The goals of this grant continue to be elucidation of mechanisms of inflammation in the airways and mechanisms by which glucocorticoids (GC) ameliorate inflammatory airway disease. Based on in vitro and in vivo studies, we have advanced four important hypotheses to test: 1) that GC inhibit the recruitment of B lymphocytes and production of high concentrations of IgA and IgE in chronic rhinosinusitis (CRS);2) that GC improve epithelial innate immune responses;3) that GC will restore the expression of proteins involved in barrier maintenance in the upper airways;and 4) that glucocorticoid receptor (GR) translational isoforms are modulated during inflammation, altering the response to GC. We will test these hypotheses in a clinical study of the influence of oral prednisone on CRS in human subjects combined with in vitro model systems. The in vivo study involves collecting biopsies, epithelial cell scrapings and nasal lavage in subjects with or without CRS prior to and after 5 days of treatment with oral prednisone or no treatment.
Aim 1 will test the hypothesis that GC inhibit the pronounced B cell response in CRS. We have discovered that nasal polyp tissue contains very high levels of B lymphocytes, the B cell activator BAFF, the B cell chemokines CXCL12 and CXCL13, IgA and IgE. We will determine whether treatment with prednisone diminishes the local presence of B cells, plasma cells, and these cytokines and immunoglobulins.
Aim 2 is based on extensive preliminary results and will test in vivo the hypothesis that GC simultaneously spare innate immune host defense and inhibit inflammation.
Aim 3 will test the hypothesis that GC treatment will recover the loss of expression of molecules involved in barrier function in CRS, based on our findings that epithelial cells from individuals with CRS express dramatically lower levels of the barrier-preserving serine protease inhibitor SPINK5 and molecules in the epidermal differentiation complex (EDC), including S100A7 (psoriasin), S100A8 and S100A9 (calgranulins A and B). We will determine whether GC regulate the expression of these genes in airway epithelial cells in vitro and in vivo.
Specific Aim 4 will determine whether alterations of GR isoforms occur in T cells and B cells in CRS. Our co-Investigator, Dr Nick Lu, has discovered eight distinct translational isoforms of the alpha form of the GR and shown that A, B and C mediate apoptosis while D does so poorly or not at all;they all mediate anti-inflammatory effects. We have shown that activation of purified T and B cells leads to increased expression of GR-A and GR-C, an event that is likely to change their responses to GC. We will develop molecular biomarkers of the switch in GR isoforms and propose to use these markers to determine whether the T and B cells that populate CRS nasal polyp tissue have altered GR isoform expression and altered responses to GC. In summary, we will utilize in vitro and in vivo human model systems to study the influence of GC on processes that are linked to human disease in the airways. Our successful completion of the aims described in this proposal will yield valuable new insight into the mechanisms of glucocorticoid action in human disease.
We are proposing studies to determine how prednisone works to improve chronic diseases such as chronic rhinosinusitis, a disease of the upper airways and sinuses that often is characterized by the formation of nasal polyps and blockade of the sinus openings and the upper airway passages. This disease affects over 30 million people in the US alone and is a cause of considerable morbidity, leading to over 200,000 surgical interventions each year. We have new hypotheses about how prednisone and other steroids improve this disease, including blockade of local accumulation of inflammatory B lymphocytes, improvement of the barrier function of the upper airways and exerting anti-inflammatory effects while preserving or enhancing innate immunity that prevents infections from occurring. Studies in this grant will test whether these hypotheses are correct and give us valuable new insight into the pathogenesis of chronic rhinosinusitis as well as the mechanism by which steroids improve it.
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|Pothoven, Kathryn L; Schleimer, Robert P (2017) The barrier hypothesis and Oncostatin M: Restoration of epithelial barrier function as a novel therapeutic strategy for the treatment of type 2 inflammatory disease. Tissue Barriers 5:e1341367|
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