Utjecaj sistemske upale na homeostazu željeza u egzacerbaciji i stabilnoj fazi kronične opstrukcijske plućne bolesti

doctoral thesis

• Title (english): Influence of systematic inflammation on iron homeostasis during exacerbation and stabile chronic obstructive pulmonary disease
• Author: Leida Tandara
• Mentor: Tihana Žanić Grubišić (mentor)
• Committee member: Lada Rumora (predsjednik povjerenstva)
• Committee member: Karmela Barišić (član povjerenstva)
• Committee member: Sanja Popović-Grle (član povjerenstva); MBZ: 9875674
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2016, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy
• Universal decimal classification (UDC): 615 - Pharmacology. Therapeutics. Toxicology

Abstract

Uvod: Glavni regulator sistemske homeostaze željeza je hepcidin, čiju sintezu reguliraju status željeza, upalni citokini, eritropoetska aktivnost, hipoksija i anemija. Cilj ovoga rada bio je ispitati povezanost između serumskog hepcidina i čimbenika koji ga reguliraju u skupini bolesnika s KOPB-om, da bi se ispitalo kako ovi čimbenici utječu na koncentraciju hepcidina i osiguravanje opskrbe željezom neophodnim za eritropoezu. Hipoteze istraživanja: koncentracija hepcidina u serumu bolesnika s KOPB-om promijenjena je u odnosu na kontrolnu skupinu i mijenja se tijekom egzacerbacije u odnosu na stabilnu fazu bolesti; na koncentraciju hepcidina u KOPB-u utječu upala i/ili hipoksija.
Metode i ispitanici: U istraživanje je bilo uključeno 40 bolesnika s KOPB-om i 30 zdravih ispitanika. U KOPB-u skupini parametri su longitudinalno praćeni u tri vremenske točke: u egzacerbaciji, fazi rezolucije i stabilnoj fazi bolesti. Svim ispitanicima određena je koncentracija hepcidina, pokazatelja statusa željeza (serumsko željezo, TIBC, saturacija transferina, feritin); pokazatelja upale (broj leukocita i neutrofilnih granulocita, IL-6 i CRP-a), eritropoetske aktivnosti (broj retikulocita, topivi transferinski receptor i eritropoetin) i koncentracija hemoglobina. Svim bolesnicima s KOPB-om određeni su parcijalni tlak kisika i saturacija hemoglobina kisikom kao pokazatelji hipoksije.
Rezultati: Serumska koncentracija hepcidina bila je povišena u egzacerbaciji i stabilnoj fazi KOPB-a u odnosu na kontrolnu skupinu, te je pozitivno korelirala s IL-6 i CRP-om. Koncentracija hepcidina je bila pozitivno povezana s feritinom i negativno s TIBC-om. Eritropoetska aktivnost, mjerena apsolutnim brojem retikulocita bila je u svim fazama istraživanja niža od kontrolne skupine, a negativna povezanost je pokazana u egzacerbaciji. Koncentracija hepcidina nije bila povezana s parametrima hipoksije. U kontrolnoj skupini hepcidin je korelirao samo s pokazateljima statusa željeza, negativno s TIBC-om i pozitivno s feritinom.
Zaključak: Istraživanje je pokazalo da prisutna sistemska upala i povišena razina IL-6 u egzacerbaciji i stabilnoj fazi KOPB-a mogu biti odgovorne za opaženi porast koncentracije hepcidina. Porast koncentracije hepcidina mogao bi biti povezan s restriktivnom eritropoezom koja se očituje sniženim brojem retikulocita u svim fazama istraživanja, kao i snižavanju koncentracije hemoglobina u stabilnoj fazi bolesti. Dobiveni rezultati pružaju uvid u dinamičke promjene metabolizma željeza i povezanosti s razinom hepcidina. Sistemska upala prisutna kod velikog broja bolesnika s KOPB-om jača kako bolest napreduje, te bi porast razine IL-6 mogao voditi do daljnjeg porasta koncentracije hepcidina.

Abstract (english)

Background: Hepcidin is the main regulator of systemic iron homeostasis, and its expression is modulated by iron status, hypoxia, erythroid factors and inflammation. The aim of this study was to examine a relationship between level of hepcidin and iron status, erythropoietic activity, hypoxia and inflammation in exacerbations and stable COPD. We hypothesized that hepcidin concentration is changed compared to control group and is changing in acute exacerbation compared to stable COPD; hepcidin concentration is substantially influenced by inflammation and/or hypoxia.
Methods: The study included 40 COPD patients and 30 healthy subjects. In COPD group parameters were longitudinally monitored at three time points: at exacerbation, on resolution and in stable disease. We determined concentration of hepcidin and hemoglobin; parameters of iron status: serum iron, total iron binding capacity (TIBC), ferritin and calculated transferrin saturation. Soluble transferrin receptors, reticulocyte number (Rtc), and regulatory hormone erythropoietin were measured as indicators of erythropoietic activity. Systemic inflammation was assessed by determination of CRP, IL-6, and number of white blood cells and neutrophils. In COPD group partial oxygen pressure and haemoglobin oxygen saturation were determined.
Results: Hepcidin was elevated in exacerbations and in a stable phase compared to the control group and we found positive correlations of hepcidin with inflammatory markers IL-6 and CRP. Hepcidin also correlated positively with ferritin and inversely with TIBC. Erythropoietic activity, measured by absolute Rtc number, was significantly reduced in COPD compared to the control group in all study phases, and negative correlation with hepcidin was established in exacerbation. In exacerbation and stable disease hepcidin correlated with ferritin and TIBC. No correlations were observed with indices of hypoxia. In the control group, positive associations were observed only with indices of iron status, positive with ferritin and negative one with TIBC.
Conclusion: This study shows that elevated values of IL-6 present in exacerbations and stabile COPD might be responsible for the observed increased hepcidin level. These might be associated with restricted erythropoiesis as shown by lower number of reticulocytes and decreased level of haemoglobin at the stable phase. The results obtained might provide new insights into dynamic changes of iron metabolism and its relation to hepcidin level in COPD. Systemic inflammation present in majority of COPD patients increases over time as disease progresses so raising of IL-6 level could lead to further up-regulation of hepcidin.

• Keywords: hepcidin; COPD; interleukin-6; sistemska upala; metabolizam željeza
• Keywords (english): hepcidin; COPD; interleukin-6; systemic inflammation; iron metabolism
• Language: croatian
• URN:NBN: urn:nbn:hr:163:078764
• Study programme: Title: Pharmacy and biochemistry; Study programme type: university; Study level: postgraduate; Academic / professional title: doktor znanosti (doktor znanosti)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2016-05-09 14:03:53