Investigating the pathways involved in the progression of fibrosis in tuberculous pericarditis

Fikamva, Siyavuya

Investigating the pathways involved in the progression of fibrosis in tuberculous pericarditis

Thesis / Dissertation

2023

Abstract

Extrapulmonary tuberculosis (EPTB) accounts for about 15% of all cases of tuberculosis (TB) globally. Tuberculous pericarditis (TBP) is a severe form of EPTB involving the pericardium that is present in 1-2% of TB cases, and poses diagnostic and therapeutic challenges, with mortality rates ranging between 8-34% despite anti- tuberculous therapy. TBP is the leading cause of pericardial constriction in Africa which is a life-threatening TBP complication. There has been significant progress towards understanding the pathogenesis of TBP. However, the mechanisms leading to the fibrotic phenotype are poorly understood, and the definitive pathophysiology is not clear. Various immune-modulatory and fibrotic cytokines, peptides, and pathways have been studied to improve our understanding of the mechanism of TBP progression. These findings prompted the investigation of the pathogenesis of TBP by identifying proteins and novel pathways that may contribute to TBP disease progression. This thesis aimed to investigate a) the molecular mechanisms involved in the development of fibrosis in TBP, and b) the potential of ACE inhibitors (ACEi) for managing fibrosis progression. Pericardial fluid was obtained from patients with TBP and patients undergoing coronary artery bypass surgery (non-infectious controls). Label-free quantitative discovery mass spectrometry (MS) was employed to investigate the TBP proteome. Proteins involved in fibrotic pathways were identified, with proteins of interest involved in wound healing, extracellular matrix (ECM) organisation, and regulation of TGF-β production. Autoantibody profiling was used to investigate whether the post-translational modification citrullination is involved in autoantibody production. Thirteen autoantibodies were expressed in the TBP pericardial fluid samples. The levels of leucine-rich repeat flightless-interacting protein 2 (LRRFIP2) were increased in TBP samples compared to in control samples. LRRFIP2 functions as part of a checkpoint connecting innate and adaptive immunity in autoimmune diseases. Finally, a systematic review was conducted to investigate the antifibrotic potential of ACEi in myocardial fibrosis. ACEi results in a significant reduction in the progression of fibrosis as monotherapy, and shows an even greater reduction in fibrosis when used in combination with other renin aldosterone angiotensin (RAAS)

Keywords

Medicine

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