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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078860-08
Application #
8463231
Study Section
Special Emphasis Panel (ZRG1-CVRS-J (03))
Program Officer
Noel, Patricia
Project Start
2004-12-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
8
Fiscal Year
2013
Total Cost
$359,320
Indirect Cost
$123,700
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Mahdavinia, Mahboobeh; Suh, Lydia A; Carter, Roderick G et al. (2015) Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second-generation Asians suggest genetic regulation of eosinophilia. J Allergy Clin Immunol 135:576-9
Mahdavinia, Mahboobeh; Carter, Roderick G; Ocampo, Christopher J et al. (2014) Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity. J Allergy Clin Immunol 133:1759-63
Cao, P-P; Zhang, Y-N; Liao, B et al. (2014) Increased local IgE production induced by common aeroallergens and phenotypic alteration of mast cells in Chinese eosinophilic, but not non-eosinophilic, chronic rhinosinusitis with nasal polyps. Clin Exp Allergy 44:690-700
Cho, Seong H; Hong, Seung J; Chen, Haimei et al. (2014) Plasminogen activator inhibitor-1 in sputum and nasal lavage fluids increases in asthmatic patients during common colds. J Allergy Clin Immunol 133:1465-7, 1467.e1-2
Hulse, Kathryn E; Chaung, Katrina; Seshadri, Sudarshan et al. (2014) Suppressor of cytokine signaling 3 expression is diminished in sinonasal tissues from patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol 133:275-7.e1
Hsu, Joy; Avila, Pedro C; Kern, Robert C et al. (2013) Genetics of chronic rhinosinusitis: state of the field and directions forward. J Allergy Clin Immunol 131:977-93, 993.e1-5
Hulse, Kathryn E; Norton, James E; Suh, Lydia et al. (2013) Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression. J Allergy Clin Immunol 131:1075-83, 1083.e1-7
Jeffe, Jill S; Seshadri, Sudarshan; Hamill, Kevin J et al. (2013) A role for anti-BP180 autoantibodies in chronic rhinosinusitis. Laryngoscope 123:2104-11
Keswani, Anjeni; Kern, Robert C; Schleimer, Robert P et al. (2013) Role of interleukin-32 in chronic rhinosinusitis. Curr Opin Allergy Clin Immunol 13:13-8
Nagarkar, Deepti R; Poposki, Julie A; Tan, Bruce K et al. (2013) Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis. J Allergy Clin Immunol 132:593-600.e12

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