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Dietary Docosahexaenoic Acid as a Potential Treatment for Semi-acute and Chronic Particle-Induced Pulmonary Inflammation in Balb/c Mice

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Abstract—

Acute and chronic inflammation are vital contributing factors to pulmonary diseases which can be triggered by exposure to occupational and man-made particles; however, there are no established treatments. One potential treatment shown to have anti-inflammatory capabilities is the dietary supplement docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid found in fish oil. DHA’s anti-inflammatory mechanisms are unclear for particle-induced inflammation; therefore, this study evaluated DHA as a prophylactic treatment for semi-acute and chronic particle-induced inflammation in vivo. Balb/c mice were fed a control or 1% DHA diet and exposed to dispersion media, an inflammatory multi-walled carbon nanotube (MWCNT), or crystalline silica (SiO2) either once (semi-acute) or once a week for 4 weeks (chronic). The hypothesis was that DHA will decrease pulmonary inflammatory markers in response to particle-induced inflammation. Results indicated that DHA had a trending anti-inflammatory effect in mice exposed to MWCNT. There was a general decrease in inflammatory signals within the lung lavage fluid and upregulation of M2c macrophage gene expression in the spleen tissue. In contrast, mice exposed to SiO2 while on the DHA diet significantly increased most inflammatory markers. However, DHA stabilized the phagolysosomal membrane upon prolonged treatment. This indicated that DHA treatment may depend upon certain inflammatory particle exposures as well as the length of the exposure.

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Acknowledgements

The authors would like to thank the technical support from the Center for Environmental Health Sciences’ (CEHS) Core Facilities at University of Montana (UM): Inhalation and Pulmonary Physiology Core, Molecular Histology and Fluorescence Imaging Core, and the Fluorescence Cytometry Core. A special thank you to Dr. Joanna Kreitinger at Dermaxon and Dr. Sarjubhai Patel at FYR Diagnostics for use of their Bio-Rad 384-well CFX Maestro’s; Lou Herritt and Pamela Shaw within the CEHS Core facilities; Dr. Jack Harkema at Michigan State University for help with the semi-acute histopathology scoring; Iheanyi Amadi for help with lung airway wall thickness analysis; and UM’s Laboratory Animal Resources technicians and facility.

Funding

Paige Fletcher was supported by the Ruth L. Kirschstein NRSA Pre-doctoral Fellowship from the National Institute of Environmental Health Sciences (F31 ES028100). This research was supported by grants from the National Institute of Environmental Health Sciences (R01 ES023209 and R01 ES027353) and National Institute of General Medical Sciences (P30 GM103338). Paige Fletcher was awarded one of QIAGEN’s featured young scientists of the month (November 2018) where she received QIAGEN products that contributed to this research.

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  1. Department of Biomedical and Pharmaceutical Sciences, Center for Environmental Health Sciences, University of Montana, Missoula, MT, USA

    Paige Fletcher, Raymond F. Hamilton Jr., Joseph F. Rhoderick, Britten Postma, Mary Buford & Andrij Holian

  2. Department of Food Science and Human Nutrition, Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, USA

    James J. Pestka

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Contributions

PF designed and carried out the studies, analyzed the in vivo and ex vivo studies, and performed statistical analysis. PF wrote the first draft of the manuscript. RFH set up the ex vivo studies, assisted in lung pathology scoring, and provided statistical advice. JFR assisted with mRNA quantification by qPCR and provided qPCR advice. BP and MB assisted PF with the in vivo studies. JJP assisted PF with logistics of the in vivo studies and supplied the DHA microalgal oil within the diets. AH assisted PF with overall study design and coordination. All authors contributed to furthering the manuscript’s drafts and approved the final manuscript.

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Correspondence to Paige Fletcher.

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The animal use protocol (035-16AHCEHS-062816) was approved by the University of Montana Institutional Animal Care and Use Committee for all mouse studies described within this manuscript. The mice are maintained in microisolation containers within the BSL-2 Laboratory Animal Resources facility at the University of Montana in the accordance with the Guide for the Care and Use of Laboratory Animals. The animal care facility at the University of Montana is staffed with full-time veterinarians that are AAALAC accredited. Mice were monitored on a daily basis along with during/after exposure to particles. Mice were anesthetized with isoflurane before particle or vehicle control exposures so as not to use any restraints or cause distress. All procedures within these studies caused minimal discomfort to the mice; however, in any cases where it was deemed that the mice were in pain or distress (adverse body weight, abnormal activity, poor grooming, abnormal posture), the animal was humanely euthanized.

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Fletcher, P., Hamilton, R.F., Rhoderick, J.F. et al. Dietary Docosahexaenoic Acid as a Potential Treatment for Semi-acute and Chronic Particle-Induced Pulmonary Inflammation in Balb/c Mice. Inflammation 45, 677–694 (2022). https://doi.org/10.1007/s10753-021-01576-y

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