Glycoprotein YKL-40 levels in plasma are associated with fibrotic changes on HRCT in asbestos-exposed subjects

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