Chitinase 3-like 1 suppresses injury and promotes fibroproliferative responses in Mammalian lung fibrosis

Sci Transl Med. 2014 Jun 11;6(240):240ra76. doi: 10.1126/scitranslmed.3007096.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines / genetics
  • Adipokines / metabolism*
  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Bone Marrow Transplantation
  • Cell Proliferation
  • Chitinase-3-Like Protein 1
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Humans
  • In Situ Nick-End Labeling
  • Lectins / genetics
  • Lectins / metabolism*
  • Lung / cytology*
  • Mice
  • Mice, Knockout
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / metabolism*

Substances

  • Adipokines
  • CHI3L1 protein, human
  • Chitinase-3-Like Protein 1
  • Lectins