Resea ch A icle
Glycop o ein YKL-40 Le els in Plasma A e Associa ed wi h
Fib o ic Changes on HRCT in Asbes os-Exposed Subjec s
Tuija Väänänen,
1
Lau i Leh imäki,
2
Ka iina Vuol eenaho,
1
Ma i Hämäläinen,
1
Panu Oksa,
3,4
Tuula Vie ikko,
5
Ri a Jä enpää,
5
Jukka Ui i,
3,4,6
Hannu Kankaan an a,
2,7
and Ee a Moilanen
1
1
The Immunopha macology Resea ch G oup, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e and Tampe e Uni e si y
Hospi al, P.O. Box 100, 33014 Tampe e, Finland
2
Alle gy Cen e, Tampe e Uni e si y Hospi al and Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, P.O. Box 100,
33014 Tampe e, Finland
3
Clinic o Occupa ional Medicine, Tampe e Uni e si y Hospi al, P.O. Box 486, 33101 Tampe e, Finland
4
Finnish Ins i u e o Occupa ional Heal h, P.O. Box 486, 33101 Tampe e, Finland
5
Depa men o Radiology, Tampe e Uni e si y Hospi al, P.O. Box 2000, 33521 Tampe e, Finland
6
Occupa ional Heal h, Facul y o Medicine and Li e Sciences, Uni e si y o Tampe e, P.O. Box 100, 33014 Tampe e, Finland
7
Depa men o Respi a o y Medicine, Seinäjoki Cen al Hospi al, 60220 Seinäjoki, Finland
Co espondence should be add essed o Ka iina Vuol eenaho; ka iina. uol eenaho@u a.fi
Recei ed 2 Decembe 2016; Re ised 5 Ap il 2017; Accep ed 12 Ap il 2017; Published 14 May 2017
Academic Edi o : Dianne Coope
Copy igh © 2017 Tuija Väänänen e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License,
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
YKL-40 is a chi inase-like glycop o ein p oduced by al e na i ely ac i a ed mac ophages ha a e associa ed wi h wound healing
and fib osis. Asbes osis is a ch onic asbes os-induced lung disease, in which inju y o epi helial cells and ac i a ion o al eola
mac ophages lead o enhanced collagen p oduc ion and fib osis. We s udied i YKL-40 is ela ed o inflamma ion, fib osis, and/o
lung unc ion in subjec s exposed o asbes osis. Venous blood samples we e collec ed om 85 men wi h mode a e o hea y
occupa ional asbes os exposu e and om 28 heal hy, age-ma ched con ols. Le els o plasma YKL-40, CRP, IL-6, adipsin, and
MMP-9 we e measu ed wi h enzyme-linked immunoso ben assay (ELISA). Plasma YKL-40 le els we e significan ly highe in
subjec s wi h asbes osis (n=19) han in hose wi h no fib o ic findings in HRCT ollowing asbes os exposu e (n=66)o in
unexposed heal hy con ols. In asbes os-exposed subjec s, plasma YKL-40 co ela ed nega i ely wi h lung unc ion capaci y
pa ame e s FVC (Pea son’s −0.259, p=0018) and FEV
1
(Pea son’s −0.240, p=0028) and posi i ely wi h CRP (Spea man’s
ho 0.371, p<0001), IL-6 (Spea man’s ho 0.314, p=0003), adipsin (Spea man’s ho 0.459, p<0001), and MMP-9 (Spea man’s
ho 0.243, p=0025). The p esen finding sugges s YKL-40 as a bioma ke associa ed wi h fib osis and inflamma ion in asbes os-
exposed subjec s.
1. In oduc ion
Asbes osis is a ch onic in e s i ial fib osing lung disease
de eloping slowly a e exposu e o asbes os fibe s. As he
clea ance o hese fibe s is e y slow, exposu e o asbes os
can lead o ch onic inflamma o y changes and e en ually o
clinically de ec able fib osis a e a la en pe iod. In he
pa hogenesis o asbes osis, fib osis is loca ed fi s a he si e
o asbes os bodies, whe e mac ophages accumula e and
inflamma o y eac ion akes place, ollowed by a mo e
diffuse fib osis in he lungs, which is cha ac e ized by
apop osis o epi helial cells, fib oblas p oli e a ion, and
collagen deposi ion [1].
Asbes osis is classified as a a e disease by O phane
po al o a e diseases [2] (i.e., i is affec ing less han one
pe son pe 2000 in he Eu opean popula ion, as defined
by he EU Commission Public Heal h Policy on Ra e
Diseases [3]). In wes e n coun ies, he use o asbes os
Hindawi
Media o s o Inflamma ion
Volume 2017, A icle ID 1797512, 7 pages
h ps://doi.o g/10.1155/2017/1797512
has been banned o es ic ed in he de eloped coun ies
s a ing om 1990s: asbes os is no anymo e used in con-
s uc ion wo k oday, and he isks o asbes os fibe s in
eno a ion a e acknowledged [4, 5]. As fib osis mani es s
15 o 40 yea s a e exposu e o asbes os and highes le el
o asbes os use ook place in he 1970s and 1980s in Eu o-
pean coun ies, peak in he incidence o asbes os- ela ed
diseases is now le elling off[1, 4]. In con as , asbes os
use is s ill significan o inc easing in coun ies such as
B azil, China, India, I an, Kazakhs an, Russia, Thailand,
and Uk aine [4]. The Wo ld Heal h O ganiza ion
(WHO) has es ima ed ha abou 125 million people a e
s ill exposed o asbes os a he wo kplace and hal o he
dea hs om occupa ional cance a e caused by asbes os
[5, 6]. Measu es o p e en exposu e o asbes os a e he
mos efficien way o elimina e hese diseases, bu he
WHO calls also o imp o emen s in diagnos ics and
ea men . In es iga ion o inflamma o y and fib o ic p o-
cesses in asbes osis is needed o allow d ug de elopmen
and o find no el bioma ke s o diagnose and ollow up
hese diseases [6].
YKL-40, a chi in-binding glycop o ein wi hou he ca a-
ly ic ac i i y cha ac e is ic o he ue chi inases, is ela ed
o a ious inflamma o y and issue- emodeling diseases.
YKL-40 and i s homologues a e known by a ious names
such as chi inase-3-like p o ein 1 (Chi3-l1), b eas eg ession
p o ein 39 (BRP-39), human ca ilage glycop o ein 39 (HC
gp-39), and chond ex [7, 8]. YKL-40 has been shown o asso-
cia e wi h fib osis and mac ophage ac i a ion [8–10].
Inc eased ci cula ing le els o YKL-40 we e epo ed in
fib o ic li e disease: high YKL-40 le els a e associa ed wi h
his ologically mo e se e e fib o ic changes in ch onic alco-
holic hepa i is, p ima y bilia y ci hosis, au oimmune
hepa i is-induced ci hosis, and hepa i is C [11–14], and
YKL-40 was desc ibed as a ma ke o ea men esponse in
in e e on- ea ed pa ien s wi h hepa i is C [14]. High YKL-
40 le els ha e also been shown o associa e wi h a ious
o ms o in e s i ial lung diseases (ILD), such as idiopa hic
pulmona y fib osis (IPF), idiopa hic nonspecific in e s i ial
pneumonia (iNSIP), and c yp ogenic o ganizing pneumoni-
is (COP) [15–17]. The aim o he p esen s udy was o in es-
iga e he hypo hesis ha YKL-40 is ela ed o inflamma ion,
fib osis, and/o lung unc ion in asbes os-exposed subjec s.
2. Ma e ials and Me hods
2.1. Subjec s. The s udy subjec s (one hund ed and eigh een
men) we e ec ui ed among indi iduals wi h known his o y
o mode a e o hea y occupa ional exposu e o asbes os
who we e he e o e ollowed up a he Clinic o Occupa ional
Medicine a Tampe e Uni e si y Hospi al [18]. All o hem
we e nonsmoke s o had qui o e fi e yea s p e iously.
Thi y- h ee men we e excluded due o mee ing he exclu-
sion c i e ia ha we e as hma o as hma medica ion,
FEV
1
/FVC <0.7, and b onchiec asis o emphysema on
high- esolu ion compu ed omog aphy (HRCT) o he
ches . The emaining 85 men o med he asbes os-
exposed g oup in he s udy, and hey we e u he di ided
in o wo g oups acco ding o he HRCT findings: 66 had
no mal lung pa enchyma (HRCT class 0) o only mino
bo de line fib o ic findings (HRCT class 1), and 19 had
bila e al pa enchymal fib osis, ha is, asbes osis (HRCT
classes 2–5), see below. The con ol g oup was ec ui ed
om he communi y and consis ed o 28 heal hy non-
smoking men wi h no espi a o y symp oms and no mal
lung unc ion. This s udy was app o ed by he E hics
Commi ee o Tampe e Uni e si y Hospi al. All he
subjec s ga e hei w i en in o med consen .
2.2. HRCT. HRCT was scanned (Siemens Soma om Plus 4;
Siemens Medical, E langen, Ge many) wi h 1 mm slices
aken a 3 cm in e als using imaging pa ame e s o 130–
140 kV and 100–111 mA. The HRCT images we e sco ed
using consensus eading by wo expe ienced ho acic adiol-
ogis s as desc ibed p e iously [19, 20]. Findings indica ing
in e s i ial lung fib osis (sep al hickening, subpleu al lines,
pa enchymal bands, o honeycombing) in bo h lungs we e
semiquan i a i ely sco ed acco ding o a scale o classes om
0 o 5. Class 0 ep esen s no mal pa enchymal finding, class 1
ep esen s bo de line pa enchymal finding wi h mino
spo adic changes only, and classes 2 o 5 ep esen mild o
ex eme diffuse pulmona y fib osis [19].
2.3. Measu emen s o Ci cula ing Bioma ke s. Venous blood
samples we e d awn, and plasma/se um samples we e s o ed
a −70
°
C un il analyzed. Enzyme-linked immunoso ben
assay (ELISA) was pe o med using comme cial eagen s
o YKL-40, adipsin, MMP-9, CRP (R&D Sys ems Eu ope
L d., Abingdon, U.K.), and IL-6 (Sanquin, Ams e dam, The
Ne he lands).
2.4. S a is ical Analysis. Dis ibu ion o plasma YKL-40 was
skewed (Kolmogo o -Smi no ’s es ), and log ans o ma-
ion was used in s a is ical calcula ions o gua an ee no mally
dis ibu ed da a when needed. Co ela ions we e calcula ed
using Pea son’s be ween no mally dis ibu ed a iables
and Log-YKL-40 and by using Spea man’s ho be ween
nonno mally dis ibu ed a iables and YKL-40. No mally
dis ibu ed da a a e p esen ed as mean (SD) and skewed da a
as median (in e qua ile ange, IQR). Compa ison be ween
g oups was pe o med wi h unpai ed - es , Mann–Whi ney
U es , o one-way ANOVA wi h leas significan diffe ence
(LSD) pos es whe e app op ia e. p alues less han 0.05
we e conside ed significan . SPSS S a is ics 23 so wa e (SPSS
Inc., Chicago, IL, USA) was used in he s a is ical analysis.
3. Resul s
Subjec cha ac e is ics, lung unc ion pa ame e s, and ci cu-
la ing concen a ions o inflamma o y and fib osis ma ke s
a e gi en in Table 1. Based on HRCT findings, 66 o he 85
asbes os-exposed subjec s had no mal lung pa enchyma
(HRTC class 0) o only mino bo de line fib o ic changes
(HRTC class 1) and 19 had bila e al pa enchymal fib osis,
ha is, asbes osis (HRCT classes 2–5) [20]. Asbes os-
exposed subjec s wi h asbes osis we e olde han exposed
subjec s wi hou fib o ic changes (p=0015, Table 1). How-
e e , he e was no diffe ence in he ime since he beginning
o he exposu e be ween hese wo g oups (Table 1) and
2 Media o s o Inflamma ion
YKL-40 did no co ela e wi h age ( =0102,p=0355,
Table 2). In subjec s wi h asbes osis, diffusing capaci y o
ca bon monoxide (D
L,CO
) was dec eased by 18% compa ed
o asbes os-exposed subjec s wi hou HRCT findings, bu
he e was no diffe ence be ween hese g oups in FVC o
FEV
1
. Adipsin and MMP-9 le els we e inc eased in subjec s
wi h asbes osis (Table 1).
Plasma YKL-40 concen a ion (median and IQR) was
highe in subjec s wi h asbes osis (64.4, 35.1–138.1 ng/ml)
han in asbes os-exposed subjec s wi hou asbes osis
(36.4, 27.3–76.7 ng/ml, p=0033) o in unexposed con ols
(32.8, 23.5–59.3 ng/ml, p=0008), as p esen ed in Figu e 1.
In asbes os-exposed subjec s, fib o ic changes de ec ed on
HRCT a ied om 0 o 4, and in 32 o he 85 subjec s,
no changes we e obse ed (i.e., we e classified as 0).
YKL-40 showed a posi i e co ela ion wi h he deg ee
o de eloping/fib o ic changes ( om 0.5 o 4, n=53,
ho = 0.392, p=0005).
To u he in es iga e he associa ion o YKL-40 wi h
asbes osis, we assessed he co ela ions be ween YKL-40
and lung unc ion indices, inflamma o y, and fib osis
ma ke s (Table 2). YKL-40 was ound o co ela e nega i ely
wi h lung unc ion capaci y pa ame e s FVC and FEV
1
(Figu e 2) and posi i ely wi h inflamma ion ma ke s CRP
and IL-6, as well as wi h fib osis ma ke s adipsin and
MMP-9, adipsin showing he s onges co ela ion
( ho = 0.459, p<0001, Figu e 3).
4. Discussion
To ou knowledge, he p esen s udy is he fi s o show
inc eased plasma YKL-40 le els in subjec s wi h asbes osis.
Ci cula ing YKL-40 le els we e significan ly highe in sub-
jec s wi h asbes osis compa ed o subjec s who did no
de elop lung fib osis a e mode a e o hea y exposu e o
asbes os o o heal hy con ols. Mo eo e , in he subjec s
Table 1: Subjec cha ac e is ics.
Exposed Unexposed
No fib osis Asbes osis Heal hy con ols
N66 19 28
Age (yea s) 64.5 (6.2) 68.5 (6.0) p=0015 62.2 (6.6)
Time since he beginning o he exposu e (yea s) 43.6 (0.9) 46.2 (3.4) p=0464
FVC (% p ed) 88.8 (15.6) 83.7 (10.8) p=0194 99.5 (10.8)
FEV
1
(% p ed) 88.5 (14.2) 81.8 (12.0) p=0071 96.7 (11.6)
D
L,CO
(% p ed) 106.4 (17.4) 87.1 (16.8) p<0001 N.A.
IL-6 (pg/ml) 3.2 (2.4–4.3) 3.2 (2.0–5.0) p=0728 2.1 (1.6–2.8)
CRP (μg/ml) 0.93 (0.37–1.99 1.20 (0.60–2.94) p=0282 0.47 (0.27–1.00)
Adipsin (ng/ml) 893 (777–1069) 1022 (950–1224) p=0004 908 (757–1045)
MMP-9 (ng/ml) 28.1 (22.4–36.9) 54.7 (32.8–70.9) p<0001 30.3 (25.4–38.9)
Values a e p esen ed as mean (SD) o median (IQR) when app op ia e acco ding o he dis ibu ion o a iables. FVC: o ced i al capaci y; FEV
1
: o ced
expi a o y olume in 1 second; D
L,CO
:diffusing capaci y o ca bon monoxide; IL-6: in e leukin 6; CRP: C- eac i e p o ein; MMP-9: ma ix
me allop o einase-9; N.A: no assessed. p alues we e calcula ed be ween asbes os-exposed subjec s wi hou fib osis and asbes os-exposed subjec s wi h
asbes osis using unpai ed - es o Mann–Whi ney U es when app op ia e.
Table 2: Co ela ions be ween YKL-40 and o he pa ame e s in
asbes os-exposed subjec s (n=85).
YKL-40
Age (yea s) =0102 p=0355
FVC (% p ed) =−0259 p=0018
FEV
1
(% p ed) =−0 240 p=0028
D
L,CO
(% p ed) =0127 p=0246
IL-6 (pg/ml) ho = 0.314 p=0003
CRP (μg/ml) ho = 0.371 p<0001
Adipsin (ng/ml) ho = 0.459 p<0001
MMP-9 (ng/ml) ho = 0.243 p=0025
Pea son’s( ) o Spea man’s ( ho) co ela ion coefficien was used acco ding
o he dis ibu ion o a iables. FVC: o ced i al capaci y; FEV
1
: o ced
expi a o y olume in 1 second; D
L,CO
:diffusing capaci y o ca bon
monoxide; IL-6: in e leukin 6; CRP: C- eac i e p o ein; MMP-9: ma ix
me allop o einase-9.
YKL-40 (ng/ml)
Heal hy con ols
Asbes osis
ns
p=0.008p=0.033
No ib osis
Exposed Unexposed
40
20
0
60
80
100
120
140
160
Figu e 1: Plasma YKL-40 concen a ions in subjec s wi h asbes osis
(n=19), asbes os-exposed subjec s who did no de elop lung
fib osis (n=66), and heal hy con ols (n=28). Medians and
in e qua ile anges (IQR) o he h ee g oups a e shown. One-
way ANOVA wi h leas significan diffe ence (LSD) pos es was
used. ns: no significan .
3Media o s o Inflamma ion
exposed o asbes os, plasma YKL-40 was nega i ely associ-
a ed wi h lung unc ion pa ame e s (FVC and FVE
1
) and
posi i ely wi h bioma ke s o inflamma ion and issue inju y
sugges ing a ole o YKL-40 in he o ma ion o pulmona y
fib osis ollowing exposu e o asbes os.
Suppo ing ou findings, p e ious s udies ha e shown
inc eased le els o YKL-40 in o he fib o ic pulmona y dis-
eases. Inc eased le els o YKL-40 ha e been shown in
pa ien s wi h idiopa hic pulmona y fib osis, IPF [9, 15, 21],
in which high YKL-40 le els we e associa ed wi h p og es-
sion o he disease [9, 21]. YKL-40 le els ha e been shown
o associa e also wi h o he idiopa hic in e s i ial lung
diseases including nonspecific in e s i ial pneumonia,
smoking- ela ed in e s i ial lung disease, and c yp ogenic
o ganizing pneumonia [16], pulmona y sa coidosis [22],
pos ansplan a ion b onchioli is obli e ans [23], and pulmo-
na y mani es a ions o cys ic fib osis o sys emic scle osis
[24–26]. Co adi e al. epo ed inc eased YKL-40 le els also
in pa ien s wi h malignan meso helioma (n=50), a disease
o en associa ed wi h asbes os exposu e [27]. These s udies
suppo ou esul s ha high le els o YKL-40 a e associa ed
wi h he pa hogenic p ocess in asbes osis and o he fib o ic
pulmona y diseases.
The effec s o asbes os exposu e depend on se e al ac o s
including he in ensi y and du a ion o he exposu e, fibe
ype and size, and suscep ibili y o he exposed indi idual.
Asbes osis is ela ed especially o long (>20 μm) fibe s, and
low-dose exposu e associa es wi h a mac ophage-dominan
immune esponse whe eas high doses o asbes os lead o
neu ophil-dominan inflamma ion. Inges ion o asbes os
ac i a es mac ophages, in a pa e n ypical o al e na i ely
ac i a ed M2 mac ophages ela ed o wound healing and
fib osis, o p oduce g ow h ac o s and cy okines ha p o-
mo e collagen o ma ion in he fib oblas s [1, 28]. In igu-
ingly, YKL-40 is p oduced by human monocy e-de i ed
diffe en ia ed mac ophages [10] and has been sugges ed as
a ma ke o al e na i ely ac i a ed M2 mac ophages [28].
In pe iphe al blood o IPF pa ien s, high le els o ci cula ing
YKL-40 we e accompanied wi h M2-skewed gene exp ession
p ofile in he pe iphe al blood mononuclea cells (PBMCs)
[9]. Mo eo e , YKL-40 was a di ec s imula o o al e na i e
ac i a ion in mice al eola and pe i oneal mac ophages [29].
In asbes os-exposed a s, al eola mac ophages we e shown
o ha e al e ed pheno ype wi h long su i al and high g ow h
ac o p oduc ion esul ing in fib ogenesis [30]. These find-
ings sugges YKL-40 as a ma ke o M2 mac ophage-d i en
fib ogenic p ocesses in asbes osis, which could be po en ially
p e en able by affec ing YKL-40 le els.
In addi ion o i s ole in al e na i e ac i a ion o mac-
ophages, he e a e se e al o he possible effec o unc ions
o YKL-40 in asbes osis. Asbes os is known o induce o -
ma ion o eac i e oxygen species (ROS) in mac ophages,
on he su ace o asbes os fibe s and in he mi ochond ia
o se e al cell ypes con ibu ing o DNA damage and sub-
sequen pulmona y oxici y h ough oxida i e s ess [1].
YKL-40, in u n, has been sugges ed o p o ec he lung
by inhibi ing oxidan -induced inju y, ascula pe meabil-
i y, and apop osis [8]. Mo eo e , YKL-40 is able o bind
YKL-40 (ng/ml)
FVC (% p ed)
120
100
80
60
40
0.0 100.0 200.0 300.0 400.0
=‒0.259
p=0.018
FEV
1
(% p ed)
YKL-40 (ng/ml)
120
140
100
80
60
40
0.0 100.0 200.0 300.0 400.0
=‒0.240
p=0.028
(a) (b)
Figu e 2: Co ela ions be ween YKL-40 and measu es o espi a o y unc ion in asbes os-exposed subjec s (n=85). YKL-40 co ela ed wi h
(a) FVC: o ced i al capaci y and (b) FEV
1
: o ced expi a o y olume in 1 second. Pea son’s co ela ion coefficien was used because o
skewed dis ibu ion o he da a.
Adipsin (ng/ml)
YKL-40 (ng/ml)
1500
2000
1000
500
00.0 100.0 200.0 300.0 400.0
ho=0.459
p< 0.001
Figu e 3: Co ela ion be ween YKL-40 and fib osis ma ke adipsin
in asbes os-exposed subjec s (n=85). YKL-40 co ela ed posi i ely
wi h adipsin. Spea man’s co ela ion coefficien was used because
o skewed dis ibu ion o he da a.
4 Media o s o Inflamma ion
collagen ypes I, II, and III and o ha e modula o y effec s
on collagen fib illa ion and collagenoly ic clea age, which
could play a pa in he fib o ic p ocess [31].
In he p esen s udy, o assess he ole o YKL-40 in
asbes osis, we examined i s associa ions wi h ma ke s known
o ela e o he disease. YKL-40 showed posi i e co ela ions
o ma ke s o inflamma ion and fib osis, suppo ing he iew
ha YKL-40 is linked o he pa hogenesis o asbes osis. Fi s ,
plasma YKL-40 co ela ed wi h inflamma ion ma ke s CRP
and IL-6 in asbes os-exposed subjec s. This is suppo ed by
p e ious s udies showing simila findings in pa ien s wi h
hea ansplan a ion, a ial fib illa ion, ype 2 diabe es, o
heuma oid a h i is [32–35] and in subjec s du ing ongoing
dialysis ea men [36]. Mo eo e , IL-6 has p e iously been
shown o s imula e YKL-40 sec e ion om human
chond ocy es [37] and human bone ma ow-de i ed s em
cells [38]. Ci cula ing le els o IL-6 ha e been shown o
be inc eased in asbes os-exposed subjec s [39, 40] and
sugges ed o be sec e ed om ype II al eola cells [39].
Howe e , mac ophages ha e been implica ed also as a
possible sou ce o IL-6 [10, 41].
Secondly, YKL-40 co ela ed wi h adipsin and MMP-9,
ma ke s ha we e also ound o be inc eased in subjec s wi h
asbes osis in he p esen s udy. Plasma adipsin has been
shown o be associa ed wi h he deg ee o lung fib osis in
asbes os-exposed subjec s [20]. The associa ion o YKL-40
and adipsin has no been epo ed be o e. Ou finding on
he associa ion o YKL-40 wi h MMP-9 is suppo ed by find-
ings in p e ious in i o s udies. YKL-40 has been shown o
s imula e MMP-9 syn hesis in BAL al eola mac ophages
om smoking COPD pa ien s [42] and in human fib oblas s
om nasal mucosa [43]. Mo eo e , in cul u ed mu ine mac-
ophages, YKL-40 has been epo ed o s imula e MMP-9
exp ession and inhibi ion o YKL-40 wi h siRNA was ound
o dec ease MMP-9 exp ession [44].
In he p esen s udy, subjec s wi h asbes osis had on a e -
age a mild disease wi h well-p ese ed lung unc ion and had
no ye de eloped se e e es ic i e lung unc ion which can
be ega ded as a limi a ion o he s udy. Only D
L,CO
was signi -
ican ly lowe in asbes osis subjec s. Howe e , a p esen , his is
cha ac e is ic o asbes osis diagnosed in indus ialized coun-
ies: mos cases o asbes osis a e de ec ed in an ea ly phase
when hey show up only on adiological examina ions p io
o possible p og ession o se e e es ic ion o espi a o y
insufficiency [45]. The asbes os-exposed g oup wi hou asbes-
osismaywellde elopasbes osisin hecomingyea s,al hough
ime a e he beginning o he exposu e was simila in bo h
g oups. Ou finding on he inc eased YKL-40 le els in subjec s
wi h asbes osis compa ed o subjec s who had no de eloped
lung fib osis may hus well eflec he ea ly fib o ic changes
de ec ed by HRCT. Fu he mo e, we p esen he e co ela ions
o YKL-40 wi h known inflamma o y and fib o ic ma ke s,
which may eflec in e es ing possible mechanisms in he
pa hogenesis o asbes osis. Addi ional expe imen al s udies
a e needed o confi m i he obse ed co ela ions a e ans-
la ed o causali y. Howe e , p e ious esul s in he scien ific
li e a u e do sugges ha YKL-40 could also play a ole in he
pa hogenesis o fib o ic changes and he findings p esen ed
in ou clinical coho suppo hese in iguing hypo heses.
Imp o ed bioma ke s and ea men op ions a e needed
in he diagnos ics and managemen o fib o ic pulmona y dis-
eases. Acco ding o ou findings, YKL-40 could be a po en ial
no el bioma ke o fib osis and inflamma ion in asbes osis.
Con lic s o In e es
The au ho s decla e ha he e is no conflic o in e es s
ega ding he publica ion o his pape .
Acknowledgmen s
The excellen echnical assis ance o Ma ja-Leena Lampén
and Te hi Salonen and he skill ul sec e a ial help o Heli
Mää ä a e g ea ly acknowledged. This s udy was financially
suppo ed by he Compe i i e Resea ch Funding o he
Pi kanmaa Hospi al Dis ic and Tampe e Tube culosis
Founda ion.
Re e ences
[1] G. Liu, P. Che esh, and D. W. Kamp, “Molecula basis o
asbes os-induced lung disease,”Annual Re iew o Pa hology,
ol. 8, pp. 161–187, 2013.
[2] O phane ,”Ma ch 2017, h p://www.o pha.ne .
[3] EU commision public heal h policy on a e diseases,”Ma ch
2017, h p://ec.eu opa.eu/heal h/ a e_diseases/policy_en.
[4] L. S ayne , L. S. Welch, and R. Lemen, “The wo ldwide
pandemic o asbes os- ela ed diseases,”Annual Re iew o
Public Heal h, ol. 34, pp. 205–216, 2013.
[5] T. Kameda, K. Takahashi, R. Kim e al., “Asbes os: use, bans
and disease bu den in Eu ope,”Bulle in o he Wo ld Heal h
O ganiza ion, ol. 92, no. 11, pp. 790–797, 2014.
[6] WHO I asbes os: elimina ion o asbes os- ela ed diseases,
ac shee ,”Ma ch 2017, h p://www.who.in /mediacen e/
ac shee s/ s343/en/.
[7] F. D. Coffman, “Chi inase 3-like-1 (CHI3L1): a pu a i e dis-
ease ma ke a he in e ace o p o eomics and glycomics,”
C i ical Re iews in Clinical Labo a o y Sciences, ol. 45, no. 6,
pp. 531–562, 2008.
[8] C. G. Lee, C. A. Da Sil a, C. S. Dela C uz e al., “Role o chi in
and chi inase/chi inase-like p o eins in inflamma ion, issue
emodeling, and inju y,”Annual Re iew o Physiology,
ol. 73, pp. 479–501, 2011.
[9] Y. Zhou, H. Peng, H. Sun e al., “Chi inase 3-like 1 supp esses
inju y and p omo es fib op oli e a i e esponses in mamma-
lian lung fib osis,”Science T ansla ional Medicine, ol. 6,
no. 240, p. 240 a76, 2014.
[10] M. Di Rosa, G. Malagua ne a, C. De G ego io, F. D ago, and L.
Malagua ne a, “E alua ion o CHI3L-1 and CHIT-1 exp es-
sion in diffe en ia ed and pola ized mac ophages,”Inflamma-
ion, ol. 36, no. 2, pp. 482–492, 2013.
[11] J. S. Johansen, S. Molle , P. A. P ice e al., “Plasma YKL-40: a
new po en ial ma ke o fib osis in pa ien s wi h alcoholic ci -
hosis?”Scandina ian Jou nal o Gas oen e ology, ol. 32,
no. 6, pp. 582–590, 1997.
[12] J. S. Johansen, P. Ch is offe sen, S. Molle e al., “Se um YKL-
40 is inc eased in pa ien s wi h hepa ic fib osis,”Jou nal o
Hepa ology, ol. 32, no. 6, pp. 911–920, 2000.
[13] C. Nojgaa d, J. S. Johansen, E. Ch is ensen e al., “Se um le els
o YKL-40 and PIIINP as p ognos ic ma ke s in pa ien s wi h
5Media o s o Inflamma ion

alcoholic li e disease,”Jou nal o Hepa ology, ol. 39, no. 2,
pp. 179–186, 2003.
[14] Y. Sai ou, K. Shi aki, Y. Yamanaka e al., “Nonin asi e es ima-
ion o li e fib osis and esponse o in e e on he apy by a
se um fib ogenesis ma ke , YKL-40, in pa ien s wi h HCV-
associa ed li e disease,”Wo ld Jou nal o Gas oen e ology,
ol. 11, no. 4, pp. 476–481, 2005.
[15] K. Fu uhashi, T. Suda, Y. Nakamu a e al., “Inc eased exp es-
sion o YKL-40, a chi inase-like p o ein, in se um and lung
o pa ien s wi h idiopa hic pulmona y fib osis,”Respi a o y
Medicine, ol. 104, no. 8, pp. 1204–1210, 2010.
[16] N. M. Ko hagen, C. H. an Moo sel, P. Zanen, H. J. Ru en,
and J. C. G u e s, “E alua ion o ci cula ing YKL-40 le els
in idiopa hic in e s i ial pneumonias,”Lung, ol. 192, no. 6,
pp. 975–980, 2014.
[17] X. Long, X. He, S. Ohshimo e al., “Se um YKL-40 as p edic o
o ou come in hype sensi i i y pneumoni is,”The Eu opean
Respi a o y Jou nal, ol. 49, no. 2, a icle 1501924, 2017.
[18] L. Leh imäki, P. Oksa, R. Jä enpää e al., “Pulmona y inflam-
ma ion in asbes os-exposed subjec s wi h bo de line pa en-
chymal changes on HRCT,”Respi a o y Medicine, ol. 104,
no. 7, pp. 1042–1049, 2010.
[19] O. Huuskonen, L. Ki isaa i, A. Zi ing, K. Taskinen, A.
Tossa ainen, and T. Vehmas, “High- esolu ion compu ed
omog aphy classifica ion o lung fib osis o pa ien s wi h
asbes os- ela ed disease,”Scandina ian Jou nal o Wo k,
En i onmen & Heal h, ol. 27, no. 2, pp. 106–112, 2001.
[20] S. Lei o-Ko pela, L. Leh imäki, R. Nieminen e al., “Adipokine
adipsin is associa ed wi h he deg ee o lung fib osis in
asbes os-exposed wo ke s,”Respi a o y Medicine, ol. 106,
no. 10, pp. 1435–1440, 2012.
[21] N. M. Ko hagen, C. H. an Moo sel, N. P. Ba lo e al., “Se um
and BALF YKL-40 le els a e p edic o s o su i al in idio-
pa hic pulmona y fib osis,”Respi a o y Medicine, ol. 105,
no. 1, pp. 106–113, 2011.
[22] J. S. Johansen, N. Milman, M. Hansen, C. Ga ba sch, P. A.
P ice, and N. G audal, “Inc eased se um YKL-40 in pa ien s
wi h pulmona y sa coidosis—a po en ial ma ke o disease
ac i i y?”Respi a o y Medicine, ol. 99, no. 4, pp. 396–402,
2005.
[23] P. Jaksch, S. Tagha i, W. Klepe ko, and M. Salama, “P e ans-
plan se um human chi inase-like glycop o ein YKL-40 con-
cen a ions independen ly p edic b onchioli is obli e ans
de elopmen in lung ansplan ecipien s,”The Jou nal o
Tho acic and Ca dio ascula Su ge y, ol. 148, no. 1,
pp. 273–281, 2014.
[24] A. Hec o , M. S. Ko mann, I. Mack e al., “The chi inase-like
p o ein YKL-40 modula es cys ic fib osis lung disease,”PLoS
One, ol. 6, no. 9, a icle e24399, 2011.
[25] T. Ra h, L. Zwaschka, L. Hage e al., “Iden ifica ion o
neu ophil ac i a ion ma ke s as no el su oga e ma ke s
o CF lung disease,”PLoS One, ol. 9, no. 12, a icle
e115847, 2014.
[26] C. No denbaek, J. S. Johansen, P. Halbe g e al., “High se um
le els o YKL-40 in pa ien s wi h sys emic scle osis a e associ-
a ed wi h pulmona y in ol emen ,”Scandina ian Jou nal o
Rheuma ology, ol. 34, no. 4, pp. 293–297, 2005.
[27] M. Co adi, M. Goldoni, R. Alino i e al., “YKL-40 and
meso helin in he blood o pa ien s wi h malignan meso heli-
oma, lung cance and asbes osis,”An icance Resea ch, ol. 33,
no. 12, pp. 5517–5524, 2013.
[28] P. J. Mu ay and T. A. Wynn, “P o ec i e and pa hogenic unc-
ions o mac ophage subse s,”Na u e Re iews Immunology,
ol. 11, no. 11, pp. 723–737, 2011.
[29] C. G. Lee, D. Ha l, G. R. Lee e al., “Role o b eas eg ession
p o ein 39 (BRP-39)/chi inase 3-like-1 in Th2 and IL-13-
induced issue esponses and apop osis,”The Jou nal o Expe -
imen al Medicine, ol. 206, no. 5, pp. 1149–1166, 2009.
[30] Y. Nishimu a, M. Maeda, N. Kumagai-Takei e al., “Al e ed
unc ions o al eola mac ophages and NK cells in ol ed in
asbes os- ela ed diseases,”En i onmen al Heal h and P e en-
i e Medicine, ol. 18, no. 3, pp. 198–204, 2013.
[31] H. F. Bigg, R. Wai , A. D. Rowan, and T. E. Caws on, “The
mammalian chi inase-like lec in, YKL-40, binds specifically
o ype I collagen and modula es he a e o ype I collagen
fib il o ma ion,”The Jou nal o Biological Chemis y,
ol. 281, no. 30, pp. 21082–21095, 2006.
[32] K. M. Henningsen, S. K. The kelsen, J. S. Johansen, H.
B uunsgaa d, and J. H. S endsen, “Plasma YKL-40, a new
bioma ke o a ial fib illa ion?”Eu opace, ol. 11, no. 8,
pp. 1032–1036, 2009.
[33] P. P zybylowski, L. Janik, G. Wasilewski, E. Nowak, P. Kozlik,
and J. Malyszko, “YKL-40, a no el ma ke o ca dio ascula
complica ions, is ela ed o kidney unc ion in hea ansplan
ecipien s,”T ansplan a ion P oceedings, ol. 46, no. 8,
pp. 2860–2863, 2014.
[34] A. R. Nielsen, C. E iks up, J. S. Johansen e al., “Plasma YKL-
40: a BMI-independen ma ke o ype 2 diabe es,”Diabe es,
ol. 57, no. 11, pp. 3078–3082, 2008.
[35] T. Ma sumo o and T. Tsu umo o, “Se um YKL-40 le els in
heuma oid a h i is: co ela ions be ween clinical and labo -
a o y pa ame e s,”Clinical and Expe imen al Rheuma ology,
ol. 19, no. 6, pp. 655–660, 2001.
[36] G. U. Okyay, R. E. E , M. Y. Tekbudak e al., “No el inflamma-
o y ma ke in dialysis pa ien s: YKL-40,”The apeu ic Aphe e-
sis and Dialysis, ol. 17, no. 2, pp. 193–201, 2013.
[37] T. Väänänen, A. Koskinen, E. L. Paukke i e al., “YKL-40 as a
no el ac o associa ed wi h inflamma ion and ca abolic mech-
anisms in os eoa h i ic join s,”Media o s o Inflamma ion,
ol. 2014, A icle ID 215140, p. 7, 2014.
[38] R. Liede and O. E. Sigu jonsson, “The effec o ecombi-
nan human in e leukin-6 on os eogenic diffe en ia ion
and YKL-40 exp ession in human, bone ma ow-de i ed
mesenchymal s em cells,”BioResea ch Open Access, ol. 3,
no. 1, pp. 29–34, 2014.
[39] S. Ila ska, E. Jahno a, J. Tulinska e al., “Immunological mon-
i o ing in wo ke s occupa ionally exposed o asbes os,”Toxi-
cology, ol. 206, no. 2, pp. 299–308, 2005.
[40] H. Leh onen, P. Oksa, L. Leh imäki e al., “Inc eased al eola
ni ic oxide concen a ion and high le els o leuko iene B(4)
and 8-isop os ane in exhaled b ea h condensa e in pa ien s
wi h asbes osis,”Tho ax, ol. 62, no. 7, pp. 602–607, 2007.
[41] F. O. Ma inez and S. Go don, “The M1 and M2 pa adigm o
mac ophage ac i a ion: ime o eassessmen ,”F1000P ime
Repo s, ol. 6, no. 13.10, p. 12703, 2014.
[42] S. Le u e, A. Kozhich, N. A ouche e al., “YKL-40 is ele a ed in
pa ien s wi h ch onic obs uc i e pulmona y disease and ac i-
a es al eola mac ophages,”Jou nal o Immunology, ol. 181,
no. 7, pp. 5167–5173, 2008.
[43] S. J. Pa k, Y. J. Jun, T. H. Kim e al., “Inc eased exp ession o
YKL-40 in mild and mode a e/se e e pe sis en alle gic hini-
is and i s possible con ibu ion o emodeling o nasal
6 Media o s o Inflamma ion
mucosa,”Ame ican Jou nal o Rhinology & Alle gy, ol. 27,
no. 5, pp. 372–380, 2013.
[44] S. Lib e os, R. Ga cia-A eas, Y. Shiba a, R. Ca io, M.
To oella-Kou i, and V. I aga a apu-Cha yulu, “Induc ion o
p oinflamma o y media o s by CHI3L1 is educed by chi in
ea men : dec eased umo me as asis in a b eas cance
model,”In e na ional Jou nal o Cance , ol. 131, no. 2,
pp. 377–386, 2012.
[45] In o ma ion no ices on occupa ional diseases: a guide o
diagnosis (2009). Luxembou g: office o official publica-
ions o he Eu opean communi ies,”Ma ch 2017,
h ps://osha.eu opa.eu/fi/legisla ion/guidelines/in o ma ion-
no ices-on-occupa ional-diseases-a-guide- o-diagnosis.
7Media o s o Inflamma ion
Submi you manusc ip s a
h ps://www.hindawi.com
S em Cells
In e na ional
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
MEDIATORS
INFLAMMATION
o
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Beha iou al
Neu ology
Endoc inology
In e na ional Jou nal o
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Disease Ma ke s
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
BioMed
Resea ch In e na ional
Oncology
Jou nal o
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Oxida i e Medicine and
Cellula Longe i y
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
PPAR Resea ch
The Scien i ic
Wo ld Jou nal
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Immunology Resea ch
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Jou nal o
Obesi y
Jou nal o
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Compu a ional and
Ma hema ical Me hods
in Medicine
Oph halmology
Jou nal o
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Diabe es Resea ch
Jou nal o
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Resea ch and T ea men
AIDS
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Gas oen e ology
Resea ch and P ac ice
Hindawi Publishing Co po a ion
h p://www.hindawi.com Volume 2014
Pa kinson’s
Disease
E idence-Based
Complemen a y and
Al e na i e Medicine
Volume 2014
Hindawi Publishing Co po a ion
h p://www.hindawi.com