Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Chitinase 3 like 1 contributes to the development of pulmonary vascular remodeling in pulmonary hypertension
Xiuna Sun, … , James R. Klinger, Yang Zhou
Xiuna Sun, … , James R. Klinger, Yang Zhou
Published August 11, 2022
Citation Information: JCI Insight. 2022;7(18):e159578. https://doi.org/10.1172/jci.insight.159578.
View: Text | PDF
Research Article Cardiology Pulmonology

Chitinase 3 like 1 contributes to the development of pulmonary vascular remodeling in pulmonary hypertension

  • Text
  • PDF
Abstract

Chitinase 3 like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggest CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including group 1 PAH and group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1-null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a target for the treatment of PAH and PH associated with fibrotic lung disease.

Authors

Xiuna Sun, Erika Nakajima, Carmelissa Norbrun, Parand Sorkhdini, Alina Xiaoyu Yang, Dongqin Yang, Corey E. Ventetuolo, Julie Braza, Alexander Vang, Jason Aliotta, Debasree Banerjee, Mandy Pereira, Grayson Baird, Qing Lu, Elizabeth O. Harrington, Sharon Rounds, Chun Geun Lee, Hongwei Yao, Gaurav Choudhary, James R. Klinger, Yang Zhou

×

Figure 4

CHI3L1 plays a critical role in vascular remodeling responses in a bleomycin-induced pulmonary fibrosis model.

Options: View larger image (or click on image) Download as PowerPoint
CHI3L1 plays a critical role in vascular remodeling responses in a bleom...
WT (+/+), CHI3L1-null mice (-/-), and CHI3L1-transgenic overexpression mice (Tg+) were subjected to intratracheal PBS or bleomycin administration. Mice were sacrificed at day 14 after bleomycin challenge. (A) Whole lung RNA was extracted and CHI3L1 mRNA levels were measured by RT-PCR. (B) CHI3L1 protein levels were measured in the BAL fluid by ELISA. (C) RVSP was measured by right heart catheterization. (D) Fulton’s index was calculated based on the dry weight of right ventricle and left ventricle plus the septum. (E) Aperio digital pathology slide scanner was used to assess the medial remodeling of pulmonary arteries. The thickness of the medial layer was expressed as a fraction of the external diameter of the pulmonary artery. (F) Ashcroft histology scores were assessed to evaluate levels of lung fibrosis. (G) Collagen deposition in the lung was assessed by Sircol assay. (H) H&E staining of the lungs from WT mice, CHI3L1-null mice, and CHI3L1-Tg mice challenged with bleomycin. (I) Vessel wall muscularization of distal pulmonary arterioles (<100 μm in diameter) was quantified based on immunostaining of α-SMA. (J) α-SMA staining of the lungs from WT mice, CHI3L1-null mice, and CHI3L1-Tg mice challenged with bleomycin. Scale bar, 50 μm. Values are mean ± SEM with 4–6 mice in each group. Groups were compared by ANOVA with Bonferroni’s posttest; follow-up comparisons between groups were conducted using a 2-tailed Student’s t test. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. Images are representatives of 4 to 6 mice in each group.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts