Chronic rhinosinusitis (CRS) is a disease of mucosal inflammation that affects 30 million Americans, causes significant morbidity and leads to several hundred thousand surgical procedures annually. The main hypothesis of these studies is that airway epithelium plays central roles in innate and adaptive immune responses as well as inflammation in CRS. We have discovered that there is selective impairment in the expression of the important antimicrobial peptides psoriasin (S100A7) and calprotectin (S100A8/S100A9) in the epithelium of patients with CRS, suggesting diminished innate immune host defense. Compromise of innate host defense responses could explain why patients with CRS experience frequent bacterial and fungal colonization of their airways and sinuses causing chronic inflammation. Other recent data from our laboratories show evidence for impairment in activation of STAT3, a molecule that is known to mediate immune and protective responses. Loss of STAT3 signaling by genetic mutation leads to the Hyper IgE syndrome (HIES;Job's disease), a mucosal inflammatory disease with impaired host defense and other similarities to CRS, and we hypothesize that restricted local mucosal inhibition of STAT3 signaling may underlie the mechanism of CRS in an analogous fashion. We will use a combined in vivo and in vitro approach to test three main hypotheses. We will test the hypothesis that epithelial host defense is impaired in CRS by assessing levels of psoriasin, calprotectin, and other host defense and barrier molecules in CRS patients and by assessing the antimicrobial properties of upper airways secretions in patients and controls. We will test the hypothesis that activation of STAT3 is inhibited in CRS by assessing formation of pSTAT3 in sinus tissue epithelial cells and lymphocytes from patients with CRS and control subjects. We will evaluate the state of phosphorylation of STAT3 in epithelial cells derived by scraping of the upper airways of patients and control subjects and relate the level of STAT3 signaling with host defense molecule expression. Finally, we will test the hypothesis that STAT3 mediates activation of the expression of host defense and barrier genes in epithelial cells in vitro. We will assess the ability of carefully selected stimuli to activate STAT3 and induce expression of host defense molecules and determine the role of STAT3 activation in the response. The proposed studies will test the important central hypothesis that the immune barrier is compromised in patients with CRS and that dysfunction of activation of STAT3 plays a role in this deficient response. Having the ability to identify molecular pathways in vitro and test their relevance in vivo in humans and in disease processes has been a powerful and longstanding central feature of our approach. We believe that successful completion of the aims described in this proposal will yield valuable new insight into the mechanisms of pathogenesis of chronic rhinosinusitis and potentially lead the way to new therapeutic strategies.

Public Health Relevance

Nearly ten percent of the US population suffers from chronic inflammation of the nose and sinuses with chronic rhinosinusitis (CRS), a disease that is not improved by treatment with anti-inflammatory steroids or antibiotics and often requires surgery for treatment. We have discovered that the ability of the surface barrier of the nose and sinuses to resist entry by microorganisms and foreign material is defective in patients with CRS and have discovered what we believe what may be the molecular process that has failed in the nose of CRS patients. We propose to test whether our ideas about the cause of CRS are correct since we believe that this work will lead to a new understanding of CRS and a new opportunity to develop drugs that treat it better than the available drugs or surgery.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVRS-J (03))
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Noel, Patricia
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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