Modulatori metabolizma arahidonske kiseline u procesu inflamacije: uticaj odabranih polifenola na produkciju prostaglandina E2 i tromboksana A2

Abstract

Inflamacija predstavlja imuni odgovor organizma na povredu i rezultuje oporavkom organizma. Ukoliko se naruši mehanizam imunog odgovora, inflamacija postaje hronična, a kao takva, doprinosi patogenzi nekih od najtežih bolesti današnjice. Usled nedovoljne aktivnosti i/ili kontraindikacija postojećih anti-inflamatornih lekova, intenzivno se traga za novim terapeuticima, a prirodni proizvodi predstavljaju jedne od potencijalnih, bezbednih anti-inflamatornih agenasa. Sa druge strane, eikozanoidi, proizvodi metabolizma arahidonske kiseline, imaju važnu ulogu u fiziološkim i patofiziološkim procesima, a naročito u inflamaciji. U fokusu ovih istraživanja, bila su dva eikozanoida: prostaglandin E2 i tromboksan A2, jedni od najvažnijih proizvoda ciklooksigenaznog puta metabolizma arahidonske kiseline. Naime, ispitivan je potencijal polifenolnih jedinjenja, ekstrakata bokvica i uzoraka Merlo vina (kao bogatih izvora polifenola) da inhibiraju produkciju prostaglandina E2 i tromboksana A2 u procesu inflamacije, kao i uticaj ispitivanih uzoraka na ekspresiju mRNK enzima koji su uključeni u sintezu prostaglandina E2 i tromboksana A2. Kao model sitem korišćena jekontinualna ćelijska linija humanih monocita i makrofaga (U937). Dobijeni rezultati pokazuju da modulacija ciklooksigenaznog puta metabolizma arahidonske kiseline može da bude jedan od mehanizama anti-inflamatornog delovanja bokvica i vina. Tokom homeostaze, luteolin i luteolin-7-O-glukuronid su bili najpotentniji inhibitori produkcije prostaglandina E2 i tromboksana A2. U ranim fazama inflamatornog procesa, kao najbolji inhibitor produkcije prostaglandina E2 izdvojio se pterostilben, dok su galna i ursolna kiselina, apigenin, luteolin-7-O-glukozid i rezveratrol najviše inhibirali sintezu tromboksana A2. Takođe, polifenolna jedinjenja mogu da moduliraju metabolizam arahidonske kiseline i na nivou ekspresije mRNK enzima uključenih u sintezu prostaglandina E2 i tromboksana A2. U model sistemu kasnije faze inflama tornog odgovora, fenolne kiseline najbolje inhibiraju produkciju prostaglandina E2, a rezveratrol, galna i kafena kiselina tromboksana A2. Različiti nivoi i mehanizmi aktivnosti ispitanih polifenola ukazuju na potrebu za daljim ispitivanjima potencijalnog sinergističkog delovanja polifenola u cilju povećanja efikasnosti inhibicije produkcije prostaglandina E2 i tromboksana A2 u procesima inflamacije .

Inflammation is immune response to damage, which results in the recovery of organism. If the mechanism of immune response is dysregulated, inflammation becomes chronic. Chronic inflammation is involved in som e of the most severe diseases of the modern age. Numerous anti-inflammatory drugs are currently approved, but due to their low activity or contraindications an intensive research on new drugs is ongoing, and natural compounds are one of the possible, safe anti-inflammatory agents. On the other h and, eicosanoids, products of arachidonic acid metabolism, have an important role in physiological and pathophysiological processes, particularly inflammation. In the focus of this study were prostaglandin E2 (PGE2) and thromboxane A2 (TXA2), one of the most important products of the cyclooxygenase pathway of arachidonic acid metabolism. Namely, the potential of polyphenols, as well as Plantago extracts and Merlot wine (a rich sources of polyphenols), to inhibit the production of PGE2 and TXA2 in infammation processes was investigated, followed by determination of their effect on expression of mRNA of the enzymes involved in synthesis of PGE2 and TXA2. In vitro model system, U937 monocytes and macrophages were used. Obtained results showed that modulation of cyclooxygenase pathway of arachidonic acid metabolism could be one of the mechanism of anti-inflammatory action of Plantago species and wine. During homeostasis, luteolin and luteolin-7-O-glucuronide were the most potent inhibitors of PGE2 and TXA2 production. During the initial phase of inflammation, pterostilbene showed the best potential in reduction of PGE2 production, while apigenin, luteolin-7-O-glucoside, resveratrol, gallic and ursolic acid were the most powerful inhibitors of TXA2 synthesis. Moreover, polyphenols modulate arachidonic acid metabolism at the mRNA expression level related to enzymes involved in the production of PGE2 and TXA2. In the late phase of inflammation, PGE2 production was greatly suppressed by phenolic acids, while resveratrol, gallic, and caffeic acid were the best modulators of TXA2 production. Polyphenols could exert influence on PGE2 and TXA2 production on different levels and through different mechanisms. Therefore, in order to obtain more effective inhibitors of PGE2 and TXA2 production in inflammation, further studies on potential synergistic effect of polyphenols are necessary.