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1.  Segmental Allergen Challenge Enhances Chitinase Activity and Levels of CCL18 in Mild Atopic Asthma 
Background
Allergic airway inflammation contributes to the airway remodeling that has been linked to increased obstruction and morbidity in asthma. However, the mechanisms by which allergens contribute to airway remodeling in humans are not fully established. CCL18, chitotriosidase (CHIT1) and YKL-40 are readily detectable in the lungs and contribute to remodeling in other fibrotic diseases, but their involvement in allergic asthma is unclear.
Objective
We hypothesized that CCL18, YKL-40, and CHIT1 bioactivity are enhanced in allergic asthma subjects after segmental allergen challenge and are related to increased profibrotic and Th2-associated mediators in the lungs.
Methods
Levels of CCL18 and YKL-40 protein and CHIT1 bioactivity in bronchoalveolar lavage (BAL) fluid, as well as CCL18, YKL-40, and CHIT1 mRNA levels in BAL cells, were evaluated in patients with asthma at baseline and 48 h after segmental allergen challenge. We also examined the correlation between CCL18 and YKL-40 levels and CHIT1 activity with the levels of other profibrotic factors and chemokines previously shown to be up-regulated after allergen challenge.
Results
CHIT1 activity and YKL-40 and CCL18 levels were elevated after segmental allergen challenge and these levels correlated with those of other profibrotic factors, T cell chemokines, and inflammatory cells after allergen challenge. CCL18 and YKL-40 mRNA levels also increased in BAL cells after allergen challenge.
Conclusions & Clinical Relevance
Our results suggest that CCL18 and YKL-40 levels and CHIT1 activity are enhanced in allergic airway inflammation and thus may contribute to airway remodeling in asthma.
doi:10.1111/cea.12032
PMCID: PMC3623278  PMID: 23331560
asthma; segmental bronchoprovocation; CHIT1; YKL-40; CCL18
2.  Role of Breast Regression Protein–39 in the Pathogenesis of Cigarette Smoke–Induced Inflammation and Emphysema 
The exaggerated expression of chitinase-like protein YKL-40, the human homologue of breast regression protein–39 (BRP-39), was reported in a number of diseases, including chronic obstructive pulmonary disease (COPD). However, the in vivo roles of YKL-40 in normal physiology or in the pathogenesis of specific diseases such as COPD remain poorly understood. We hypothesized that BRP-39/YKL-40 plays an important role in the pathogenesis of cigarette smoke (CS)–induced emphysema. To test this hypothesis, 10-week-old wild-type and BRP-39 null mutant mice (BRP-39−/−) were exposed to room air (RA) and CS for up to 10 months. The expression of BRP-39 was significantly induced in macrophages, airway epithelial cells, and alveolar Type II cells in the lungs of CS-exposed mice compared with RA-exposed mice, at least in part via an IL-18 signaling–dependent pathway. The null mutation of BRP-39 significantly reduced CS-induced bronchoalveolar lavage and tissue inflammation. However, CS-induced epithelial cell apoptosis and alveolar destruction were further enhanced in the absence of BRP-39. Consistent with these findings in mice, the tissue expression of YKL-40 was significantly increased in the lungs of current smokers compared with the lungs of ex-smokers or nonsmokers. In addition, serum concentrations of YKL-40 were significantly higher in smokers with COPD than in nonsmokers or smokers without COPD. These studies demonstrate a novel regulatory role of BRP-39/YKL-40 in CS-induced inflammation and emphysematous destruction. These studies also underscore that maintaining physiologic concentrations of YKL-40 in the lung is therapeutically important in preventing excessive inflammatory responses or emphysematous alveolar destruction.
doi:10.1165/rcmb.2010-0081OC
PMCID: PMC3135840  PMID: 20656949
YKL-40/BRP-39; COPD; emphysema; cigarette smoke
3.  Pathways Activated during Human Asthma Exacerbation as Revealed by Gene Expression Patterns in Blood 
PLoS ONE  2011;6(7):e21902.
Background
Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations.
Methodology/Principal Findings
Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations.
Conclusions/Significance
This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.
doi:10.1371/journal.pone.0021902
PMCID: PMC3136489  PMID: 21779351
4.  The Chitinase and Chitinase-Like Proteins: A Review of Genetic and Functional Studies in Asthma and Immune-Mediated Diseases 
Purpose of Review
This review provides an overview of the chitinase and chitinase-like proteins, chitotriosidase (CHIT1), YKL-40, and acid mammalian chitinase (AMCase), and to summarize the genetic studies of asthma and immune mediated diseases with polymorphisms in the genes encoding these proteins: CHIT1, CHI3L1, and CHIA, respectively.
Recent Findings
Polymorphisms in the CHIT1, CHIA, and CHI3L1 genes influence chitotriosidase enzyme activity, AMCase activity, and YKL-40 levels, respectively. Regulatory SNPs in CHI3L1 were also associated with asthma, atopy, and immune-mediated diseases, and nonsynonymous SNPs in CHIA were associated with asthma. No CHIT1 polymorphisms, including a common nonfunctional 24-bp duplication allele, have been associated with asthma.
Summary
These genes represent novel asthma susceptibility genes. Variation in CHI3L1 and CHIA have been associated with asthma risk. Polymorphisms in CHIT1 have not yet been associated with asthma, but few studies have been reported. Given that chitotriosidase is the major chitinase in the airways and a common nonfunctional allele is present in many populations, additional studies of this gene are also warranted. Lastly, studies of all three genes need to be conducted in populations of diverse ancestries.
doi:10.1097/ACI.0b013e3283306533
PMCID: PMC3018778  PMID: 19644363
Chitotriosidase; CHIT1; YKL-40; CHI3L1; AMCase; CHIA
5.  Hyperoxia causes angiopoietin 2–mediated acute lung injury and necrotic cell death 
Nature medicine  2006;12(11):1286-1293.
The angiogenic growth factor angiopoietin 2 (Ang2) destabilizes blood vessels, enhances vascular leak and induces vascular regression and endothelial cell apoptosis. We considered that Ang2 might be important in hyperoxic acute lung injury (ALI). Here we have characterized the responses in lungs induced by hyperoxia in wild-type and Ang2–/– mice or those given either recombinant Ang2 or short interfering RNA (siRNA) targeted to Ang2. During hyperoxia Ang2 expression is induced in lung epithelial cells, while hyperoxia-induced oxidant injury, cell death, inflammation, permeability alterations and mortality are ameliorated in Ang2–/– and siRNA-treated mice. Hyperoxia induces and activates the extrinsic and mitochondrial cell death pathways and activates initiator and effector caspases through Ang2-dependent pathways in vivo. Ang2 increases inflammation and cell death during hyperoxia in vivo and stimulates epithelial necrosis in hyperoxia in vitro. Ang2 in plasma and alveolar edema fluid is increased in adults with ALI and pulmonary edema. Tracheal Ang2 is also increased in neonates that develop bronchopulmonary dysplasia. Ang2 is thus a mediator of epithelial necrosis with an important role in hyperoxic ALI and pulmonary edema.
doi:10.1038/nm1494
PMCID: PMC2768268  PMID: 17086189
6.  Effect of Variation in CHI3L1 on Serum YKL-40 Level, Risk of Asthma, and Lung Function 
The New England journal of medicine  2008;358(16):1682-1691.
BACKGROUND
The chitinase-like protein YKL-40 is involved in inflammation and tissue remodeling. We recently showed that serum YKL-40 levels were elevated in patients with asthma and were correlated with severity, thickening of the subepithelial basement membrane, and pulmonary function. We hypothesized that single-nucleotide polymorphisms (SNPs) that affect YKL-40 levels also influence asthma status and lung function.
METHODS
We carried out a genomewide association study of serum YKL-40 levels in a founder population of European descent, the Hutterites, and then tested for an association between an implicated SNP and asthma and lung function. One associated variant was genotyped in a birth cohort at high risk for asthma, in which YKL-40 levels were measured from birth through 5 years of age, and in two populations of unrelated case patients of European descent with asthma and controls.
RESULTS
A promoter SNP (−131C→G) in CHI3L1, the chitinase 3–like 1 gene encoding YKL-40, was associated with elevated serum YKL-40 levels (P = 1.1×10−13), asthma (P = 0.047), bronchial hyperresponsiveness (P = 0.002), and measures of pulmonary function (P = 0.046 to 0.002) in the Hutterites. The same SNP could be used to predict the presence of asthma in the two case–control populations (combined P = 1.2×10−5) and serum YKL-40 levels at birth (in cord-blood specimens) through 5 years of age in the birth cohort (P = 8.9×10−3 to 2.5×10−4).
CONCLUSIONS
CHI3L1 is a susceptibility gene for asthma, bronchial hyperresponsiveness, and reduced lung function, and elevated circulating YKL-40 levels are a biomarker for asthma and decline in lung function.
doi:10.1056/NEJMoa0708801
PMCID: PMC2629486  PMID: 18403759
7.  Attenuated Host Resistance against Mycobacterium bovis BCG Infection in Mice Lacking Osteopontin 
Infection and Immunity  1999;67(8):4223-4230.
Expression of the cytokine osteopontin (OPN) is elevated in granulomas caused by Mycobacterium tuberculosis. We tested the hypothesis that OPN contributes to host protection in a mouse model of mycobacterial infection. When infected with Mycobacterium bovis BCG, mice lacking a functional OPN gene had more severe infections characterized by heavier bacterial loads and a delayed clearance of the bacteria. The OPN-null mice had greater granuloma burdens consistent with the elevated bacterial load. The ability of osteopontin to facilitate the clearance of mycobacteria was most pronounced early after infection and appeared to be independent of known mediators of resistance to infection by mycobacteria: antigen-specific T-cell immunity, gamma interferon production, and nitric oxide production. BCG grew more rapidly in macrophages derived from OPN-null mice than in those from wild-type mice, demonstrating that the null phenotype was due to an intrinsic macrophage defect. These results indicate that osteopontin augments the host response against a mycobacterial infection and that it acts independently from other antimycobacterial resistance mechanisms.
PMCID: PMC96728  PMID: 10417195

Results 1-7 (7)