Asthma is a disease of airway inflammation, and patients with severe or refractory asthma suffer from frequent exacerbations despite being on high doses of glucocorticoid (GC). Vitamin D (vit D) is used in psoriasis as a steroid sparing agent and inhibits chemokine secretion from keratinocytes in vitro. We have shown that administration of vit D to airway smooth muscle (ASM) cells inhibits inflammatory cytokine induced chemokine secretion and preliminary data suggests that treating ASM with a combination of GC and vit D has additive effects on inhibition of chemokine secretion from inflammatory cytokine stimulated ASM. We postulate that nuclear receptor activation using vit D decreases inflammatory gene expression in ASM by modulating glucocorticoid receptor and/or transcription factor expression. To test these hypotheses, in Aim 1, the role of vit D and glucocorticoid (GC) in mediating cytokine induced chemokine release from ASM will be determined by treating ASM with vit D and/or GC prior to stimulation with cytokines, then assessing chemokine release in steroid sensitive and insensitive states by quantitative methods to determine if vit D inhibits steroid insensitive chemokine secretion from ASM or works as a steroid sparing agent.
In Aim 2 we will determine whether the additive effects of GC and vit D on chemokine secretion from cytokine stimulated ASM require augmentation of GR activation. This will involve assessing affects of vit D administration on GC induced GR translocation, DNA binding, and gene transcription.
In Aim 3, vit D interaction with transcription factors NFkB and AP-1 will be assessed in ASM treated with vit D and inflammatory cytokines.
These studies will identify the mechanisms by which vit D inhibits steroid sensitive and steroid insensitive chemokine secretion from ASM and provide insight into new therapeutic targets to decrease asthma morbidity and prevent exacerbations.
| Banerjee, Audreesh; Trivedi, Chinmay M; Damera, Gautam et al. (2012) Trichostatin A abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 46:132-8 |
