Coughlan, Catherine A. and Chotirmall, Sanjay H. and Renwick, Julie and Hassan, Tidi and Low, Teck Boon and Bergsson, Gudmundur and Eshwika, Ahmed and Bennett, Kathleen and Dunne, Katie and Greene, Catherine M. and Gunaratnam, Cedric and Kavanagh, Kevin and Logan, Patrick M. and Murphy, Philip and Reeves, Emer P. and McElvaney, Noel G. (2012) The Effect of Aspergillus fumigatus Infection on Vitamin D Receptor Expression in Cystic Fibrosis. American Journal of Respiratory and Critical Care Medicine, 186 (10). pp. 999-1007. ISSN 1535-4970

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Abstract

Rationale: Aspergillus fumigatus (A. fumigatus) in cystic fibrosis (CF) is increasingly recognized. Although allergic bronchopulmonary aspergillosis (ABPA) leads to deterioration of pulmonary function, the effect of A. fumigatus colonization in the absence of ABPA remains unclear. Objectives: To address this, we examined individuals with CF with A. fumigatus who were ABPA negative to identify the effects of itraconazole therapy on Aspergillus-induced lung inflammation. Methods: The effect of A. fumigatus on nuclear vitamin D receptor (VDR) expression was investigated using qRT-PCR and Western blotting. IL-5 and IL-13 levels were quantified by ELISA. The effect of itraconazole was assessed by a combination of high-resolution computed tomography, lung function test, and microbiological analysis. Measurements and Main Results: We demonstrate that A. fumigatus down-regulates VDR in macrophages and airway epithelial cells and that the fungal metabolite gliotoxin (Gt) is the main causative agent. Gt overcame the positive effect of 1,25-OH vitamin D3 on VDR expression in vitro, resulting in increased IL-5 and IL-13 production. In vivo, A. fumigatus positivity was associated with increased Gt in CF bronchoalveolar lavage fluid and increased bronchoalveolar lavage fluid levels of IL-5 and IL-13. After airway eradication of A. fumigatus with itraconazole, we observed decreased Gt, IL-5 and IL-13, improved respiratory symptoms, and diminished high-resolution computed tomography mosaic pattern consistent with sustained pulmonary function. Conclusions: This study provides a rationale for the therapeutic effect of itraconazole and implied that the therapeutic potential of vitamin D supplementation in preventing ABPA is only feasible with concurrent elimination of A. fumigatus to permit VDR expression and its positive functional consequences.

Item Type:	Article
Keywords:	cystic fibrosis; vitamin D receptor; Aspergillus fumigatus; itraconazole; inflammation;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	11107
Identification Number:	https://doi.org/10.1164/rccm.201203-0478OC
Depositing User:	Dr. Kevin Kavanagh
Date Deposited:	30 Sep 2019 16:40
Journal or Publication Title:	American Journal of Respiratory and Critical Care Medicine
Publisher:	American Thoracic Society
Refereed:	Yes
Funders:	Health Research Board (HRB), Medical Research Charities Group Ireland, Irish Research Council for Science, Engineering and Technology (IRCSET), Program for Research in Third Level Institutes (PRTLI)
URI:	https://www.atsjournals.org
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

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