YKL-40 Is Elevated in Patients with Chronic Obstructive Pulmonary Disease and Activates Alveolar Macrophages

Abstract

YKL-40 is a chitin-binding protein that is elevated in patients with various inflammatory conditions associated with ongoing remodeling. We investigated whether the levels of YKL-40 were up-regulated in the circulation and the airways of patients with chronic obstructive pulmonary disease (COPD), and whether it promoted the production of inflammatory mediators from macrophages. Serum, bronchoalveolar lavage (BAL), bronchial biopsies, lung tissue specimens, and alveolar macrophages from never-smokers (n = 15), smokers without COPD (n = 20), and smokers with COPD (n = 30) were assessed for YKL-40 levels and immunolocalization. In addition, YKL-40-induced mediator release from alveolar macrophages was examined. We found that smokers with COPD had elevated levels of YKL-40 in serum (p ≤ 0.027) and BAL (p ≤ 0.007), more YKL-40-positive cells in bronchial biopsies (p ≤ 0.03), and a greater proportion of alveolar macrophages expressing YKL-40 than smokers without COPD or never-smokers. YKL-40 levels in serum and BAL were associated with airflow obstruction (pre-β2 agonist forced expiratory volume in 1 s, rs = −0.3892, p = 0.0072 and rs = −0.5491, p < 0.0001, respectively) and impaired diffusion lung capacity (transfer factor of the lung for carbon monoxide, rs = −0.4667, p = 0.002 and rs = −0.3854, p = 0.0045, respectively). TNF-α stimulated YKL-40 synthesis in alveolar macrophages from smokers with COPD, and exposure of these cells to YKL-40 promoted the release of IL-8, MCP-1, MIP-1α, and metalloproteinase-9. We conclude that YKL-40 is up-regulated in COPD, in which it may contribute to tissue inflammation and remodeling by sustaining the synthesis of proinflammatory and fibrogenic chemokines and of metalloproteinases by alveolar macrophages.

Macrophage Chitinase 1 Stratifies Chronic Obstructive Lung Disease

“…Thus, in contrast to previous studies of chitinase and chitinase-like proteins in chronic obstructive lung disease (11)(12)(13)(14)(15), we assessed the level of expression for each of the possible chitinase and chitinase-like family members that may be found in human lung: chitinase A (also known as CHIA or AMCase), chitinase 3 like 1 (also known as CHI3L1, HC gp-39, or YKL-40), and chitinase 1 (also known as CHIT1 or chitotriosidase). In addition, we designed our study to continue successful approaches in mice (where whole lung samples for gene expression better avoided sampling errors) and humans (where subjects with more severe lung disease manifest activation of the iNKT cell-macrophage immune axis).…”

“…In fact, chitinase 1 (but not chitinase 3L1) may be found at increased levels in bronchoalveolar lavage (BAL) samples from subjects who are current cigarette smokers (14,15). To determine whether chitinase and chitinase-like proteins might also be detectable in the circulation as a noninvasive biomarker of lung disease, we analyzed plasma levels of chitinase 3L1 and chitinase 1 in smokers without COPD and in current and former smokers with COPD.…”

Ym1/2 Promotes Th2 Cytokine Expression by Inhibiting 12/15(S)-Lipoxygenase: Identification of a Novel Pathway for Regulating Allergic Inflammation

“…However, further studies are required to determine whether Ym1/2 modulates the biosynthesis of molecules other than 12(S)-HETE by the 12/15-LOX pathway. Interestingly, the human Ym1/2 homolog YKL-40, which has been linked to disease severity in asthmatics (36), has recently been ascribed a proinflammatory role in chronic obstructive pulmonary disease (37). Whether YKL-40 can similarly potentiate aspects of allergic inflammation in asthmatics awaits further investigation.…”

Plasma YKL-40 and Total and Disease-Specific Mortality in the General Population

“…YKL-40 has been regarded as an acute-phase protein, because its plasma concentration increases more than 25% after an inflammatory stimulus, but YKL-40 is different from and independent of C-reactive protein (CRP). Increased plasma YKL-40 concentrations have been seen in patients with diseases characterized by inflammation and ongoing tissue remodeling, such as ischemic cardiovascular diseases, cancer, diabetes, asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, pneumonia, and liver fibrosis (1)(2)(3)(4)(5)(6)(7).…”