Dimeric procyanidins as modulators of airway inflammation in the context of allergic asthma : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy (PhD) in Human Physiology at Massey University, Manawatū, Palmerston North, New Zealand
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Date
2017
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Massey University
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Abstract
Procyanidins are polyphenolic compounds that have come to be known as
biologically active in the context of promoting human health. Epidemiological evidence
suggests that populations that consume diets rich in procyanidins are less susceptible to
inflammatory diseases. Allergic asthma is an inflammatory lung disease with an
estimated 100 million affected individuals worldwide, with New Zealand having the
world’s second highest rate. Inflammation at the airway epithelium and infiltration of
immune cells, specifically eosinophils, into the lung tissue are two central
characteristics of allergic asthma. Thymic stromal lymphopoietin (TSLP) and eotaxin
isoforms, eotaxin-1 (CCL11) and eotaxin-3 (CCL26), are three biomarkers of airway
inflammation produced by the epithelium. Cell culture models were successfully
optimized for CCL11 and CCL26 production in A549 cells. Investigation of
procyanidins effect on epithelial TSLP production was not possible because TSLP
production in A549 cells was undetectable. Data suggests that dimeric A-type linked
procyanidin A2, but not B-type linked procyanidin B1 or B2, is capable of inhibiting
IL-4-induced CCL11 production when incubated on A549 cells prior to an
inflammatory insult. Co-incubation of A549 cells with procyanidin A2 and procyanidin
B2 demonstrated no evidence of a synergistic relationship for inhibiting cytokine-
induced CCL11 production. Similarly, A549 cells exposed to procyanidin A2, and to a
lesser extent procyanidin B2, had reduced production of cytokine-induced CCL26
production. An inhibition time course demonstrated procyanidin A2 had greatest
inhibition efficacy on cytokine-induced CCL26 production when incubated for 2 h prior
to an inflammatory insult. Comparison of procyanidin A2 inhibition to the known
CCL26 inhibitor, IFN , demonstrated that procyanidin A2 and IFN did not share the
same temporal inhibition patterns. Furthermore, experiments investigating concomitant
incubation of procyanidin A2 and IFN demonstrated that procyanidin A2 could
interfere with IFN –mediated CCL26 inhibition. Two possible mechanisms responsible
for the procyanidin A–mediated inhibition of cytokine-induced CCL11 and CCL26
were investigated: the modulation of cytokine receptor expression, and modulation of
plasma membrane fluidity. However, there was no evidence to support either of these
modes of action. The data presented in this thesis collectively demonstrate the ability of
procyanidin A2 to inhibit cytokine-induced eotaxin production from the lung epithelium
in vitro and support further investigation of procyanidin A2 as a preventative approach
for managing airway inflammation.
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Keywords
Polyphenols, Physiological aspects, Airway (Medicine), Inflammation, Respiratory allergy, Nutritional aspects, Research Subject Categories::MEDICINE::Physiology and pharmacology::Physiology