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Converging evidence for the pro-inflammatory role of p-glycoprotein in Th2 polarized chronic rhinosinusitis endotypes


T-helper 2 (Th2) inflammation is a hallmark of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and eosinophilic CRS (eCRS) although the pathogenesis is poorly understood. P-glycoprotein (P-gp) is an efflux pump which is expressed within sinonasal mucosa and is capable of regulating cytokine transport in both epithelial and T-cells. The purpose of this study was to synthesize multiple lines of evidence suggesting that P-gp may promote inflammation in Th2 polarized CRS endotypes.


The findings of 8 prior studies (5 in vitro and 3 clinical) by our research consortium were examined for the presence of a consistent mechanistic framework linking the presence of altered P-gp expression and function to enhanced Th2 inflammation.


Two studies performed in primary epithelial cell culture demonstrated that P-gp expression is responsive to TLR4 stimulation and modulates Th2 cytokine secretion. These findings were replicated in 2 organotypic nasal polyp explant studies which demonstrated that the secretion of IL-5 and TSLP was highly correlated with P-gp expression and could be blocked using the P-gp inhibitors Verapamil or Zosuquidar. Three complimentary clinical studies demonstrated that P-gp was specifically overexpressed in polyp tissue and that expression correlated with tissue eosinophilia, Lund-Mackay Scores, and Kennedy Osteitis scores. A final in vitro study demonstrated that Clarithromycin and Itraconazole possess occult P-gp inhibitory properties.


Multiple lines of evidence suggest that P-gp regulates the secretion of Th2 polarizing cytokines from its host cell. Furthermore, the concentration of secretion is strongly correlated with the level of P-gp expression indicating a direct pro-secretory role. The P-gp overexpression found in CRSwNP and eCRS may therefore be interpreted as playing a central role in the maintenance of Th2 inflammation through enhanced cytokine secretion. The anti-P-gp effects of Clarithromycin and Itraconazole, two drugs with known anti-inflammatory properties, hint at a possible novel therapeutic strategy mediated by P-gp inhibition.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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Bleier, B. Converging evidence for the pro-inflammatory role of p-glycoprotein in Th2 polarized chronic rhinosinusitis endotypes. Clin Transl Allergy 5 (Suppl 4), P7 (2015).

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