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Inflammation and Monocyte Recruitment Due to Aging and Mechanical Stretch in Alveolar Epithelium are Inhibited by the Molecular Chaperone 4-Phenylbutyrate

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Abstract

Introduction

Ventilator-Induced lung injury (VILI) is a form of acute lung injury that is initiated or exacerbated by mechanical ventilation. The aging lung is also more susceptible to injury. Harmful mechanical stretch of the alveolar epithelium is a recognized mechanism of VILI, yet little is known about how mechanical stretch affects aged epithelial cells. Disruption to Endoplasmic Reticulum (ER) homeostasis results in a condition known as ER stress that leads to disruption of cellular homeostasis, apoptosis, and inflammation. ER stress is increased with aging and other pathological stimuli. We hypothesized that age and mechanical stretch increase alveolar epithelial cells’ proinflammatory responses that are mediated by ER stress. Furthermore, we believed that inhibition of this upstream mechanism with 4PBA, an ER stress reducer, alleviates subsequent inflammation and monocyte recruitment.

Methods

Type II alveolar epithelial cells (ATII) were harvested from C57Bl6/J mice 2 months (young) and 20 months (old) of age. The cells were cyclically stretched at 15% change in surface area for up to 24 h. Prior to stretch, groups were administered 4PBA or vehicle as a control.

Results

Mechanical stretch and age upregulated ER stress and proinflammatory MCP-1/CCL2 and MIP-1β/CCL4 chemokine expression in ATIIs. Age-matched and mismatched monocyte recruitment by ATII conditioned media was also quantified.

Conclusions

Age increases susceptibility to stretch-induced ER stress and downstream inflammatory gene expression in a primary ATII epithelial cell model. Administration of 4PBA attenuated the increased ER stress and proinflammatory responses from stretch and/or age and significantly reduced monocyte migration to ATII conditioned media.

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Acknowledgments

The authors acknowledge the assistance of Niraja Bohidar in aiding in cell isolation experiments.

Funding

This study was funded by the National Institutes of Health (R01AG041823) and the National Science Foundation (CMMI-1351162).

Conflict of interest

MSV, PAL, JAH, FKG, MBS, SK, JN, AMR, and RLH declares that they have no conflict of interest.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

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Authors and Affiliations

  1. Department of Biomedical Engineering, Virginia Commonwealth University, Box 843067, Richmond, VA, 23284, USA

    M. S. Valentine, P. A. Link, J. A. Herbert, F. J. Kamga Gninzeko, M. B. Schneck, K. Shankar, J. Nkwocha & R. L. Heise

  2. Department of Mathematics and Applied Mathematics, Virginia Commonwealth University, Richmond, VA, 23220, USA

    A. M. Reynolds

  3. Victoria Johnson Center for Lung Disease Research, Virginia Commonwealth University, Richmond, VA, 23298, USA

    A. M. Reynolds & R. L. Heise

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Associate Editor Kris Noel Dahl oversaw the review of this article.

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Valentine, M.S., Link, P.A., Herbert, J.A. et al. Inflammation and Monocyte Recruitment Due to Aging and Mechanical Stretch in Alveolar Epithelium are Inhibited by the Molecular Chaperone 4-Phenylbutyrate. Cel. Mol. Bioeng. 11, 495–508 (2018). https://doi.org/10.1007/s12195-018-0537-8

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