Ozone-induced acute phase response in lung versus liver: the role of adrenal-derived stress hormones

ABSTRACT

Acute-phase response (APR) is an innate stress reaction to tissue trauma or injury, infection, and environmental insults like ozone (O₃). Regardless of the location of stress, the liver has been considered the primary contributor to circulating acute-phase proteins (APPs); however, the mechanisms underlying APR induction are unknown. Male Wistar–Kyoto rats were exposed to air or O₃ (1 ppm, 6-hr/day, 1 or 2 days) and examined immediately after each exposure and after 18-hr recovery for APR proteins and gene expression. To assess the contribution of adrenal-derived stress hormones, lung and liver global gene expression data from sham and adrenalectomized rats exposed to air or O₃ were compared for APR transcriptional changes. Data demonstrated serum protein alterations for selected circulating positive and negative APPs following 2 days of O₃ exposure and during recovery. At baseline, APP gene expression was several folds higher in the liver relative to the lung. O₃-induced increases were significant for lung but not liver for some genes including orosomucoid-1. Further, comparative assessment of mRNA seq data for known APPs in sham rats exhibited marked elevation in the lung but not liver, and a near-complete abolishment of APP mRNA levels in lung tissue of adrenalectomized rats. Thus, the lung appears to play a critical role in O₃-induced APP synthesis and requires the presence of circulating adrenal-derived stress hormones. The relative contribution of lung versus liver and the role of neuroendocrine stress hormones need to be considered in future APR studies involving inhaled pollutants.

KEYWORDS:

• Acute-phase response
• gene expression
• lung
• liver
• adrenalectomy
• stress hormones

Acknowledgments

The authors would like to thank Drs. Ian Gilmour and Stephen Gavett of the U.S. EPA and Dr. Jonathan Shannahan of Purdue University (Lafayette, IN) for their critical review of the manuscript. We thank Dr. Mark Higuchi, Mr. Allen Ledbetter (retired), and Mr. Malek Khan of the U.S. EPA for their help in conducting ozone exposures and Ms. Judy Richards of the U.S. EPA (retired) for assessing select serum proteins.

Declaration

Authors declare no competing financial interests.

Disclosures

The research described in this article has been reviewed by the Center for Public Health and Environmental Assessment, U.S. EPA, and approved for publication. Approval does not signify that the contents necessarily reflect the views and the policies of the Agency, nor does mention of trade names of commercial products constitute endorsement or recommendation for use.

Abbreviations

APR: Acute-phase response, APPs: Acute-phase proteins, O₃: Ozone, SHAM: Sham surgery, ADREX: Adrenalectomy surgery, HPA: Hypothalamus-pituitary-adrenal, SAM: Sympathetic-adrenal-medullary, PM: Particulate matter, CRP: C-reactive protein (protein), A2M: α2-macroglobulin (protein), ORM-1: Orosomucoid-1 (protein), TRF: Transferrin (protein), HP: Haptoglobin (protein), CP: Ceruloplasmin (protein), HAMP: Hepcidin (protein), Actb: β-actin (gene), A2m: α2-macroglobulin (gene), Orm1: Orosomucoid-1 (gene), Serpina1: Serpin peptidase inhibitor, clade A, member 1 (gene), Crp: C-reactive protein (gene), Hp: Haptoglobin (gene), Cp: Ceruloplasmin (gene), Hamp: Hepcidin (gene).

Additional information

Funding

This work was supported by the U.S. EPA Intramural Research funds. ARH was the recipient of the Fulbright (CONICYT) and a trainee under the EPA-UNC Cooperative Agreement (CR-83515201). DIA was supported in part by an appointment to the Research Participation Program at the Center for Public Health and Environmental Assessment at the U.S. EPA, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and U.S. EPA.