title: Role of breast regression protein-39 in the pathogenesis of cigarette smoke-induced inflammation and emphysema.
abstract: 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.
authors.affiliation: Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Min-Jong
authors.initials: MJ
authors.lastname: Kang
authors.forename: Charles S
authors.initials: CS
authors.lastname: Dela Cruz
authors.forename: Barbara
authors.initials: B
authors.lastname: Koller
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Chupp
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.forename: Won-Kyung
authors.initials: WK
authors.lastname: Cho
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
mesh_terms: D054392:Adipokines; D000368:Aged; D000818:Animals; D000071451:Chitinase-3-Like Protein 1; D004646:Emphysema / Q000378:metabolism*; D005260:Female; D006023:Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D006801:Humans; D007249:Inflammation; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D037102:Lectins / Q000096:biosynthesis / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism; D015398:Signal Transduction; D012906:Smoke; D012907:Smoking / Q000009:adverse effects
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; C509289:Chil1 protein, mouse; D000071451:Chitinase-3-Like Protein 1; D006023:Glycoproteins; D020382:Interleukin-18; D037102:Lectins; D012906:Smoke