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Title:MODELNA SIMULACIJA VPLIVA ASPIRINA NA PRODUKCIJO EIKOZANOIDOV V LEVKOCITIH
Authors:ID Maglica, Samo (Author)
ID Fajmut, Aleš (Mentor) More about this mentor... New window
ID Dobovišek, Andrej (Comentor)
Files:.pdf UNI_Maglica_Samo_2013.pdf (1,41 MB)
MD5: D5800E089DDE6FE1CA386E8C3E23AC64
PID: 20.500.12556/dkum/07e1607f-8824-4fee-aa19-ee7a945ec30a
 
Language:Slovenian
Work type:Undergraduate thesis
Typology:2.11 - Undergraduate Thesis
Organization:FNM - Faculty of Natural Sciences and Mathematics
Abstract:V diplomskem delu apliciramo fizikalno-matematični model presnove arahidonske kisline (AA) na razlago pojava aspirinsko inducirane astme oz. aspirinske intolerance. Aspirinska intoleranca je vnetna bolezen zgornjih in spodnjih dihalnih poti, ki prizadene aspirinsko intolerantne astmatike. Klinični znaki aspirinske intolerance se pojavijo po zaužitju aspirina ali kakšnega drugega nesteroidnega antirevmatika (NSAR). V delu opišemo in nato v nekaterih podrobnostih dopolnimo že obstoječ matematični model presnove AA, ki je plod izvirnega raziskovalnega dela članov Oddelka za fiziko na FNM UM. Omenjeni model nadgradimo z upoštevanjem ireverzibilne vezave aspirina na dva encima, ki ju aspirin inhibira. To sta encima prostaglandin H sintaza 1 in 2 (PGHS1 in PGHS2). Originalni model namreč upošteva, da se NSAR reverzibilno veže na encima in ju inhibira, kar velja za večino NSAR, ne velja pa za aspirin. Le-ta se na omenjena encima kovalentno veže in ju s tem trajno onemogoči. Z modelom realistično napovemo časovne poteke koncentracij prostaglandinov in levkotrienov v odvisnosti od različnih oralno zaužitih doz aspirina ter določimo mejne doze in napovemo čas trajanja bronhokonstrikcije po zaužitju tipičnih doz aspirina pri aspirinsko intolerantnih astmatikih. Napoved časa trajanja bronhokonstrikcije in mejnih doz temelji na izračunu razmerja med koncentracijama prostaglandina E2 (PGE2) in levkotriena C4 (LTC4). Za aspirinsko intolerantne astmatike je značilno, da je to razmerje pred in po zaužitju aspirina manjše od ena, medtem ko je za zdrave osebke in za aspirinsko tolerantne astmatike vselej večje od ena. Vzrok za to naj bi bile spremenjene ekspresije encimov PGHS1 in PGHS2 ter encima levkotrien C4 sintaze (LTC4S). Po originalnem modelu povzamemo opis različnih populacij, ki se razlikujejo po ekspresijah teh encimov, izvedemo modelne simulacije in primerjamo dobljene rezultate.
Keywords:aspirinska intoleranca, arahidonska kislina, levkotrieni, prostaglandini, matematični model, astma, aspirin, inhibicija encimov
Place of publishing:Maribor
Publisher:[S. Maglica]
Year of publishing:2013
PID:20.500.12556/DKUM-40477 New window
UDC:53(043.2)
COBISS.SI-ID:19917064 New window
NUK URN:URN:SI:UM:DK:GDVX6ELW
Publication date in DKUM:12.06.2013
Views:2278
Downloads:213
Metadata:XML DC-XML DC-RDF
Categories:FNM
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Secondary language

Language:English
Title:MODEL SIMULATIONS OF THE EFFECT OF ASPIRIN ON EICOSANOID PRODUCTION IN LEUKOCYTES
Abstract:The mathematical model of arachidonic acid (AA) metabolism is applied to the study of aspirin induced asthma or aspirin intolerance. Aspirin intolerance is an inflammatory disease of upper and lower airways that affects aspirin intolerant asthmatics. Clinical signs of aspirin intolerance occur after ingestion of aspirin or any other non-steroidal anti-inflammatory drug (NSAID). The original mathematical model of AA metabolism, published by the members of the Department of physics FNM UM, is upgraded here by taking into account the irreversible inhibition of two enzymes in the cyclooxygenase pathway by aspirin. These are prostaglandin H synthase 1 and 2 (PGHS1 and PGHS2). The original model describes only the reversible inhibition of the enzymes by NSAID. Such description is valid for all NSAIDs except for the aspirin. Aspirin binds covalently with both enzymes and inhibits them permanently. By the model we predict the time dependencies of prostaglandin and leukotriene concentrations with respect to different oral doses of aspirin, limiting doses of aspirin and the duration of bronchoconstriction in case of aspirin induced asthma. The prediction of the duration of bronchoconstriction and the limiting doses is based on the calculation of the ratio between the concentrations of prostaglandin E2 (PGE2) and leukotriene C4 (LTC4). For aspirin intolerant asthmatics the typical value of this ratio before and after ingestion of aspirin is lower than one whereas for healthy subjects and aspirin tolerant asthmatics it is always higher than one. The origin of the differences between aspirin intolerant and tolerant asthmatics is altered expression of the enzymes PGHS1, PGHS2 and leukotriene C4 synthase (LTC4S). Different populations, which are similar to those in the original model, are considered in the model simulations and analysis.
Keywords:aspirin intolerance, arachidonic acid, leukotrienes, prostaglandins, mathematical model, asthma, aspirin, enzyme inhibition


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