Discovery And Validation Of Early Life Plasma Protein Biomarkers For Childhood Asthma

Abstract

Asthma is a lung disease which features chronic inflammation. Multiple genetic and environmental factors increase susceptibility and provoke episodes of asthma. However, the mechanisms responsible for asthma development are not well characterized. Although allergy is associated with asthma, it has not been shown to precede or predict asthma. To date, there are no clearly established biomarkers of asthma, reflecting our less adequate understanding of asthma pathobiology. In order to identify a plasma proteomic biomarker as an indicator that plasma constituents are altered early in childhood asthma, this study employed a high-throughput antibody array technique which simultaneously profiled relative expression of 507 proteins in human plasma samples from asthma and non-asthma groups. It was hypothesized that alterations of proteomic profiles are accompanied with asthma development. Out of 444 proteins, 4 proteins (erythropoietin, sGP130, galectin-3, and eotaxin-3) were identified with differential expression between asthma and non-asthma groups. Erythropoietin and sGP130 were validated with quantitative differences, which were consistent in direction with the findings from the antibody array, between two groups after having all 4 proteins assessed by ELISAs. Erythropoietin then was assessed for its biological effects in in vivo and in vitro models. It was hypothesized that EPO has influences on acetylcholine-induced airway resistance in animals and on cytokine production from peripheral blood mononuclear cells. EPO's inhibitory effect on IL-2 production and its excitatory effect on IL-6 production were demonstrated; however, the inhibitory effect of EPO on increases in airway resistance in animals was not evident. The results here suggested that asthma has identifiable components in the circulation; these plasma biomarkers may develop via distinct pathways. The demonstrated EPO's capacity of influencing on cytokine production from human immune cells, together with its systemic involvement in asthma, may reveal new opportunities for therapeutics and insights into pathogenesis of asthma.