Glucocorticoid induced G-CSF in lung inflammation

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date9/15/161/31/17

Funding

  • National Heart, Lung, and Blood Institute (1R56HL133058-01)

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