| Abstract | Kronična opstrukcijska plućna bolest (KOPB) je složeni poremećaj koji zahvaća pluća, ali
i sistemski odjeljak. Naše se istraživanje temeljilo na hipotezi da je u bolesnika s KOPB-om
prisutna sistemska upala i sistemski oksidacijski stres. Sukladno tome, cilj ovog istraživanja
bio je istražiti sistemske pokazatelje oksidacijskih i upalnih promjena u bolesnika sa stabilnim
KOPB-om te ispitati povezanost sistemskih antioksidansa s poremećajem funkcije pluća i
biljezima sistemske upale. Ispitali smo i dijagnostičku učinkovitost biljega sistemskog
oksidacijskog stresa u razlikovanju zdravih i oboljelih od KOPB-a.
Sistemski biljezi oksidacijskog stresa (albumin, transferin, ceruloplazmin, ukupni bilirubin,
slobodne tiolne skupine, malondialdehid (MDA), paraoksonazna i arilesterazna aktivnost
paraoksonaze 1 (PON1), te ekspresija i aktivacija unutarstaničnih signalnih molekula Hsp27,
Hsp70, ERK, JNK i p38) određeni su u 106 bolesnika sa stabilnim KOPB-om i 45 zdravih
ispitanika. Ispitane su i njihove povezanosti s biljezima sistemske upale (CRP, fibrinogen,
ukupni leukociti), pušenjem i pokazateljima funkcije pluća (FEV1 i FEV1/FVC).
Bolesnici s KOPB-om su imali povišene koncentracije ceruloplazmina i MDA, snižene
koncentracije albumina, transferina i tiola, te snižene obje ispitane aktivnosti PON1.
Koncentracije ukupnog bilirubina nisu se razlikovale usporedbom ispitivanih skupina.
Ceruloplazmin je pokazao pozitivnu korelaciju s CRP-om i fibrinogenom. Albumin i
transferin su pokazali negativnu korelaciju s CRP-om, te pozitivnu korelaciju sa slobodnim
tiolima. Transferin je negativno korelirao s fibrinogenom. Jedini pokazatelj povezan s
funkcijom pluća bio je MDA. Usporedbom pušača, bivših pušača i nepušača iz skupine
bolesnika s KOPB-om nisu nađene razlike u koncentracijama promatranih biljega
oksidacijskog stresa i upale. Povišene koncentracije ceruloplazmina su najsnažniji prediktor
prisutnosti KOPB-a. Model koji uključuje ceruloplazmin, albumin, MDA i arilesteraznu
aktivnost PON1 te biljege sistemske upale pokazao je najbolju dijagnostičku učinkovitost u
predviđanju KOPB-a (AUC (95%CI) = 0,96 (0,92 – 0,99)). Predloženi bi model mogao
ispravno predvidjeti prisutnost KOPB-a u 89% bolesnika. Također, naši su rezultati ukazali da
je razina ekspresije Hsp27 i Hsp70 u leukocitima periferne bila je najniža u pušača s KOPBom.
Ekspresija svih ispitivanih MAPK (ERK, JNK i p38) u perifernim leukocitima bolesnika
s KOPB-om nije se razlikovala u usporedbi sa zdravim ispitanicima. Aktivacija ERK bila je
značajnija kod zdravih i bolesnih nepušača, dok je aktivacija JNK i p38 bila najizraženija u
pušača s KOPB-om.
Rezultati su ukazali da prisutnost bolesti i pušenje utječu na ispitane unutarstanične
signalne molekule. Bolje razumijevanje ovih molekularnih mehanizama moglo bi pomoći u
dijagnozi i pronalaženju novih terapijskih meta za KOPB. Dijagnostičke karakteristike
predloženog modela koji kombinira koncentracije biljega sistemske upale i sistemskog
oksidacijskog stresa ukazuju da bi se on mogao koristiti kao vrijedan alat u razlikovanju
zdravih ispitanika i bolesnika s KOPB-om. |
| Abstract (english) | Background: Chronic obstructive pulmonary disease (COPD) is a complex disorder
affecting the lungs and the systemic compartment. We hypothesized that systemic
inflammation and systemic oxidative stress are present in patients with COPD. Therefore, we
aimed to investigate markers of systemic oxidative and inflammatory alterations in patients
with stable COPD, and to test the association of systemic antioxidants with indicators of lung
function and systemic inflammation. The diagnostic accuracy of systemic oxidative stress
parameters in distinguishing between healthy subjects and patients with COPD was also
evaluated.
Materials and methods: Systemic oxidative stress markers (albumin, transferrin,
ceruloplasmin, total bilirubin, thiols, malondialdehyde (MDA), paraoxonase and arylesterase
activity of paraoxonase 1 (PON1), and the expression and activation of intracellular signalling
molecules Hsp27, Hsp70, ERK, JNK i p38) were assessed in 106 stable COPD patients and
45 healthy subjects. Their association with systemic inflammatory markers (CRP, fibrinogen,
total leukocytes), smoking status and lung function parameters (FEV1 i FEV1/FVC) was
investigated.
Results: Higher ceruloplasmin and MDA concentrations, and lower albumin, transferrin,
thiols and PON1 activities (paraoxonase and arylesterase) were found in patients with COPD.
Total bilirubin concentrations were similar in the studied groups. Ceruloplasmin showed a
positive correlation with CRP and fibrinogen. Albumin and transferrin showed a negative
correlation with CRP, and a positive corelation with thiols. Transferrin negatively correlated
with fibrinogen. Only MDA showed an association with pulmonary function. No differences
were found comparing concentrations of oxidative stress and inflammatory markers between
COPD patients subdivided according to their smoking status. Ceruloplasmin was the strongest
single predictor of COPD. The model combining ceruloplasmin, albumin, MDA, arylesterase
PON1 activity, and markers of systemic inflammation demonstrated very good diagnostic
performances (AUC (95%CI) = 0,96 (0,92 – 0,99)). The proposed model correctly identifies
89% of patients with COPD. In addition, our results showed that the decrease in expression of
peripheral blood leukocytes' Hsp27 and Hsp70 was the most prominent in COPD smokers.
Expression levels of all three MAPKs investigated was not altered in leukocytes of COPD
patients compared to healthy subjects. However, ERK activation was stimulated in healthy and COPD non-smokers, while JNK and p38 activation was the most pronounced in COPD
smokers.
Conclusions: Our results showed that COPD and smoking affect the intracellular
signalling pathways investigated. Improved understanding of these molecular mechanisms
could help identify novel targets for diagnosis and therapeutic interventions in COPD.
Diagnostic characteristics of the proposed model, obtained by combining markers of systemic
inflammation and systemic oxidative stress, suggest its potential value as an additional tool in
COPD diagnosis. |
