Effects of LGM on a Primate Model of Asthma

PROJECT SUMMARY We previously demonstrated in mice that the major pathogenic features eosinophilic airway inflammation and airway hyperresponsiveness AHR were markedly enhanced in mice exposed to repeated social stress and these changes were associated with impaired glucocorticoid receptor GR expression and function In studies on non human primates rhesus macaques at the California National Primate Research Center CNPRC at UC Davis anxious temperament an early manifestation of psychosocial stress in young monkeys was significantly associated with AHR and glucocorticoid non responsiveness of immune cells We propose to investigate secoisolariciresinol diglucoside SDG a novel antiinflammatory molecule and natural non toxic bioactive component of flaxseed as an alternative adjunct therapy for glucocorticoid resistant asthma SDG has proven reducing chelating and free radical scavenging activities in vitro and in vivo and it induces activation of nuclear factor erythroid related factor NRF a major anti oxidant transcription regulator and inhibitor of NF kB Our aim is to evaluate the effects of the synthetic version of SDG LGM on airway hyperresponsiveness AHR inflammatory markers of blood and bronchoalveolar lavage BAL immune cells and glucocorticoid function of peripheral blood mononuclear cells of socially stressed rhesus macaques Aim is to assess LGM treatment on genetic and epigenetic regulation of the GR NF kB and NRF using bronchial brush biopsies The strength and novelty of our proposal is the unique Rhesus macaque model system of asthma associated with psychosocial stress and glucocorticoid resistance and the synthetic availability of LGM through LignaMed Upon completion these studies will lay the groundwork for subsequent Phase II trial and ultimately to human clinical projects NARRATIVE We previously found in murine non human primate and patient studies that severe asthma was associated with psychosocial stress and glucocorticoid resistance Here we will establish the effects of the synthetic version of SDG LGM a natural flaxseed lignan compound with demonstrated strong antioxidant properties on a stress related asthma model in non human primates Our studies will guide a Phase II project to verify the effectiveness and mechanism of action of this compound leading to investigations in asthma patients and ultimately to an alternative adjunct therapy of glucocorticoid resistant asthma