The Effect of Aspergillus fumigatus Infection on Vitamin D Receptor Expression in Cystic Fibrosis

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. To address this, we examined...

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Published in:American journal of respiratory and critical care medicine 2012-11, Vol.186 (10), p.999-1007
Main Authors: COUGHLAN, Catherine A, CHOTIRMALL, Sanjay H, GUNARATNAM, Cedric, KAVANAGH, Kevin, LOGAN, Patrick M, MURPHY, Philip, REEVES, Emer P, MCELVANEY, Noel G, RENWICK, Julie, HASSAN, Tidi, TECK BOON LOW, BERGSSON, Gudmundur, ESHWIKA, Ahmed, BENNETT, Kathleen, DUNNE, Katie, GREENE, Catherine M
Format: Article
Language:English
Subjects:
Adult
Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy
Antifungal Agents - therapeutic use
Antigens
Aspergillus fumigatus
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Blotting, Western
Bronchi - metabolism
Cells, Cultured
Cystic fibrosis
Cystic Fibrosis - complications
Cystic Fibrosis - metabolism
Cystic Fibrosis - microbiology
Dietary supplements
Down-Regulation
Epithelium - metabolism
Female
Gliotoxin - pharmacology
Humans
Immunosuppressive Agents - pharmacology
Infections
Inflammation
Intensive care medicine
Interleukin-13 - metabolism
Interleukin-5 - metabolism
Itraconazole - therapeutic use
Lavage
Male
Medical sciences
Patients
Pharmacology. Drug treatments
Pulmonary Aspergillosis - complications
Pulmonary Aspergillosis - drug therapy
Pulmonary Aspergillosis - metabolism
Receptors, Calcitriol - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Th2 Cells - metabolism
Tomography
Trachea - metabolism
Vitamin D
Vitamin deficiency
Young Adult
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Summary: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. 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. 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. 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 D(3) 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. 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.
ISSN:1073-449X
1535-4970
DOI:10.1164/rccm.201203-0478OC