Modeling vascular inflammation and atherogenicity after inhalation of ambient levels of ozone: exploratory lessons from transcriptomics

Abstract

Background: Epidemiologic studies have linked inhalation of air pollutants such as ozone to cardiovascular mortality. Human exposure studies have shown that inhalation of ambient levels of ozone causes airway and systemic inflammation and an imbalance in sympathetic/parasympathetic tone.

Methods: To explore molecular mechanisms through which ozone inhalation contributes to cardiovascular mortality, we compared transcriptomics data previously obtained from bronchoalveolar lavage (BAL) cells obtained from healthy subjects after inhalational exposure to ozone (200 ppb for 4 h) to those of various cell samples from 11 published studies of patients with atherosclerotic disease using the Nextbio genomic data platform. Overlapping gene ontologies that may be involved in the transition from pulmonary to systemic vascular inflammation after ozone inhalation were explored. Local and systemic enzymatic activity of an overlapping upregulated gene, matrix metalloproteinase-9 (MMP-9), was measured by zymography after ozone exposure.

Results: A set of differentially expressed genes involved in response to stimulus, stress, and wounding were in common between the ozone and most of the atherosclerosis studies. Many of these genes contribute to biological processes such as cholesterol metabolism dysfunction, increased monocyte adherence, endothelial cell lesions, and matrix remodeling, and to diseases such as heart failure, ischemia, and atherosclerotic occlusive disease. Inhalation of ozone increased MMP-9 enzymatic activity in both BAL fluid and serum.

Conclusions: Comparison of transcriptomics between BAL cells after ozone exposure and various cell types from patients with atherosclerotic disease reveals commonly regulated processes and potential mechanisms by which ozone inhalation may contribute to progression of pre-existent atherosclerotic lesions.

Keywords:

• Vascular inflammation
• atherosclerosis
• systemic inflammation
• cardiovascular disease
• air pollution
• ozone
• airway inflammation
• gene expression
• transcriptomics
• leukocyte trafficking
• matrix metalloproteinase-9

Acknowledgements

The authors would like to thank University of Southern California Library of Sciences for providing availability to NextBio and Ingenuity Pathway Analysis software, and Mr. Pryor Vu from University of California San Diego for technical assistance.

Disclosure statement

Authors disclose no financial conflict of interest. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The statements and conclusions in this publication are those of the authors and not necessarily those of the funding agency. The mention of commercial products, their source, or their use in connection with the material reported herein is not to be construed as an actual or implied endorsement of such products.

Additional information

Funding

This work was supported by (1) The American Heart Association Western States Affiliates Medical Student Research Program Award (Tham). (2) Stromedix, Inc. unrestricted research gift (Arjomandi). (3) NIH/NHLBI K23 HL083099 (Arjomandi). (4) NIH/NCRR/OD UCSF–CTSI Grant Number KL2 RR024130 and UL1 RR024131.