Rux largely restores lungs in Iraq PM-exposed mice, Up-regulating regulatory T-cells (Tregs)

ABSTRACT

Background Military personnel post-deployment to Iraq and Afghanistan have noted new-onset respiratory illness. This study's primary objective was to further develop an animal model of Iraq Afghanistan War Lung Injury (IAW-LI) and to test a novel class of anti-injury drug called RuX. Methods Particulate Matter (PM) samples were obtained in Iraq then characterized by spectromicroscopy. C57BL/6 mice underwent orotracheal instillation with PM, followed by drinkable treatment with RuX. Lung histology, inspiratory capacity (FlexiVent), thymic/splenic regulatory T cell (Treg) number, and whole-lung genomics were analyzed. Results Tracheal instillation of Iraq PM led to lung septate thickening and lymphocytic inflammation. PM-exposed mice had suppression of thymic/splenic regulatory T-cells (Tregs). Drinking RuX after PM exposure attenuated the histologic lung injury response, improved lung inspiratory capacity, and increased Tregs. Pooled whole lung genomics suggest differences among gene expression of IL-15 among control, PM, and PM + RuX groups. Conclusions RuX, a ruthenium and alpha-lipoic acid complex, attenuates lung injury by improving histology and inspiratory capacity via upregulation of Tregs in Iraq PM-exposed C57BL/6. Plausible genomic effects may involve IL-15 whole lung gene expression.

KEYWORDS:

• Burn pits
• dust
• fibrosis
• iraq
• inflammation
• lung injury
• mice
• particulate matter
• rux

Acknowledgements

We acknowledge the consultative geologic advice from Richard Reeder, Ph.D.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Author contributions

Anthony M. Szema, M.D. conceived, designed and conducted experiments, analyzed data and wrote the manuscript.

Rabail Razi, M.D. and Niha Qamar, M.D. assisted in animal husbandry and conduct of experiments.

Laurie Levine, A.A.S. and Thomas Zimmerman, D.V.M. bred C57BL/6 mice and helped perform orotracheal instillation with PM.

Sayyed A. Hamidi, M.D., M.P.H., M.B.A. conducted experiments and analyzed data.

David Lin and Jonathan Li, B.S., conducted PM-exposure experiments and flow cytometry, and helped write the manuscript.

Sami I. Said, M.D. provided mentorship and guidance regarding planning of experiments.

Todd Rueb, B.S. and Marc G. Golightly, Ph.D. analyzed flow cytometric data.

Merrill Garnett, D.D.S. and Frank Antonawich, Ph.D. developed RuX.

Andrea Harrington, Ph.D., Millicent Schmidt, Ph.D. analyzed PM.

Additional information

Funding

A.M.S. NIH K08 HL071263; NIH LTRC, Concept Sheet, 08-99-0002; NIH R21 ES023583; New York State Department of Economic Development New York State Center for Biotechnology (NYSTAR) C070127; Garnett McKeen Laboratory.