Association of neutrophil-derived inflammatory mediator levels with lung pathology in active tuberculosis at diagnosis
Muefong CN 1,2,*, Owolabi O1, Donkor S1, Charalambous S3, Bakuli A2, Rachow A2, Geldmacher C2, Sutherland JS1
1MRC Unit The Gambia at LSHTM; 2Ludwig Maximilian University, Munich, Germany, 3Aurum Institute, Johannesburg, South Africa
Background: Neutrophils are the first cells recruited to the lung during active TB disease and are likely to contribute to TB-induced lung damage considering their extensive inflammatory potential. The aim of this study was to assess the variation of neutrophil-related soluble inflammatory mediators in relation to the degree of lung pathology in patients with active pulmonary TB (ATB).
Methods: Sputum and plasma samples were obtained from 138 ATB patients. These were classified into mild (n=57) or severe (n=61) lung pathology based on chest x-ray Ralph scores. Samples were analysed for GM-CSF, IFNy, TNF, IL8, IL10, IL12/23(p40), MMP1, MMP3, MMP8, MMP9, MPO, S100A8 and S100A9 using Bio-Plex 200 system (Bio-Rad, Belgium). The Wilcoxon rank sum test was used to compare medians between severity groups.
Results: Plasma levels of MMP1 (p=0.0092), MMP8 (p=0.00093), S100A8 (p=0.0051), IL8 (p=0.01), IL12.23(p40) (p=0.0051) and IFNy (p=0.011) are significantly higher in severe than mild groups at baseline (BL). Similarly, sputum MMP8 (p=0.021) and MMP1 (p=0.045) are significantly higher in severe than in mild groups. In contrast, sputum MPO (p=0.0021) and IL10 (p=0.031) are lower in the severe group. Meanwhile, lower MPO levels in sputum (p=0.041) is characteristic of severe lung disease at diagnosis.
Discussion and conclusions: Neutrophils are the major MPO-producers hence, patients with lower MPO in sputum (severe group) at presentation suggest lower neutrophil densities and/or reduced activity of recruited neutrophils into the lungs. The lower IL10 levels in this group also suggest decreased anti-inflammatory activity. Moreover, enhanced systemic levels of MMP8 (neutrophil collagenase) in sputum and plasma as well as MMP-1 (in sputum) in the severe group suggests that these MMPs are indicators of increased lung pathology. For the former, this also suggests enhanced activation and degranulation of circulating and infiltrating neutrophils. Our data also reveals that baseline sputum MPO levels at diagnosis can predict the degree of recovery from lung damage following standard 6-month anti-TB therapy. In conclusion, levels of (neutrophil) mediators are associated to the severity of lung damage in ATB.