating 15 minutes rest with 15 minutes treadmill walk exercise periods for 135 minutes in while breathing filtered air.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Ozone (O3) induced epithelial permeability, as measured by the level of clara cell secretory protein (ng/mL)	This measure is defined by the comparing each individuals baseline (following filtered air challenge) to the ozone response. The investigators will perform two tests on this response as a means of confirmation. The individual will have blood drawn to obtain serum and a bronchoscopy to obtain bronchoalveolar lavage. The serum will be used to determine the level of clara cell secretory protein. This is measured by enzyme-linked immunosorbent assay (ELISA). The value is reported as ng/mL. Each value will be compared to the individuals filtered air control and reported as a fold change from baseline. These are independent values but are both accepted in the literature as measures of epithelial permeability.	Baseline, 21 days
Change in Ozone (O3) induced epithelial permeability, as measured by albumin level (ug/mL)	This measure is defined by the comparing each individuals baseline (following filtered air challenge) to the ozone response. The investigators will perform two tests on this response as a means of confirmation. The individual will have blood drawn to obtain serum and a bronchoscopy to obtain bronchoalveolar lavage. The bronchoalveolar lavage will be similarly used to define the albumin level. Albumin is also measured by ELISA. The value is reported at ug/mL. Each value will be compared to the individuals filtered air control and reported as a fold change from baseline. These are independent values but are both accepted in the literature as measures of epithelial permeability.	Baseline, 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Ozone O3 induced alterations in gene expression of airway epithelial cells, and bronchoalveolar lavage cells	Measured by real-time PCR	Baseline, 21 days
Change in Ozone O3 induced alterations in bronchoalveolar lavage cytokines and growth factors	Measured by multiplex ELISA	Baseline, 21 days

Collaborators and Investigators

• Sponsor: Robert Tighe, MD
• Investigators: Principal Investigator: Robert Tighe, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): August 16, 2019
• Primary Completion (Actual): November 29, 2023
• Study Completion (Actual): January 24, 2024

Study Registration Dates

• First Submitted: July 3, 2018
• First Submitted That Met QC Criteria: July 23, 2018
• First Posted (Actual): July 26, 2018

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 8, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: genetic: CXCR3 polymorphism rs2280964
• Other Study ID Numbers: Pro00088966

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No