Characterising pathways that contribute to post-TB lung disease

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dc.contributor.advisorMaarman, Geralden_ZA
dc.contributor.advisorWindvogel, Shantalen_ZA
dc.contributor.authorJacobs, Steveen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.en_ZA
dc.date.accessioned2024-02-09T10:33:29Zen_ZA
dc.date.accessioned2024-04-27T01:11:20Zen_ZA
dc.date.available2024-02-09T10:33:29Zen_ZA
dc.date.available2024-04-27T01:11:20Zen_ZA
dc.date.issued2024-02en_ZA
dc.descriptionThesis (MSc)--Stellenbosch University, 2024.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Tuberkulose (TB) is 'n groot globale gesondheidsuitdaging, veral in lae- en middelinkomstelande (LMIC's). Post-tuberkulose longsiekte (PTLD) is 'n algemene en aftakelende gevolg van TB, wat kan lei tot chroniese respiratoriese simptome en verswakte longfunksie. Die patogenese van PTLD word nie goed verstaan nie, en baie moet nog ontdek word, hoewel sommige ander skrywers veronderstel het dat inflammasie 'n sleutelbydrae kan wees, ten spyte van suksesvolle voltooiing van TB-behandeling. Boonop dui die versameling van data daarop dat PTLD ook pulmonale hipertensie (PH) kan insluit. Laasgenoemde is 'n multi-orgaansiekte en hoogs morbiede kliniese toestand, met 'n wye reeks kliniese voorstellings en word veroorsaak deur 'n groot spektrum van onderliggende toestande. Die verhouding tussen PTLD en PH is kompleks en multifaktoriaal, wat gasheer-, omgewings- en patogeniese faktore insluit. Gegewe die inflammatoriese aard van TB, is dit waarskynlik dat proinflammasie kan bydra tot die ontwikkeling van PH post-TB, maar daar is tans geen data oor hierdie onderwerp nie. Dit is kommerwekkend, aangesien miljoene mense met TB leef, sterf nagenoeg 60 000 mense per jaar aan TB in Suid-Afrika, terwyl byna 600 nuwe gevalle van TB elke jaar aangemeld word. Gegewe hierdie konteks is dit kommerwekkend dat TB-pasiënte (hetsy vorige of huidige, of behandel) die risiko loop om verswakkende PTLD en dodelike PH te ontwikkel. Hierdie projek het ten doel gehad om die betrokkenheid van paaie wat kan bydra tot die ontwikkeling van PH in 'n post-TB-konteks af te baken, en om die paaie wat spesifiek tot PH bydra in dieselfde konteks te verken. In ons strewe het ons daarin geslaag om die instrumentele rolle van inflammatoriese weë as deel van PTLD-patogenese uit te lig. Ons nuwe bevindinge dui daarop dat daar 'n pro-inflammatoriese toestand is in aktiewe TB-pasiënte wat behandeling ontvang wat na TB voortduur, ongeag of hulle suksesvol vir TB behandel is. Die ongewone sirkulasiepatroon van inflammatoriese sitokiene kan toegeskryf word aan mitochondriale disfunksie in immuunselle. Met inagneming van die vernietigende aard van hierdie sitokiene, is daar 'n behoefte aan verdere navorsing om die implikasies van 'n aanhoudende pro-inflammatoriese toestand te ondersoek, aangesien dit pasiënte kan vatbaar vir PTLD. Wat PH betref, het ons talle padweë ondersoek wat kan lei tot PH, nou 'n nuwe sleutelkenmerk van PTLS. Ons oorsig van die literatuur het 'n verband tussen melatonien en PH as deel van PTLS getoon. Ons bevindinge toon ook dat melatonien 'n belangrike skakel is tussen die dermmikrobiota en die ontwikkeling van PH (waar onderdrukte melatonien-kruiskommunikasie tussen die dermkanaal en longe die ontwikkeling van PH kan bevorder). Meer studies is nodig om die verband tussen die dermmikrobiota, melatonien en PH te ondersoek. Studies kan ook ondersoek of mikrobiota-gene 'n rol speel in die epigenetiese aspekte van PH. Dit is relevant omdat bv. disbiose (veroorsaak deur epigenetiese faktore) melatoniensein tussen die ingewande en longe kan verminder, subsellulêre https://scholar.sun.ac.za 5 melatonienkonsentrasies in die derm/longe kan verminder, of melatonienserumvlakke sekondêr tot epigenetiese faktore kan verminder. PH is 'n dodelike siekte, en dit beteken in wese dat ondanks suksesvolle TB-behandeling duisende pasiënte die risiko loop om dit te ontwikkel. Tog is daar geen genesing nie en die meeste ontwikkelende lande het nie gespesialiseerde PH-middels nie. Daarom is daar 'n soeke na beter behandelings vir PH, veral in die post-TB konteks. Ons het die potensiaal van dwelmhergebruik vir lande met hulpbronbeperkings ondersoek. Studies het die voordele van medisinale plante teen PH getoon, maar waarvan die meeste plante van Indiese of Asiatiese afkoms is. Afrika is 'n ryk bron van veelvuldige medisinale plante wat wetenskaplik bewys is om talle patologieë teë te werk. Wanneer ’n mens hierdie studies bestudeer, let ons op dat Afrika se medisinale plante, biologiese effekte bied wat dieselfde molekulêre padweë teenwerk (bv. proliferasie, vasokonstriksie, inflammasie, oksidatiewe stres en mitochondriale disfunksie) wat ook betrokke is by die patogenese van PH. Lewensvatbare opsies sluit in Aspalathus linearis, Allium sativium, Trifolium pratense L, Mimosa pigra L en Aloe ferox. Die meeste van hierdie plante is egter nog nooit in 'n eksperimentele PH-model getoets nie, en daarom is ons voorstel hoogstens hipoteties. Ongeag, ons glo dat toekomstige studies hierdie en ander Afrikamedisinale plante in toepaslike modelle van PH moet ondersoek om hul doeltreffendheid en doeltreffendheid te toets. Die verhouding tussen PTLS en PH is kompleks en vereis steeds dat verskeie legkaarte geplaas moet word om dit ten volle te verstaan. Die patofisiologie van PTLS wat lei tot PH, epidemiologiese faktore en potensiële behandelingsopsies bly grootliks onontgin en is sleutelareas vir toekomstige navorsing. Navorsing na alternatiewe en nuwe terapieë is veral van kardinale belang aangesien dit die potensiaal het om pasiënt se lewenskwaliteit en kliniese uitkomste te verbeter. Uiteindelik sal verdere navorsing hopelik die weg baan vir die ontwikkeling van 'n omvattende benadering tot PH-voorkoming, opsporing en diagnose, en behandelingstrategieë.af_ZA
dc.description.versionMastersen_ZA
dc.format.extent178 pagesen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/130646en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshTuberculosis -- Pathogenesisen_ZA
dc.subject.lcshPulmonary hypertensionen_ZA
dc.subject.lcshPost-tuberculosis lung diseaseen_ZA
dc.subject.lcshInflammationen_ZA
dc.titleCharacterising pathways that contribute to post-TB lung diseaseen_ZA
dc.typeThesisen_ZA
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