期刊
CELLULAR AND MOLECULAR BIOENGINEERING
卷 12, 期 2, 页码 165-177出版社
SPRINGER
DOI: 10.1007/s12195-019-00567-2
关键词
Systems biology; Inflammation; Immune system; Data-driven models; Pulmonary disease
资金
- NIH [R01 HL14484901]
- Department of Education Graduate Assistance in Areas of National Need (GAANN) Fellowship [P200A150170]
- Department of Veterans Affairs [I01 CX001553, I01 CX000911]
- MedImmune, Ltd.
- National Heart, Lung and Blood Institute
- National Institute of Health
IntroductionChronic 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.MethodsTo 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. ResultsUsing 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.ConclusionsOur 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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