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Inference of Cellular Immune Environments in Sputum and Peripheral Blood Associated with Acute Exacerbations of COPD

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Abstract

Introduction

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, with high associated costs. Most of the cost burden results from acute exacerbations of COPD (AE-COPD), events associated with heightened symptoms and mortality. Cellular mechanisms underlying AE-COPD are poorly understood, likely because they arise from dysregulation of complex immune networks across multiple tissue compartments.

Methods

To gain systems-level insight into cellular environments relevant to exacerbation, we applied data-driven modeling approaches to measurements of immune factors (cytokines and flow cytometry) measured previously in two different human tissue environments (sputum and peripheral blood) during the stable and exacerbated state.

Results

Using partial least squares discriminant analysis, we identified a unique signature of cytokines in serum that differentiated stable and AE-COPD better than individual measurements. Furthermore, we found that models integrating data across tissue compartments (serum and sputum) trended towards being more accurate. The resulting paracrine signature defining AE-COPD events combined elevations of proteins associated with cell adhesion (sVCAM-1, sICAM-1) and increased levels of neutrophils and dendritic cells in blood with elevated chemoattractants (IP-10 and MCP-2) in sputum.

Conclusions

Our results supported a new hypothesis that AE-COPD is driven by immune cell trafficking into the lung, which requires expression of cell adhesion molecules and raised levels of innate immune cells in blood, with parallel upregulated expression of specific chemokines in pulmonary tissue. Overall, this work serves as a proof-of-concept for using data-driven modeling approaches to generate new insights into cellular processes involved in complex pulmonary diseases.

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Acknowledgments

The authors would like to thank Lisa McCloskey, RRT, Christi Getty, RRT, and Candace Flaherty, RRT for interactions with subjects in the original study.

Funding

This work was supported by NIH R01 HL144849-01 (to K.B.A.). K.C.N. was supported by a Department of Education Graduate Assistance in Areas of National Need (GAANN) Fellowship awarded to the biomedical engineering department at the University of Michigan (PR Award Number: P200A150170). C.M.F. was supported by Merit Review Awards I01 CX001553 from the Department of Veterans Affairs and by MedImmune, Ltd. M.K.H. reports a grant from the National Heart, Lung and Blood Institute. F.J.M. has received grants from the National Institute of Health. J.L.C. was supported by Merit Review Awards I01 CX000911 from the Department of Veterans Affairs and by MedImmune, Ltd.

Conflict of interest

K.C.N., C.M.F., N.S.B, J.L.C. and K.B.A. reported no conflicts of interest. M.K.H. reports consultant arrangements with GlaxoSmithKline, Boehringer Ingelheim, Novartis, Sunovion, and AstraZeneca. F.J.M. has received personal fees from Forest, Janssen, GlaxoSmithKline, Nycomed/Takeda, Amgen, AstraZeneca, Boehringer Ingelheim, Ikaria/Bellerophon, Genentech, Novartis, Pearl, Pfizer, Roche, Sunovion, Theravance, Axon, CME Incite, California Society for Allergy and Immunology, Annenberg, Integritas, InThough, Miller Medical, National Association for Continuing Education, Paradigm, Peer Voice, UpToDate, Haymarket Communications, Western Society of Allergy and Immunology, Informa, Bioscale, Unity Biotechnology, ConCert, Lucid, Methodist Hospital, Prime, WebMD, Bayer, Ikaria, Kadmon, Vercyte, American Thoracic Society, Academic CME, Falco, Axon Communication, Johnson & Johnson, Clarion, Continuing Education, Potomac, Afferent, and Adept; and has collected nonfinancial support from Boehringer Ingelheim, Centocor, Gilead, and Biogen/Stromedix; and declares other interests with Mereo, Boehringering Ingelheim, and Centocor.

Ethical Standards

All human subjects research was carried out in accordance with the Declaration of Helsinki and were approved by the Institutional Review Boards of the Veterans’ Affairs Ann Arbor Healthcare System (VAAHS) and of the University of Michigan Health System (UMHS).

Research Involved in Human or animal rights

No animal studies were carried out by the authors for this article.

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Author notes

  1. Katy C. Norman and Christine M. Freeman are co-first authors. Jeffrey L. Curtis and Kelly B. Arnold are co-senior authors.

Authors and Affiliations

  1. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA

    Katy C. Norman, Neha S. Bidthanapally & Kelly B. Arnold

  2. Division of Pulmonary & Critical Care, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA

    Christine M. Freeman, MeiLan K. Han & Jeffrey L. Curtis

  3. Research Service, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA

    Christine M. Freeman

  4. Graduate Program in Immunology, Rackham Graduate School, University of Michigan, Ann Arbor, MI, 48109, USA

    Christine M. Freeman & Jeffrey L. Curtis

  5. Joan & Sanford I. Weill Department of Medicine, Division of Pulmonary & Critical Care Medicine, Weill Cornell Medical College, New York, NY, 10065, USA

    Fernando J. Martinez

  6. Medicine Service, Pulmonary & Critical Care Section, VA Ann Arbor Healthcare System, Ann Arbor, MI, 48105, USA

    Jeffrey L. Curtis

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Norman, K.C., Freeman, C.M., Bidthanapally, N.S. et al. Inference of Cellular Immune Environments in Sputum and Peripheral Blood Associated with Acute Exacerbations of COPD. Cel. Mol. Bioeng. 12, 165–177 (2019). https://doi.org/10.1007/s12195-019-00567-2

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