The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis

Catherine A. Coughlan, Sanjay H. Chotirmall, Julie Renwick, Hassan Tidi Maharani, Teck Boon Low, Gudmundur Bergsson, Ahmed Eshwika, Kathleen Bennett, Katie Dunne, Catherine M. Greene, Cedric Gunaratnam, Kevin Kavanagh, Patrick M. Logan, Philip Murphy, Emer P. Reeves, Noel G. McElvaney

Research output: Contribution to journalArticle

65 Citations (Scopus)

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 themain 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 tomographymosaic 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.

Original languageEnglish
Pages (from-to)999-1007
Number of pages9
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume186
Issue number10
DOIs
Publication statusPublished - 15 Nov 2012
Externally publishedYes

Fingerprint

Calcitriol Receptors
Aspergillus fumigatus
Cystic Fibrosis
Gliotoxin
Allergic Bronchopulmonary Aspergillosis
Itraconazole
Interleukin-13
Interleukin-5
Infection
Bronchoalveolar Lavage Fluid
Lung
Cholecalciferol
Respiratory Function Tests
Therapeutic Uses
Aspergillus
Vitamin D
Pneumonia
Down-Regulation
Western Blotting
Epithelial Cells

Keywords

  • Aspergillus fumigatus
  • Cystic fibrosis
  • Inflammation
  • Itraconazole
  • Vitamin D receptor

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Coughlan, C. A., Chotirmall, S. H., Renwick, J., Tidi Maharani, H., Low, T. B., Bergsson, G., ... McElvaney, N. 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), 999-1007. https://doi.org/10.1164/rccm.201203-0478OC

The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis. / Coughlan, Catherine A.; Chotirmall, Sanjay H.; Renwick, Julie; Tidi Maharani, Hassan; Low, Teck Boon; Bergsson, Gudmundur; Eshwika, Ahmed; Bennett, Kathleen; Dunne, Katie; Greene, Catherine M.; Gunaratnam, Cedric; Kavanagh, Kevin; Logan, Patrick M.; Murphy, Philip; Reeves, Emer P.; McElvaney, Noel G.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 186, No. 10, 15.11.2012, p. 999-1007.

Research output: Contribution to journalArticle

Coughlan, CA, Chotirmall, SH, Renwick, J, Tidi Maharani, H, Low, TB, Bergsson, G, Eshwika, A, Bennett, K, Dunne, K, Greene, CM, Gunaratnam, C, Kavanagh, K, Logan, PM, Murphy, P, Reeves, EP & McElvaney, NG 2012, 'The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis', American Journal of Respiratory and Critical Care Medicine, vol. 186, no. 10, pp. 999-1007. https://doi.org/10.1164/rccm.201203-0478OC
Coughlan, Catherine A. ; Chotirmall, Sanjay H. ; Renwick, Julie ; Tidi Maharani, Hassan ; Low, Teck Boon ; Bergsson, Gudmundur ; Eshwika, Ahmed ; Bennett, Kathleen ; Dunne, Katie ; Greene, Catherine M. ; Gunaratnam, Cedric ; Kavanagh, Kevin ; Logan, Patrick M. ; Murphy, Philip ; Reeves, Emer P. ; McElvaney, Noel G. / The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis. In: American Journal of Respiratory and Critical Care Medicine. 2012 ; Vol. 186, No. 10. pp. 999-1007.
@article{ac9f4979a6b54522bc3a8b1dda992c74,
title = "The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis",
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 themain 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 tomographymosaic 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.",
keywords = "Aspergillus fumigatus, Cystic fibrosis, Inflammation, Itraconazole, Vitamin D receptor",
author = "Coughlan, {Catherine A.} and Chotirmall, {Sanjay H.} and Julie Renwick and {Tidi Maharani}, Hassan and Low, {Teck Boon} and Gudmundur Bergsson and Ahmed Eshwika and Kathleen Bennett and Katie Dunne and Greene, {Catherine M.} and Cedric Gunaratnam and Kevin Kavanagh and Logan, {Patrick M.} and Philip Murphy and Reeves, {Emer P.} and McElvaney, {Noel G.}",
year = "2012",
month = "11",
day = "15",
doi = "10.1164/rccm.201203-0478OC",
language = "English",
volume = "186",
pages = "999--1007",
journal = "American Journal of Respiratory and Critical Care Medicine",
issn = "1073-449X",
publisher = "American Thoracic Society",
number = "10",

}

TY - JOUR

T1 - The effect of Aspergillus fumigatus infection on vitamin D receptor expression in cystic fibrosis

AU - Coughlan, Catherine A.

AU - Chotirmall, Sanjay H.

AU - Renwick, Julie

AU - Tidi Maharani, Hassan

AU - Low, Teck Boon

AU - Bergsson, Gudmundur

AU - Eshwika, Ahmed

AU - Bennett, Kathleen

AU - Dunne, Katie

AU - Greene, Catherine M.

AU - Gunaratnam, Cedric

AU - Kavanagh, Kevin

AU - Logan, Patrick M.

AU - Murphy, Philip

AU - Reeves, Emer P.

AU - McElvaney, Noel G.

PY - 2012/11/15

Y1 - 2012/11/15

N2 - 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 themain 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 tomographymosaic 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.

AB - 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 themain 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 tomographymosaic 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.

KW - Aspergillus fumigatus

KW - Cystic fibrosis

KW - Inflammation

KW - Itraconazole

KW - Vitamin D receptor

UR - http://www.scopus.com/inward/record.url?scp=84869214356&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84869214356&partnerID=8YFLogxK

U2 - 10.1164/rccm.201203-0478OC

DO - 10.1164/rccm.201203-0478OC

M3 - Article

C2 - 22904183

AN - SCOPUS:84869214356

VL - 186

SP - 999

EP - 1007

JO - American Journal of Respiratory and Critical Care Medicine

JF - American Journal of Respiratory and Critical Care Medicine

SN - 1073-449X

IS - 10

ER -