Browsing by Author "Jacobs, Steve"

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    Characterising pathways that contribute to post-TB lung disease
    (Stellenbosch : Stellenbosch University, 2024-02) Jacobs, Steve; Maarman, Gerald; Windvogel, Shantal; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.
    ENGLISH ABSTRACT: Tuberculosis (TB) is a major global health challenge, especially in low- and middle-income countries (LMICs). Post-tuberculosis lung disease (PTLD) is a common and debilitating sequela of TB, which can lead to chronic respiratory symptoms and impaired lung function. The pathogenesis of PTLD is not well understood, and much remains to be discovered, although some other authors have hypothesized that inflammation may be a key contribution, despite successful completion of TB treatment. Moreover, accumulating data suggests that PTLD might also include pulmonary hypertension (PH). The latter is a multi-organ disease and highly morbid clinical condition, with a broad range of clinical presentations and is caused by a large spectrum of underlying conditions. The relationship between PTLD and PH is complex and multifactorial, involving host, environmental, and pathogenic factors. Given the inflammatory nature of TB, it is likely that pro-inflammation may contribute to the development of PH post-TB, however, there is currently no data on this topic. This is concerning, as millions of people live with TB, close to 60 000 people die of TB in South Africa per annum, while every year almost 600 new cases of TB are reported. Given this context, it is worrying that TB patients (whether previous or current, or treated) are at risk of developing debilitating PTLD and fatal PH. This project, aimed to delineate the involvement of pathwaysthat may contribute to the development of PH in a post-TB context, and to explore the pathways that specifically contribute to PH in the same context. In our pursuit, we managed to highlight the instrumental roles of inflammatory pathways as part of PTLD pathogenesis. Our novel findings suggest that there is a pro-inflammatory state in active TB patients on treatment that persists post-TB, regardless of being successfully treated for TB. The unusual circulation pattern of inflammatory cytokines could be ascribed to mitochondrial dysfunction in immune cells. Considering the destructive nature of these cytokines, there is a need for further research to explore the implications of a persistent pro-inflammatory state, as it may predispose patients to PTLD. In terms of PH, we explored myriad pathways that may cause PH, now a new key feature of PTLD. Our review of the literature demonstrated a link between melatonin and PH as part of PTLD. Our findings demonstrate that melatonin is an important link between the gut microbiota and the development of PH (where suppressed melatonin-crosstalk between the gut and lungs could promote the development of PH). More studies are needed to investigate the link between the gut microbiota, melatonin and PH. Studies could also investigate whether microbiota genes play a role in the epigenetic aspects of PH. This is relevant because, e.g., dysbiosis (caused by epigenetic factors) could reduce melatonin signalling between the gut and lungs, reduce subcellular melatonin concentrations in the gut/lungs, or reduce melatonin serum levels secondary to epigenetic factors. PH is a fatal disease, and this essentially means that despite successful TB treatment thousands of patients are at risk of developing PH. Yet, there is no cure for PH and most developing countries do not have specialised PH drugs. Therefore, there is a need for research on better treatments for PH, particularly, in the post-TB context. We explored the potential of the repurposing of drugs for the treatment of PH especially in countries with resource limitations. Studies have demonstrated the benefits of medicinal plants against PH, most of which are of Indian or Asian descent. Africa is a rich source of multiple medicinal plants scientifically proven to counteract myriad pathologies. When perusing these studies one can notice that African medicinal plants afford biological effects that counteract the same molecular pathways (e.g., proliferation, vasoconstriction, inflammation, oxidative stress, and mitochondrial dysfunction) also involved in the pathogenesis of PH. Viable options include Aspalathus linearis, Allium sativium, Trifolium pratense L, Mimosa pigra L, and Aloe ferox. However, most of these plants have never been tested in an experimental PH model, and https://scholar.sun.ac.za 4 therefore, our proposition is hypothetical at the most. Regardless, we believe that future studies should investigate these and other African medicinal plants in appropriate models of PH, to test their efficacy and effectiveness. The relationship between PTLD and PH is complex and still requires several puzzles to be placed to fully understand it. The pathophysiology of PTLD that leads to PH, epidemiological factors and potential treatment options remains largely unexplored and are key areas for future research. Research into alternative and novel therapies is especially crucial as this has the potential to improve patient’s quality of life and clinical outcomes. Ultimately, further research will hopefully pave the way for the development of a comprehensive approach to PH prevention, detection and diagnosis, and treatment strategies.