PROJECT SUMMARY / ABSTRACT
Identification of targeted therapies for chronic obstructive pulmonary disease (COPD), a leading cause of
morbidity and mortality in the United States and globally, has lagged other lung diseases. Eosinophil count,
which has been a good biomarker for identifying type-2 inflammation and response to monoclonal therapies in
asthma has proven to be less beneficial in COPD with unclear molecular mechanism. Since COPD is a
heterogenous disease marked by systemic inflammation and high comorbidity burden it is critical that the
impact of dysfunctional platelets, which act as immune and inflammatory cells, is considered in the mechanistic
pathway of type-2 inflammation and eosinophil activation. Mounting evidence suggests that the magnitude of
platelet activation, independent of cardiovascular comorbidity, is associated with respiratory outcomes in
COPD. Activated platelets conjugate to eosinophils which leads to eosinophil activation and translocation into
the lung tissue. Understanding the role of platelet-eosinophil conjugates in COPD morbidity and associations
between platelet activation and eosinophil activity would enhance understanding of underlying mechanisms for
type-2 inflammation in COPD and lead to novel therapeutic options. To elucidate the association of activated
platelets with eosinophils in COPD we will directly measure platelet-eosinophil conjugates and eosinophil
activation using flow cytometry in 50 individuals with COPD without overt or subclinical cardiovascular disease
co-enrolled in the ongoing study "Platelet Activation Pathways and Respiratory Morbidity in COPD" (NHLBI
K23HL151758). We hypothesize that a higher proportion of platelet-eosinophil conjugates and activated
platelets as measured by flow cytometry will be associated with disease severity, worse respiratory symptoms,
higher proportion of circulating activated eosinophils, and more type-2 inflammation. Platelet-eosinophil
conjugates will be identified in whole blood as cells simultaneously expressing eosinophil (CCR3) and platelet
(CD42a or P-selectin) surface markers in unstimulated and agonist-stimulated samples while activated
eosinophils will be distinguished as those expressing CD69, CD63, CD29, or CD18. Proportion of activated
platelets will be identified in platelet rich plasma before and after in vitro stimulation as part of the K23 study as
those expressing P-selectin, CD63, CD40L, or PAC1. Completion of the proposed aims will elucidate the role
of platelet-eosinophil conjugates and associations of activated platelets with eosinophil activation which will
inform future pathway-specific mechanistic and interventional studies toward the ultimate goal of personalized
therapy for COPD. The proposed study uses the infrastructure and refined laboratory protocols created as part
of the K23 study to investigate the role of activated platelets with eosinophils. A more refined understanding of
the mechanisms through which eosinophils are associated with COPD morbidity could potentially reveal more
broadly applicable endotypes for targeted therapy.