Development of a screening protocol to identify persons who are responsive to wood smoke particle-induced airway inflammation with pilot assessment of GSTM1 genotype and asthma status as response modifiers

Abstract

Background

We are currently screening human volunteers to determine their sputum polymorphonuclear neutrophil (PMN) response 6- and 24-hours following initiation of exposure to wood smoke particles (WSP). Inflammatory responders (≥10% increase in %PMN) are identified for their subsequent participation in mitigation studies against WSP-induced airways inflammation. In this report we compared responder status (N = 52) at both 6 and 24 hr time points to refine/expand its classification, assessed the impact of the GSTM1 genotype, asthma status and sex on responder status, and explored whether sputum soluble phase markers of inflammation correlate with PMN responsiveness to WSP.

Results

Six-hour responders tended to be 24-hour responders and vice versa, but 24-hour responders also had significantly increased IL-1beta, IL-6, IL-8 at 24 hours post WSP exposure. The GSTM1 null genotype significantly (p < 0.05) enhanced the %PMN response by 24% in the 24-hour responders and not at all in the 6 hours responders. Asthma status enhanced the 24 hour %PMN response in the 6- and 24-hour responders. In the entire cohort (not stratified by responder status), we found a significant, but very small decrease in FVC and systolic blood pressure immediately following WSP exposure and sputum %PMNs were significantly increased and associated with sputum inflammatory markers (IL-1beta, IL-6, IL-8, and PMN/mg) at 24 but not 6 hours post exposure. Blood endpoints in the entire cohort showed a significant increase in %PMN and PMN/mg at 6 but not 24 hours. Sex had no effect on %PMN response.

Conclusions

The 24-hour time point was more informative than the 6-hour time point in optimally and expansively defining airway inflammatory responsiveness to WSP exposure. GSTM1 and asthma status are significant effect modifiers of this response. These study design and subject parameters should be considered before enrolling volunteers for proof-of-concept WSP mitigation studies.

Keywords:

• Wood smoke particle exposure
• airway neutrophil response
• responder status

Ethics approval and consent to participate

This study (IRBIS 15-1775 titled ‘To identify persons who are susceptible to WSP-induced inflammation and examine the role of GSTM1 and other factors in this susceptibility’) was reviewed and approved by the Office of Human Research Ethics of the University of North Carolina at Chapel Hill (the UNC-CH IRB). All volunteers provided informed consent prior to participation in this study.

Consent for publication

All data are mean and standard error of the mean with no individually identifiable personal data being reported.

Author contributions

DBP conceived the study, oversaw regulatory and medical aspects of the study, and was involved in data collection, data analysis and manuscript preparation. LZ conducted statistical data analysis and contributed to manuscript preparation. AJB developed the IRB application and was involved in medical oversight of the study and data collection. MA was involved in IRB preparation and data collection. MLH was involved in medical oversight of the study and data collection in data collection. KHM was involved in IRB preparation and data collection. TLN was contributed to medical oversight of the study and data collection. HW oversaw sample processing and contributed to data collection and analysis. HZ oversaw statistical analysis of the data and contributed to manuscript preparation. NEA was involved in manuscript preparation and all aspects of sample collection, laboratory processing and analysis.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Additionally, this study is listed in ClinicalTrials.gov (NCT02767973), and data will be posted in that database upon completion of the study. Where informed consent was given, all unused de-identified biospecimens will be stored and curated in the CEMALB Biorepository (IRB# 05-2528) for potential future use.

Additional information

Funding

Research reported in this publication was primarily supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award number R01ES025124, with additional support from Assistance Agreement no. 83578501-0 awarded by the US Environmental Protection Agency (EPA) and Department of Defense (DoD) award W81XWH-18-1-0731 to the University of North Carolina. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Environmental Protection Agency, or the Department of Defense. The NIH, EPA and DoD does not endorse any products or commercial services mentioned in this publication. L.Z. is supported by grant 5T32ES007018. M.L.H and A.J.B. are supported by grant R01HL135235. H.Z. is supported by grant P30ES010126. The NIEHS, NHLBI, EPA and DOD had no role in the design of the study, or collection, analysis, and interpretation of data or in writing the manuscript.