Chitinase-like Protein YKL-40 Research Articles

Titanium induces pro-inflammatory and tissue-destructive responses in primary human macrophages.

Implants and medical devices are efficient and practical therapeutic solutions for a multitude of pathologies. Titanium and titanium alloys are used in orthopedics, dentistry, and cardiology. Despite very good mechanical properties, and corrosion resistance titanium implants can fail due to inflammatory or tissue-degradation related complications. Macrophages are major immune cells that control acceptance of failure of the implant. In this study, for the first time, we have performed a systematic analysis of the response of differentially activated human macrophages (M(Control), M(IFNγ) and M(IL-4)) to the polished and porous titanium surfaces in order to identify the detrimental effect of titanium leading to the tissue destruction and chronic inflammation. Transcriptome analysis revealed that the highest number of differences between titanium and control settings are found in M(IL-4) that model healing type of macrophages. RT-qPCR analysis confirmed that both polished and porous titanium affected expression of cytokines, chitinases/chitinase-like proteins and matrix metalloproteinases. Titanium-induced release and activation of MMP7 by macrophages was enhanced by fibroblasts in both juxtacrine and paracrine cell interaction models. Production of titanium-induced MMPs and cytokines associated with chronic inflammation were independent of the presence of Staphylococcus aureus. MMP7, one of the most pronounced tissue-destroying factor and chitinase-like protein YKL-40 were expressed in CD68+ macrophages in peri-implant tissues of patients with orthopedic implants. In summary, we demonstrated that titanium induces pro-inflammatory and tissue-destructing responses mainly in healing macrophages, and the detrimental effects of titanium surfaces on implant-adjacent macrophages are independent on the bacterial contamination.

Endotoxin of Porphyromonas gingivalis amplifies the inflammatory response in hyperglycemia-induced zebrafish through a mechanism involving chitinase-like protein YKL-40 analogs.

Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontal diseases, is also associated with hyperglycemia-associated systemic diseases, including diabetes mellitus (DM). Gingipains are the most important endotoxins of P. gingivalis, and in vivo studies using gingipains are scarce. Zebrafish (Danio rerio) is a vertebrate with high physiological and genetic homology with humans that has multiple co-orthologs for human genes, including inflammation-related proteins. The aim of our study was to determine the effects of gingipain in a hyperglycemia-induced zebrafish model by evaluating inflammation, oxidant-antioxidant status, and the cholinergic system. Adult zebrafish were grouped into the control group (C), hyperglycemia-induced group subjected to 15days of overfeeding (OF), gingipain-injected group (GP), and gingipain-injected hyperglycemic group (OF + GP). At the end of 15days, an oral glucose tolerance test (OGTT) was performed, and fasting blood glucose (FBG) levels were measured. Lipid peroxidation (LPO), nitric oxide (NO), glutathione (GSH), glutathione S-transferase, catalase, acetylcholinesterase (AChE), alkaline phosphatase (ALP), and sialic acid (SA) levels were determined spectrophotometrically in the hepatopancreas. The expression levels of tnf-⍺, il-1β, ins, crp, and the acute phase protein YKL-40 analogs chia.5 and chia.6 were evaluated by RT‒PCR. After two weeks of overfeeding, significantly increased weight gain, FBG, and OGTT confirmed that the zebrafish were hyperglycemic. Increased oxidative stress, inflammation, and AChE and ALP activities were observed in both the overfeeding and GP groups. Amplification of inflammation and oxidative stress was evident in the OF + GP group through increased expression of crp, il-1β, chia.5, and chia.6 and increased LPO and NO levels. Our results support the role of gingipains in the increased inflammatory response in hyperglycemia-associated diseases.

Further evidence for association of YKL-40 with severe asthma airway remodeling

BackgroundThe chitinase-like protein YKL-40 is associated with airflow limitation on spirometry and airway remodeling in patients with asthma. It remains unclear whether YKL-40 is associated with morphologic changes in the airways and parenchyma or with future progression of airflow limitation in severe asthma. ObjectiveTo evaluate the association of circulating YKL-40 levels with morphologic changes in the airways and parenchyma and with longitudinal progression of airflow limitation. MethodsThe patients were participants in the Hokkaido Severe Asthma Cohort Study (n = 127), including smokers. This study consisted of 2 parts. In analysis 1, we analyzed associations between circulating YKL-40 levels and several asthma-related indices, including computed tomography–derived indices of proximal wall area percentage, the complexity of the airways (airway fractal dimension), and the parenchyma (exponent D) cross-sectionally (n = 97). In analysis 2, we evaluated the impact of circulating YKL-40 levels on forced expiratory volume in 1 second (FEV1) decline longitudinally for a 5-year follow-up (n = 103). ResultsCirculating YKL-40 levels were significantly associated with proximal wall area percentage and airway fractal dimension (r = 0.25, P = .01; r = −0.22, P = .04, respectively), but not with exponent D. The mean annual change in FEV1 was −33.7 (± 23.3) mL/y, and the circulating YKL-40 level was a significant independent factor associated with annual FEV1 decline (β = −0.24, P = .02), even after controlling for exponent D (β = −0.26, P = .01). ConclusionThese results provide further evidence for the association of YKL-40 with the pathogenesis of airway remodeling in severe asthma.

Chitinase 3-like 1 is a profibrogenic factor overexpressed in the aging liver and in patients with liver cirrhosis

Older age at the time of infection with hepatitis viruses is associated with an increased risk of liver fibrosis progression. We hypothesized that the pace of fibrosis progression may reflect changes in gene expression within the aging liver. We compared gene expression in liver specimens from 54 adult donors without evidence of fibrosis, including 36 over 40 y old and 18 between 18 and 40 y old. Chitinase 3-like 1 (CHI3L1), which encodes chitinase-like protein YKL-40/CHI3L1, was identified as the gene with the greatest age-dependent increase in expression in liver tissue. We investigated the cellular source of CHI3L1 in the liver and its function using liver tissue specimens and in vitro models. CHI3L1 expression was significantly higher in livers of patients with cirrhosis of diverse etiologies compared with controls represented by patients who underwent liver resection for hemangioma. The highest intrahepatic CHI3L1 expression was observed in cirrhosis due to hepatitis D virus, followed by hepatitis C virus, hepatitis B virus, and alcohol-induced cirrhosis. In situ hybridization of CHI3L1 messenger RNA (mRNA) identified hepatocytes as the major producers of CHI3L1 in normal liver and in cirrhotic tissue, wherein hepatocytes adjacent to fibrous septa showed higher CHI3L1 expression than did those in more distal areas. In vitro studies showed that recombinant CHI3L1 promotes proliferation and activation of primary human hepatic stellate cells (HSCs), the major drivers of liver fibrosis. These findings collectively demonstrate that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression.

Chitinase 3-like-1 protects airway function despite promoting type 2 inflammation during fungal-associated allergic airway inflammation.

Exposure to fungi can result in a wide range of comorbidities depending on the immune status of the host. Chronic exposure and reactivity to fungi such as Aspergillus fumigatus can result in conditions such as severe asthma with fungal sensitization (SAFS) or allergic bronchopulmonary aspergillosis (ABPA). However, the pathophysiology of SAFS and ABPA are not well understood. Here, we report that the chitinase-like protein YKL-40 is elevated in lung lavage fluid from human asthmatics that are sensitized to fungi. Initial studies demonstrated that mice deficient in the murine ortholog of YKL-40, breast regression protein-39 (BRP-39, chitinase-3-like 1, Chi3l1), were not more susceptible to acute infection with A. fumigatus. However, in an experimental model of fungal-associated allergic airway inflammation (fungal asthma), Chi3l1-/- mice had significantly increased airway hyperresponsiveness (AHR). Surprisingly, increased AHR in Chi3l1-/- mice occurred in the presence of significantly lower type 2 responses (decreased eosinophil numbers and decreased IL-4, IL-5, IL-33, CCL17 and CCL22 levels), although type 1 and type 17 responses were not different. Increased AHR was not associated with differences in Periodic-acid-Schiff staining of lung tissue, differences in the expression of Muc5ac and Clca3, nor differences in lung edema. Bone marrow chimera studies revealed that the presence of BRP-39 in either the hematopoietic or non-hematopoietic compartment was sufficient for controlling AHR during fungal asthma. Collectively, these results indicate that BRP-39 protects against AHR during fungal asthma despite contributing to type 2 inflammation, thus highlighting an unexpected protective role for BRP-39 in allergic fungal asthma.

153 Poster - Chitinase-like proteins as candidate markers for tamoxifen responsiveness

Background: The interplay between the tumor cells and regulatory microenvironment proteins such as chitinase-like proteins YKL-39, YKL-40, SI-CLP and stabilin-1 may play a critical role in the disease progression and response to treatment. The aim of this study was to examine the expression levels of the CHI3L2, CHI3L1, CHID1, STAB1 gene coding chitinase-like proteins in relation to tamoxifen treatment in hormone-receptor positive breast cancer patients; and the relationship between these levels and expression of Akt1-associated genes.

HOXA-AS2 promotes type I endometrial carcinoma via miRNA-302c-3p-mediated regulation of ZFX

BackgroundHOXA cluster antisense RNA2 (HOXA-AS2), a long-chain non-coding RNA, plays an important role in the behavior of various malignant tumors. The roles of HOXA-AS2 in endometrial cancer remain unclear.MethodsWe test expression levels of HOXA-AS2, miRNA-302c-3p, the transcription factor zinc finger X-chromosomal protein (ZFX), and the chitinase-like protein YKL-40 in endometrial carcinoma by qRT-PCR and western blotting. Luciferase reporter and qRT-PCR assays were conducted to identify potential binding sites of HOXA-AS2 to miRNA-302c-3p. Cell cycle, migration and invasion ability of endometrial cancer cells were investigated using flow-cytometric analysis, CCK-8 and transwell assays, respectively.ResultsHOXA-AS2 levels were significantly increased in endometrial cancer specimens compared to normal endometrial specimens. Upregulated HOXA-AS2 promoted invasion and proliferation of type I endometrial cancer cells. HOXA-AS2 silenced miRNA-302c-3p by binding to it. MiRNA-302c-3p negatively regulates ZFX and YKL-40. Thus HOXA-AS2 promotes the development of type I endometrial cancer via miRNA-302c-3p-mediated regulation of ZFX.ConclusionsThese findings suggest that HOXA-AS2 can act as a new therapeutic target for type I endometrial cancer.

The correlation between Chitinase-Like Protein YKL-40 and Childhood Asthma in Zagazig University Hospitals

The correlation between Chitinase-Like Protein YKL-40 and Childhood Asthma in Zagazig University Hospitals

Chitinase-like protein YKL-40 regulates human bronchial epithelial cells proliferation, apoptosis, and migration through TGF-β1/Smads pathway

In order to study the effects of chitinase-like protein YKL-40 on proliferation, apoptosis, and migration of human bronchial epithelial cell line (BEAS-2B), and the underlying mechanisms, we cultured BEAS-2B alone or with different concentrations of YKL-40. thiazolyl blue tetrazolium bromide (MTT) assay was used to examine the cell proliferation. Annexin V-fluorescein isothiocyanate isomer (FITC)/propidium iodide staining and scratch assay were performed to test the cell apoptosis and migration. The concentrations of transforming growth factor-β1 (TGF-β1), Smad3, Smad7, alpha-smooth muscle actin (α-SMA), interleukin-4 (IL-4), IL-6, and IL-8 in the cell culture supernatant were detected by enzyme-linked immunosorbent assay. The messenger RNA and protein levels of YKL-40, TGF-β1, Smad3, Smad7, and α-SMA were detected by reverse transcription polymerase chain reaction and Western blot. BEAS-2B cells cultured with different concentrations of YKL-40 showed significantly higher cell proliferation and migration and inflammatory cytokines compared with that of control group, while the cell apoptosis was significantly lower than that of control group (p < 0.05). In addition, BEAS-2B cells cultured with YKL-40 had increased TGF-β1, Smad3, Smad7, and α-SMA levels in the supernatant, compared with that of BEAS-2B cells cultured alone (p < 0.05). Furthermore, LY364947, as TGF-β1/Smads signaling pathway inhibitor, decreased cell proliferation and migration ability and enhanced cell apoptosis of BEAS-2B cells compared with control group (p < 0.05). However, YKL-40 administration reversed the effect of LY364947 on the biological behavior of BEAS-2B cells. YKL-40 could affect the biological behaviors of BEAS-2B cells, which might be related to the TGF-β1/Smads pathway.

Serum chitinase-like protein YKL-40 is linked to small airway function in children with asthmatic symptoms.

Lung function impairment among asthmatic children begins in early life, and biomarkers for identifying this impairment are needed. The chitinase-like protein YKL-40 has been associated with asthma and lung function in adults, but studies in children have yielded conflicting results. We evaluated the potential of YKL-40 and other systemic biomarkers for identifying lung function deficits in children with asthmatic symptoms. We determined the levels of serum YKL-40, periostin, and high-sensitivity C-reactive protein (hs-CRP) from the blood samples of 49 children with asthmatic symptoms. Lung function was assessed with impulse oscillometry (IOS) and spirometry, combined with an exercise challenge and a bronchodilator test. Fractional exhaled nitric oxide was measured at multiple flow rates. Serum levels of YKL-40 showed significant correlations with most IOS indices at baseline (P=.008-.039), but there was no association between YKL-40 and spirometry parameters. Neither periostin nor hs-CRP were associated with baseline lung function. Children with a significant response in either the exercise challenge or the bronchodilator test had increased serum levels of YKL-40 (P=.003) and periostin (P=.035). YKL-40 correlated significantly with the blood neutrophil count (rs =.397, P=.005) but was not associated with biomarkers of eosinophilic inflammation. Serum YKL-40 is a potential biomarker for lung function deficits in children with asthmatic symptoms. These deficits appear to be focused on small airways and may remain undetected with spirometry.

Chitinase-like protein YKL-40 correlates with inflammatory phenotypes, anti-asthma responsiveness and future exacerbations

BackgroundAsthma is a heterogeneous chronic airway disease, which may be classified into different phenotypes. YKL-40 is a chitin-binding glycoprotein with unclear functions, but its expression is associated with inflammation and tissue remodeling. However, few studies have explored whether YKL-40 is associated with inflammatory phenotypes of asthma.MethodsThe study had two parts. Study I (n = 115) was a one-year prospective cohort designed to explore the relationship of serum YKL-40 levels with inflammatory phenotypes of asthma at baseline, and during exacerbations. Study II (n = 62) was a four-week prospective cohort designed to define whether serum YKL-40 levels could predict responses to a fixed anti-asthma regimen. YKL-40, IL-6 and CCL22 levels were detected using ELISA, and a sputum inflammatory panel (including IL-1β, IL-5, IL-8 and TNF-α) was assessed using Luminex-based MILLIPLEX assay.ResultsStudy I: Serum YKL-40 levels in non-eosinophilic asthma (NEA) i.e. neutrophilic (47.77 [29.59, 74.97] ng/mL, n = 40) and paucigranulocytic (47.36 [28.81, 61.68] ng/mL, n = 31) were significantly elevated compared with eosinophilic asthma (31.05 [22.41, 51.10] ng/mL, n = 44) (P = 0.015). Serum YKL-40levels positively correlated with blood neutrophils, sputum IL-1β and plasma IL-6 but negatively correlated with serum IgE and blood eosinophils (all P ≤ 0.05). Baseline YKL-40 levels predicted moderate to severe exacerbations within a one-year period (aOR = 4.13, 95% CI = [1.08, 15.83]). Study II: Serum YKL-40 was an independent biomarker of negative responses to anti-asthma regimens (adjusted Odds Ratio [aOR] = 0.82, 95% CI = [0.71, 0.96].ConclusionsThese studies show that YKL-40 is a non-type 2 inflammatory signature for NEA, which could predict responsiveness or insensitivity to anti-asthma medications and more exacerbations. Further studies are needed to assess whether monitoring YKL-40 levels could provide potential implications for clinical relevance.

A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts

BackgroundThe chitinase-like protein YKL-40 plays a major role in inhibiting the inflammasome. Deregulation of inflammasome activation is emerging as a key modulator of pathologic airway inflammation in patients with asthma. We determined whether cis-expression quantitative trait loci (eQTLs) of the gene that encodes YKL-40, chitinase 3-like 1 (CHI3L1), are involved in the onset of asthma or in specific asthma phenotypes.MethodsThis case-control study, which was conducted at the University of Tsukuba, Japan, included a total of 2709 adults from the Tsukuba genome-wide association study (GWAS) cohort (734 healthy volunteers and 237 asthma patients), the Tsukuba replication cohort (375 healthy adult volunteers and 381 adult asthma patients), and the Hokkaido replication cohort (554 healthy adult volunteers and 428 adult asthma patients). Among 34 cis-eQTLs in CHI3L1 in the lung, rs946261 was associated with adult asthma in these Japanese cohorts. The genetic impact of rs946261 on asthma was also examined according to the age at onset and adult asthma clusters.ResultsIn the Tsukuba GWAS cohort, the C allele at rs946261 was significantly associated with reduced expression of CHI3L1 mRNA in the lung and with development of asthma (odds ratio (OR) 1.27; P = 0.036). The association was also observed following analysis of the three Japanese cohorts (OR 1.16; P = 0.013). A stronger association was found with late-onset asthma that developed at 41 years of age or later (OR 1.24; 95% confidence interval (CI) 1.07–1.45; P = 0.0058) and with a specific asthma phenotype characterized by late onset, less atopy, and mild airflow obstruction (OR 1.29; 95% CI 1.03–1.61; P = 0.027).ConclusionsThe genotype consisting of the cis-eQTL allele that reduces expression of CHI3L1 was specifically associated with late-onset adult asthma. Given the important role of YKL-40 in many pathophysiological processes, including cell growth, migration, chemotaxis, reorganization, and tissue remodeling, it may be involved in an important pathogenic role in the establishment of inflammation and remodeling in asthmatic airways. Our findings may indicate the presence of a specific endotype related to exaggerated activation of YKL-40 in the pathogenesis of late-onset adult asthma.

PO-265 Cisplatin induces pro-inflammatory program and modulates pro-angiogenic potential of human tumor-associated macrophages

IntroductionChemotherapy is one of the main methods of antitumor treatment. The effect of chemotherapy depends not only on the cytotoxicity for cancer cells, but also on the response of immune component of tumour microenvironment. Key innate immune cells in tumour microenvironment are tumor-associated macrophages (TAM), that can cooperate or interfere with anti-cancer therapies.The aim of our study was to analyse how commonly used chemotherapeutic agent cisplatin affects major function of TAM that control tumour progression.Material and methodsHuman primary monocytes-derived macrophages were stimulated ex vivo by supernatants of breast cancer cells MCF-7 and colorectal cancer cells Colo206F to model cancer-specific TAM. Cisplatin treatment was performed on day 6 of macrophages differentiation. Confocal microscopy was used for the analysis of surface macrophage receptors. RT-PCR and ELISA were used to analyse production of secreted pro-inflammatory and pro-angiogenic cytokines markers.Results and discussionsIn the model breast and colon cancer-specific TAM we identified both stimulating and suppressing effects of cisplatin. The major stimulating effects were identified on the expression of pro-inflammatory cytokines IL1b, IL6, IL8, TNFa, anti-inflammatory cytokine IL10, TGFb and major pro-angiogenic factor VEGF-A. Cisplatin suppressed the expression of scavenger receptors CD163, CD206, as well as chitinase-like proteins YKL-39 and YKL-40, that support tumor-angiogenesis. Cisplatin did not significantly affect the expression of matrix metalloproteinases. ELISA demonstrated that significant levels of secreted VEGF are produced only by breast cancer TAM, and are enhanced by cisplatin treatment. Confocal microscopy analysis demonstrated the suppressive effect of cisplatin on the expression of receptors responsible for the internalisation of components of the tumour microenvironment: CD206, stabilin-1 and CD163 in both breast and colon cancer TAM. Cispalin treatment slightly enhanced expression of LYVE1 in breast cancer TAM, but not in colon cancer TAM.ConclusionWe found that cisplatin has a stimulating effects on the mixed pro-inflammatory program of TAM, and enhanced expression of major pro-angiogenic factor VEGF therefore creating supportive conditions for the enhanced mutagenesis of transformed cells and enhanced metastasis. Out data indicate that additional targeting of TAM during the chemotherapy course is a promising therapeutic strategy to avoid cancer metastasis.This study was supported by grand RNF №14-15-00350.

Characterisation of asthma subgroups associated with circulating YKL-40 levels.

The chitinase-like protein YKL-40 mediates airway inflammation and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined.We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Programme (n=167) and the New York University/Bellevue Asthma Repository (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups.Four YKL-40 clusters (C1-C4) were identified. C3 and C4 had high serum YKL-40 levels compared with C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction, and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset and less airflow obstruction, but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-type 2 inflammatory pathways.Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma.

Genetic and epigenetic regulation of YKL-40 in childhood

Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3-like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown. We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood. We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4years of age by using multivariable logistic regression. YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs ormethylation levels, were associated with childhood asthma.

High serum YKL-40 level positively correlates with coronary artery disease.

We investigated the predictive value of chitinase-like protein YKL-40 in coronary artery disease (CAD). Serum YKL-40 levels in 116 CAD patients and 82 healthy controls were analyzed. Severity of CAD was evaluated using Gensini scores. Spearman's correlation was used to evaluate the correlation between Gensini scores and YKL-40 levels. The predictive value of YKL-40 was determined by receivers operating characteristic curve analysis. Serum YKL-40 levels were significantly elevated in CAD group as compared with control group. A positive correlation was found between the serum YKL-40 level and Gensini score. The optimum cut-off value of YKL-40 concentration was 127.7 ng/ml for distinguishing CAD patients from healthy controls with a 75.9% sensitivity and 57.3% specificity. A positive correlation exists between YKL-40 levels and CAD, and YKL-40 might be a useful adjunct in the diagnosis of CAD.

A longitudinal assessment of circulating YKL-40 levels in preschool children with wheeze.

The chitinase-like protein YKL-40 (CHI3L1) is elevated in the circulation of adults and schoolchildren with chronic severe asthma. It is unknown whether YKL-40 is altered in younger, preschool children with wheeze, acute or chronic. We therefore examined YKL-40 in preschool children during an acute episode of wheeze and during remission, in comparison with healthy controls. Blood was obtained from 128 children (aged 6-44 months) at the emergency department during an acute episode of wheeze, and at two follow-up visits (approximately 3 months and 1 year later), as well as from 100 age-matched healthy controls on one occasion. Plasma YKL-40 levels were examined in relation to CHI3L1 rs4950928 genotype and clinical characteristics including Asthma Predictive Index, medication use, time spent with respiratory symptoms, atopic status, and blood leukocytes. Children with wheeze had higher median YKL-40 levels at the acute visit (14.7 (11.5-22.6) ng/ml, p < 0.001) and 3-month follow-up (15.9 (11.5-20.2), p < 0.001) compared to the 1-year follow-up (11.9 (9.5-17.3)). YKL-40 levels in healthy controls (13.6 (11.0-17.0)) tended to be lower than those during acute wheeze (p = 0.07) and 3-month follow-up (p = 0.04), but were no different at the 1-year follow-up. CHI3L1 rs4950928 affected YKL-40 in all subjects, with highest levels present in those with the CC genotype (p < 0.001). Genotype frequency was similar in the two subject groups. YKL-40 levels showed a positive correlation with blood neutrophil counts but no consistent relationships with clinical characteristics of relevance to continuous wheeze. YKL-40 levels were elevated during acute wheeze in preschool children, a finding which may be related to current neutrophilic inflammation, but YKL-40 was not associated with characteristics of persistent wheeze in this young cohort.

The role of chitin, chitinases, and chitinase-like proteins in pediatric lung diseases.

Chitin, after cellulose, the second most abundant biopolymer on earth, is a key component of insects, fungi, and house-dust mites. Lower life forms are endowed with chitinases to defend themselves against chitin-bearing pathogens. Unexpectedly, humans were also found to express chitinases as well as chitinase-like proteins that modulate immune responses. Particularly, increased levels of the chitinase-like protein YKL-40 have been associated with severe asthma, cystic fibrosis, and other inflammatory disease conditions. Here, we summarize and discuss the potential role of chitin, chitinases, and chitinase-like proteins in pediatric lung diseases.

The chitinase-like protein YKL-40 is not a useful biomarker for severe persistent asthma in children

BackgroundThe chitinase-like protein YKL-40 is thought to play a role in inflammation and tissue remodeling. In adults with severe asthma, YKL-40 is expressed in the airway and YKL-40 levels are elevated in the serum. ObjectiveTo compare YKL-40 levels in children with severe persistent asthma with those in adults with severe persistent asthma and to determine whether YKL-40 levels correlate with increasing asthma severity in childhood asthma. MethodsIn this prospective, cross-sectional study, 23 adults and 19 children with severe persistent asthma, 23 children with moderate persistent asthma, and 19 children with mild persistent asthma were enrolled. The following data were collected on each patient: spirometry, exhaled nitric oxide, percutaneous skin testing results to aeroallergens, peripheral eosinophils, serum IgE levels, and serum YKL-40 levels. ResultsCompared with adults, children with severe persistent asthma had significantly lower YKL-40 levels, higher values for forced vital capacity and forced expiration volume in 1 second, higher serum IgE levels, and higher exhaled nitric oxide levels. YKL-40 levels did not correlate with increasing asthma severity in the pediatric cohort. ConclusionSevere persistent asthma in childhood is not associated with elevated YKL-40 levels, unlike in adults with severe persistent asthma. YKL-40 is not a useful biomarker for asthma severity in childhood asthma.

Airway, but not serum or urinary, levels of YKL-40 reflect inflammation in early cystic fibrosis lung disease

BackgroundCystic fibrosis (CF) lung disease begins in early life and is progressive with the major risk factor being an exaggerated inflammatory response. Currently, assessment of neutrophilic inflammation in early cystic fibrosis (CF) lung disease relies on bronchoalveolar lavage (BAL). The chitinase-like protein YKL-40 is raised in sputum and serum of adults with CF. We investigated YKL-40 in BAL, serum and urine to determine whether this reflected inflammation and infection in young children with CF.MethodsYKL-40 was measured in matched samples of BAL, serum and urine obtained from 36 infants and young children with CF participating in an early surveillance program. Levels were compared to clinical data and markers of inflammation detected in the lung.ResultsYKL-40 in BAL correlated with pulmonary infection [β=1.30 (SE 0.34), p < 0.001] and BAL markers of inflammation [macrophage number: r2 = 0.34, p < 0.001; neutrophil number: r2 = 0.74, p < 0.001; neutrophil elastase: r2 = 0.47, p < 0.001; CXCL8: r2 = 0.45, p < 0.001; IL-β: r2 = 0.62, p < 0.001]. YKL-40 was detectable in serum but levels did not correlate with BAL levels in the same individuals (r2 = 0.04, p = 0.14) or with inflammatory markers. YKL-40 was below the limit of detection in urine (30 pg/ml).ConclusionsThis study demonstrates that levels of the chitinase-like protein YKL-40 reflect airway inflammation and infection in early CF lung disease. The lack of increased YKL-40 in serum in the absence of systemic inflammation limits the benefit of this potential biomarker in early disease.