The impact of the serum levels of soluble receptor for advanced glycation end products (sRAGE) and its ligand S100A12 for the course and extent of lung involvement in smear positive pulmonary tuberculosis in a cohort study in Hyderabad - India.
|Institution:||Freie Universität Berlin|
|Department:||FB Biologie, Chemie, Pharmazie|
|Full text PDF:||http://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000098898|
Pulmonary Tuberculosis (TB) is a chronic disease characterized by the development of lung tissue damage and neutrophils play a detrimental role in this process. Danger Associated Molecular Patterns (DAMP) accumulate during chronic inflammation and tissue damage triggering immune responses; although they could promote tissue repair, the recruited cells especially neutrophils, secrete proteases and other agents that damage viable tissues. S100A12 is a neutrophil derived DAMP with adjuvant and pro-inflammatory properties after binding the Receptor for Advanced Glycation End-products (RAGE). One soluble cleaved RAGE (sRAGE) form produced by the cleavage of ADAM10 acts as decoy receptor that counteracts proinflammatory processes. A cross sectional cohort and self controlled case series study was performed in Mahavir Hospital and Research Center in Hyderabad-India with 119 TB patients and 163 healthy controls. The observational epidemiological study was combined with In vitro experiments to demonstrate that pulmonary TB is associated to an increase in S100A12 along with a decrease in sRAGE and ADAM10 and these proteins are independent predictors of disease occurrence. The cross sectional associations of S100A12 and sRAGE with pulmonary TB were confirmed longitudinally what suggests a causal relationship with pulmonary TB. In addition, this study shows not only that S100A12 inhibits ADAM10 in vitro activity and might regulate sRAGE secretion but also that this protein is a predictor of the extent of alveolar lung infiltration. Moreover, in pulmonary TB specific radiographic features are differently associated with sputum smear positivity and Body Mass Index (BMI). Finally, this study provides a proof of principle for an affordable point of care marker to assess disease occurrence and severity based on the differences in neutrophils and lymphocytes in peripheral blood plus the BMI as indicator of malnutrition. In conclusion, the serum levels of sRAGE and S100A12 might be indicators of the extent of inflammation in pulmonary TB, S100A12 is a surrogate marker of the extent of alveolar infiltration and might express neutrophil related lung tissue damage, and the ratio between the absolute numbers of neutrophils and lymphocytes in the peripheral blood of TB patients in particular when combined with the BMI might serve as a useful marker to assess disease occurrence and pulmonary involvement. Die pulmonale Tuberkulose (pTbc) ist durch Lungengewebsschädigung gekennzeichnet bei der neutrophile Granulozyten (Neutrophile) eine führende Rolle bei der Pathogenese spielen. Sogenannte “Damage Associated Molecular Patterns” (DAMPs oder "Alarmine") akkumulieren während der chronischen Entzündungsreaktion und der Gewebeschädigung und initiieren eine Immunantwort. Insbesondere Neutrophilen Granulozyten sezernieren Proteasen und andere Stoffe, welche gesundes Gewebe schädigen. S100A12 wird von Neutrophilen sezerniert und induziert, nachdem es am Rezeptor für „Advanced Glycation End-products” (RAGE) gebunden hat, pro-inflammatorische…