Antiinflammatory effects of statins in patients with chronic obstructive pulmonary diseases

Uvod: Statini su inhibitori 3-hidroksi-3-metilglutaril koenzim A (HMG-CoA) reduktaze koji se primjenjuju za smanjenje sinteze endogenog kolesterola kod pojedinih vrsta hiperlipoproteinemija. Međutim, statini pokazuju i pleiotropne učinke te se smatra da utječu na upalu, oksidacijski stres, oslobađanje citokina i apoptozu pojedinih staničnih vrsta. Kronična opstrukcijska plućna bolest (KOPB) je kronična upalna bolest pluća sa sistemskom upalom te se smatra da bi lijekovi koji utječu na prisutni upalni proces mogli doprinjeti poboljšanju stanja u bolesnika s KOPBom. Hipoteza ovoga istraživanja je da statini posjeduju protuupalni učinak koji bi mogao usporiti progresiju KOPB-a. Metode: U istraživanje je bilo uključeno 100 bolesnika sa stabilnim KOPB-om, na terapiji statinima dulje od godinu dana (N=66) i bez terapije statinima (N=34). Svim bolesnicima je određena koncentracija citokina: IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p70, IFN-γ, TNF-α i TNF-β u plazmi metodom protočne citometrije. Relativni udio apoptoze i nekroze leukocita odnosno subpopulacija granulocita, limfocita i monocita određen je također metodom protočne citometrije. Spirometrijski, biokemijski i hematološki parametri određeni su u svih bolesnika. Rezultati: Citokini IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12p70 i TNF-α pokazali su statistički značajno smanjenje koncentracije u bolesnika s KOPB-om na terapiji statinima u odnosu na bolesnike s KOPB-om bez terapije statinima. Hijerarhijska klasterska analiza pokazala je nekoliko klastera u bolesnika s KOPB-om u skladu s vrijednostima citokina. Citokinski uzorci bili su u velikoj skupini pacijenata slični s umjerenim povećanjem vrijednosti citokina. Bolesnici s KOPB-om koji su uzimali statine pokazali su različit obrazac/uzorak citokina s nižim vrijednostima citokina. Koncentracije citokina nisu pokazale statistički značajnu razliku ovisno o podjeli bolesnika prema težini oboljenja odnosno GOLD stadiju. Statistički značajno snižene koncentracije citokina IL-4, IL-8 i IL-10 su bile prisutne u bolesnika s KOPB-om s povišenim ITM-om (> 25 kg/m2) u odnosu na bolesnike s normalnim ITM-om (20 – 25 kg/m2). U perifernoj krvi relativni udio svih leukocita, te subpopulacije limfocita i monocita u apoptozi pokazali su statistički značajno smanjenje u bolesnika s KOPB-om na terapiji statinima u odnosu na bolesnike s KOPB-om bez terapije statinima. Zaključak: Rezultati istraživanja pružaju uvid u pleiotropne učinke statina u bolesnika s KOPB-om. U ovom radu u bolesnika s KOPB-om, pored djelovanja statina na smanjenje koncentracije kolesterola i LDL-kolesterola, pokazali smo i pleiotropne učinke statina na koncentracije citokina, koji su ključni medijatori lokalne i sistemske upale u KOPBu, te na apoptozu leukocita periferne krvi. Mjerenje panela citokina, a ne samo pojedinog citokina, pruža uvid u karakteristične obrasce citokina u bolesnika s KOPB-om. Postoji prisutan Th1 (IL-2 i TNF-α) i Th2 (IL-4, IL-5, IL- 10) citokinski obrazac kod stabilnih bolesnika s KOPB-om.Background: Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used to reduce the endogenous cholesterol synthesis in some types of hyperlipoproteinemia. However, statins also show pleiotropic effects and are thought to affect inflammation, oxidative stress, release of cytokines and apoptosis of certain cell types. Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the lungs with systemic inflammation and it is considered that drugs that affect the present inflammatory process could contribute to improving the condition in patients with COPD. The hypothesis of this study is that statins possess an anti-inflammatory effect that could slow the progression of COPD. Methods: The study included 100 patients with stable COPD, who received statin therapy for longer than one year (N = 66) and no statin therapy (N = 34). Cytokine concentration of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12 p70, IFN-γ,TNF-α and TNF- β was measured in plasma by flow cytometry. The relative percentage of apoptotic and necrotic leukocytes, populations of granulocytes, lymphocytes and monocytes was determined by flow cytometry. Spirometry, biochemical and hematological parameters were determined in all patients. Results: Cytokines IL-1β, IL-2, IL-4, IL-8, IL-10, IL-12p70 and TNF-α showed a statistically significant decrease of concentrations in patients with COPD on statin therapy compared to patients without statin therapy. Hierarchical cluster analysis showed several clusters in COPD patients in accordance with cytokine values. Cytokine patterns were in a large group of patients similar with a moderate increase in the cytokine levels. COPD patients who received statins showed a different pattern of cytokines with lower cytokine values. Cytokine concentrations did not show a statistically significant difference depending on the severity of the disease, according to GOLD stages. A statistically significant decrease of cytokine levels IL-4, IL-8 and IL-10 was present in patients with COPD with a body mass index (BMI) > 25 kg/m2 compared to patients with normal BMI 20-25 kg/m2. In peripheral blood, the relative percentage of all leukocytes, as well as the lymphocyte and monocyte subpopulations in apoptosis, showed a statistically significant decrease in COPD patients on statin therapy compared with COPD patients without statin therapy. Conclusions: The results of the study provide an insight into pleiotropic effects of statins in patients with COPD. In our patients with COPD, the statins reduced cholesterol and LDL cholesterol levels, but we also demonstrated pleiotropic effects of statins on cytokines, both local and systemic inflammatory mediators in COPD as well as on apoptosis of peripheral blood leukocytes. The measurement of the cytokine panel, not just a single cytokine, provides an insight into cytokine patterns that are present in COPD patients. There is a Th1 (IL-2 i TNF-α) and Th2 (IL-4, IL- 5, IL-10) cytokine pattern present in stable COPD patients