20.500.12556/DKUM-80951 The endocannabinoid system in asthma patients and the effect of cannabinoids in the modulation of inflammatory response Endokanabinoidni sistem pri bolnikih z astmo in vpliv kanabinoidov na modulacijo vnetnega odziva. Asthma is a chronic inflammatory condition characterised by intermittent and reversible airflow obstruction caused by inflammation, bronchospasm, and increased airway secretions. Questions about the endocannabinoid system’s function in asthma pathogenesis have arisen as evidence grows, demonstrating it is a native modulator of immune functions. The main goal of this study was to genetically characterise the endocannabinoid system in naive asthma patients and determine if there is a relationship between endogenous cannabinoids and their inflammatory response. We studied a case-control cohort of 353 patients with mild/moderate persistent asthma and 276controls. The mRNA expression levels of the selected genes were quantified in peripheral blood mononuclear cells (PBMCs) and N-acylethanolamines (NAEs) quantified from plasma samples. Our results revealed that the genes for CB1 (CNR1) andCB2 (CNR2), along with genes for the enzymes NAPE-PLD (NAPEPLD), Abhd4(ABHD4) and MAGL (MGLL) were up-regulated in asthma patients and associated with their clinical and inflammatory condition. In addition, two of the genotyped polymorphisms located in the CNR2 gene were also associated with worse clinical symptoms. Palmitoylethanolamide (PEA) levels were lower and significantly different between allergic asthma patients and the control group and associated with worse clinical symptoms. Furthermore, our findings indicate that asthma patients with highCNR1mRNA expression levels at the time of diagnosis, treated with LTA, have better treatment response, while asthma patients with highCNR1mRNA expression levels, treated with ICS, had worse treatment response. Long-term ICS or LTRA therapy reduced mRNA expression ofCNR1together withIL4andIL5.It is evident from these findings that the endocannabinoid system plays a role in asthma, but it is not possible to determine whether this up-regulation is a cause or a result of the condition. Nonetheless, our findings add to a better understanding of the endocannabinoid system’s significance in asthma pathogenesis. Astma je kronično vnetno obolenje, za katero je značilna občasna in reverzibilna obstrukcija dihalnih poti, ki jo povzročajo vnetje, bronhospazem in povečano izločanje v dihalnie poti. Vprašanja o delovanju endokanabinoidnega sistema v patogenezi astme so se pojavila z vse številčnejšimi dokazi o tem, da je le-ta naravni modulator imunskih funkcij. Glavni cilj te študije je bil na genetski ravni opisati endokanabinoidni sistem pri naivnih bolnikih z astmo in ugotoviti, ali obstaja povezava med endogenimi kanabinoidi in njihovim vnetnim odzivom. Proučevali smo kohorto s 353 bolniki z blago/zmerno persistentno astmo in 276 zdravih kontrol. Ravni izražanja mRNA so bile kvantificirane v mononuklearnih celicah periferne krvi (PBMC), N-aciletanolamin (NAE) pa je bil kvantificiran v vzorcih krvne plazme. Naši rezultati so pokazali, da je izražanje CB1 (CNR1) in CB2 (CNR2), kot tudi genov za encime NAPE-PLD (NAPEPLD), ABHD4 ( ABHD4) in MAGL (MGLL), povečano pri bolnikih z astmo in povezano z njihovim kliničnim in vnetnim stanjem. Poleg tega sta bila genotipizirana dva polimorfizma, ki se nahajata v genu CNR2, povezana tudi s slabšimi kliničnimi simptomi. Ravni palmitoiletanolamida (PEA) so nižje in so se značilno razlikovale med bolniki z alergijsko astmo in kontrolno skupino ter so povezane s slabšimi kliničnimi simptomi. Poleg tega naše ugotovitve kažejo na to, da imajo bolniki z astmo zdravljeni z LTRA in z visoko ravnjo izražanja mRNA CNR1 v času diagnoze, boljši odziv na zdravljenje, medtem ko imajo bolniki z astmo z visokimi ravnmi izražanja mRNA CNR1 slabši odziv na zdravljenje z ICS. Dolgotrajna terapija z ICS ali LTRA je zmanjšala izražanje mRNA CNR1 kot tudi z IL4 in IL5. Iz teh ugotovitev sledi, da ima endokanabinoidni sistem vlogo pri astmi, vendar ni mogoče ugotoviti, ali je to povečano izražanje vzrok ali posledica obolenja. Kljub temu naše ugotovitve prispevajo k boljšemu razumevanju pomena endokanabinoidnega sistema v patogenezi astme. Asthma Endocannabinoid system Cannabinoids Inflammation Molecular genetics Astma endokanabinoidni sistem kanabinoidi vnetje molekularna genetika true true false Angleški jezik Slovenski jezik Doktorsko delo/naloga 2021-11-25 10:11:37 2024-03-18 10:12:19 2024-03-19 03:27:29 0000-00-00 00:00:00 2021 0 Maribor 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 189229315 DOK_Esteves_Pinto_Kozmus_Carina_2023.pdf DOK_Esteves_Pinto_Kozmus_Carina_2023.pdf 1 476F0B2C898A3E7052A3FA6B26544D83 7cebe93a92d5944fbc4a80152ec9f20e4517a963b1c9738baf9d39a14efd374b 6b1d0366-6828-11ee-896e-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=173491 Medicinska fakulteta 0 0 0