title: Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis.
abstract: Epithelial injury, alternative macrophage accumulation, and fibroproliferation coexist in the lungs of patients with idiopathic pulmonary fibrosis (IPF). Chitinase 3-like 1 (CHI3L1) is a prototypic chitinase-like protein that has been retained over species and evolutionary time. However, the regulation of CHI3L1 in IPF and its ability to regulate injury and/or fibroproliferative repair have not been fully defined. We demonstrated that CHI3L1 levels were elevated in patients with IPF. High levels of CHI3L1 are associated with progression--as defined by lung transplantation or death--and with scavenger receptor-expressing circulating monocytes in an ambulatory IPF population. In preterminal acute exacerbations of IPF, CHI3L1 levels were reduced and associated with increased levels of apoptosis. We also demonstrated that in bleomycin-treated mice, CHI3L1 expression was acutely and transiently decreased during the injury phase and returned toward and eventually exceeded baseline levels during the fibrotic phase. In this model, CHI3L1 played a protective role in injury by ameliorating inflammation and cell death, and a profibrotic role in the repair phase by augmenting alternative macrophage activation, fibroblast proliferation, and matrix deposition. Using three-dimensional culture system of a human fibroblast cell line, we found that CHI3L1 is sufficient to induce low grade myofibroblast transformation. In combination, these studies demonstrate that CHI3L1 is stimulated in IPF, where it represents an attempt to diminish injury and induce repair. They also demonstrate that high levels of CHI3L1 are associated with disease progression in ambulatory patients and that a failure of the CHI3L1 antiapoptotic response might contribute to preterminal disease exacerbations.
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Peng
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Huanxing
authors.initials: H
authors.lastname: Sun
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Chuyan
authors.initials: C
authors.lastname: Tang
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Gan
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Buqu
authors.initials: B
authors.lastname: Hu
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Slade
authors.affiliation: Program on Aging, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Montgomery
authors.affiliation: Program on Aging, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Shaw
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.affiliation: Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Chang-Min
authors.initials: CM
authors.lastname: Lee
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Meagan W
authors.initials: MW
authors.lastname: Moore
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Mridu
authors.initials: M
authors.lastname: Gulati
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Chun Geun
authors.initials: CG
authors.lastname: Lee
authors.affiliation: Division of Biology and Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI 02912, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Elias
authors.affiliation: Section of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
mesh_terms: D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D000071451:Chitinase-3-Like Protein 1; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D037102:Lectins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology*; D051379:Mice; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism*
chemical_list: D054392:Adipokines; C084533:CHI3L1 protein, human; D000071451:Chitinase-3-Like Protein 1; D037102:Lectins