Natalie M Niessen1,2,3, Peter G Gibson1,2,3,4, Katherine J Baines1,3, Daniel Barker3, Ian A Yang5, John W Upham6,7, Paul N Reynolds8,9,10, Sandra Hodge8,9,10, Alan L James11,12, Christine Jenkins13,14, Matthew J Peters14,15, Guy B Marks16,17, Melissa Baraket18, Jodie L Simpson1,3,4, Michael Fricker1,2,3. 1. Faculty of Health and Medicine and Priority Research Centre for Healthy Lungs, School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia. 2. National Health and Medical Research Council Centre for Excellence in Severe Asthma, Newcastle, NSW, Australia. 3. Hunter Medical Research Institute, Newcastle, NSW, Australia. 4. Department of Respiratory and Sleep Medicine, John Hunter Hospital, Newcastle, NSW, Australia. 5. Faculty of Medicine, Department of Thoracic Medicine, The Prince Charles Hospital, The University of Queensland, Brisbane, Qld, Australia. 6. Diamantina Institute, The University of Queensland, Brisbane, Qld, Australia. 7. Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Qld, Australia. 8. Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, SA, Australia. 9. Lung Research Laboratory, Hanson Institute, Adelaide, SA, Australia. 10. School of Medicine, University of Adelaide, Adelaide, SA, Australia. 11. Department of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia. 12. Medical School, The University of Western Australia, Perth, WA, Australia. 13. Respiratory Trials, The George Institute for Global Health, Sydney, NSW, Australia. 14. Department of Thoracic Medicine, Concord General Hospital, Sydney, NSW, Australia. 15. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia. 16. Woolcock Institute of Medical Research, Sydney, NSW, Australia. 17. South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia. 18. Medicine Faculty, Respiratory Medicine Department and Ingham Institute Liverpool Hospital, University of New South Wales, Sydney, NSW, Australia.
Abstract
BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.
BACKGROUND: The AMAZES randomized controlled trial demonstrated that long-term low-dose azithromycin treatment reduces exacerbations of poorly controlled asthma, but the therapeutic mechanisms remain unclear. Dysregulation of the inflammatory tumour necrosis factor (TNF) pathway is implicated in asthma and could be suppressed by azithromycin. We aimed to determine the inflammatory and clinical associations of soluble TNF signalling proteins (TNF receptors [TNFR] 1 and 2, TNF) in sputum and serum, and to test the effect of 48 weeks of azithromycin vs placebo on TNF markers. METHODS: Sputum supernatant and serum TNFR1, TNFR2 (n = 142; 75 azithromycin-treated, 67 placebo-treated) and TNF (n = 48; 22 azithromycin-treated, 26 placebo-treated) were measured by ELISA in an AMAZES trial sub-population at baseline and end of treatment. Baseline levels were compared between sputum inflammatory phenotypes, severe/non-severe asthma and frequent/non-frequent exacerbators. Effect of azithromycin on markers was tested using linear mixed models. RESULTS: Baseline sputum TNFR1 and TNFR2 were significantly increased in neutrophilic vs non-neutrophilic asthma phenotypes, while serum markers did not differ. Sputum TNFR1 and TNFR2 were increased in severe asthma and correlated with poorer lung function, worse asthma control and increasing age. Serum TNFR1 was also increased in severe asthma. Sputum and serum TNFR2 were increased in frequent exacerbators. Azithromycin treatment significantly reduced sputum TNFR2 and TNF relative to placebo, specifically in non-eosinophilic participants. CONCLUSIONS: We demonstrate dysregulation of TNF markers, particularly in the airways, that relates to clinically important phenotypes of asthma including neutrophilic and severe asthma. Suppression of dysregulated TNF signalling by azithromycin could contribute to its therapeutic mechanism.
Authors: Roberto Alfonso Accinelli; Grisel Jesús Ynga-Meléndez; Juan Alonso León-Abarca; Lidia Marianella López; Juan Carlos Madrid-Cisneros; Juan Diego Mendoza-Saldaña Journal: Travel Med Infect Dis Date: 2021-09-14 Impact factor: 6.211
Authors: Olga A Namakanova; Ekaterina A Gorshkova; Ruslan V Zvartsev; Sergei A Nedospasov; Marina S Drutskaya; Ekaterina O Gubernatorova Journal: Int J Mol Sci Date: 2022-03-24 Impact factor: 5.923
Authors: Natalie M Niessen; Peter G Gibson; Jodie L Simpson; Hayley A Scott; Katherine J Baines; Michael Fricker Journal: ERJ Open Res Date: 2021-07-19