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Understanding Steroid-Refractory Severe Asthma
Sunday, March 5, 2017: 3:00 PM
Rooms B303-B304 (Georgia World Congress Center, Building B)
Marc Gauthier, MD, , , , ,
Rationale: Severe Asthma (SA) is marked by poor corticosteroid (CS) response and frequent exacerbations leading to high cost and morbidity. Prior work showed elevated levels of airway IFN-γ in ~50% of SA which was associated with worse lung function in a mouse model.  We investigated whether CS treatment in the setting of type-1 inflammation further consolidates the type-1 signature.

Methods: mRNA levels of CXCL10 (a recruiter for IFN-γ-secreting T-cells) were measured by qPCR in a monocytic cell line, in lungs of mice subjected to mild and severe asthma models and in human bronchoalveolar-lavage (BAL) cells obtained through the Severe Asthma Research Program (SARP). Glucocorticoid receptor (GR) function was determined by luciferase reporter assay.

Results: We treated cells with stimuli known to induce CXCL10 (IFN-γ (100 ng/ml) or LPS (10 ng/ml)) and dexamethasone at two time-points (pre-treatment simulating chronic CS treatment and simultaneous treatment simulating a CS burst).  Dexamethasone inhibited LPS induction of CXCL10 at both time-points.  Dexamethasone pre-treatment increased IFN-γ induced CXCL10 while simultaneous treatment had no effect, despite no impact on GR function.  Mouse studies showed increased CXCL10 expression in SA model unchanged by dexamethasone.  Similar results were seen in human BAL cell samples.

Conclusions: We observed increased IFN-γ-induced CXCL10 expression with dexamethasone pre-treatment, potentially contributing to CS insensitivity. This finding was confirmed using a mouse model of SA and samples from SA patients maintained on high dose CS.  These findings suggest that CS may further consolidate type-1 inflammation in severe asthmatics.