Glucocorticoids are indispensable in the treatment of inflammation although they are not effective in treating neutrophilic lung inflammation in severe asthma and acute respiratory distress syndrome. Our long-term goal is to understand the mechanisms by which the glucocorticoid receptor (GR) mediates cell-specific functions, as this information may be useful in the development of glucocorticoid regimens with improved efficacy/risk ratios. The goal of this proposal is to determine whether glucocorticoids promote neutrophil apoptosis and ameliorate airway hyperresponsiveness (AHR) in the absence of G-CSF signaling. We have recently discovered that glucocorticoids significantly elevate G-CSF, a neutrophil promoting cytokine. We hypothesize that glucocorticoids protect neutrophil from apoptosis and enhance neutrophil function via stimulation of G-CSF. The mechanisms of G-CSF induction are initiated by GR and NF-B p50 interaction. We propose to increase the efficacy of glucocorticoids in circumventing neutrophilic inflammation by inhibiting G-CSF signaling. To test our hypotheses, we will examine systems in vitro and in vivo. Studies in Aim 1 will test the hypothesis that GR and p50 interactions mediate G-CSF expression in various cell types in lungs. Studies in Aim 2 will determine the role of glucocorticoids-induced G-CSF in neutrophil survival, functions, trafficking, and neutrophilic lung inflammation in two murine models. We will use three approaches to block G-CSF induction: using G-CSFR null mice, anti-G-CSF neutralizing antibodies, and the natural compounds with NF-B inhibitor activities: curcumin and parthenolide. Our preliminary data indicate that both GR and NF-B are required for G-CSF induction and p50, but not p65, is recruited to the same region of G-CSF promoter as GR. Multiple lung parenchymal cells and infiltrating leukocytes produce G-CSF upon glucocorticoid stimulation and sustain lung inflammation. Curcumin in combination with glucocorticoids reduced lung G-CSF and neutrophil numbers in an LPS lung injury model. The proposed studies will improve our understanding of the role of glucocorticoids and G-CSF in neutrophil-dominant lung inflammation. Inhibiting G-CSF signaling is anticipated to increase the ability of glucocorticoids to suppress the airway-damaging activities of neutrophils and ameliorate lung inflammation.
|Effective start/end date||9/15/16 → 1/31/17|
- National Heart, Lung, and Blood Institute (1R56HL133058-01)