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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.
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Research Article Cardiology Pulmonology

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

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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

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Figure 1

Association between Ln(CHI3L1) levels and hemodynamics in all patients with available hemodynamics.

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Association between Ln(CHI3L1) levels and hemodynamics in all patients w...
A generalized linear mixed effect model was used to examine associations between Ln(CHI3L1) levels and mPAP and PVR. (A and B) All patients. (C and D) Combined patients with group 1 PAH and group 3 PH. (E and F) Group 1 PAH patients alone. Gray circles are individual data points, dark blue line is regression line, and light blue lines represent 95% confidence bands. Parametric data were compared by 2-tailed Student’s t test. Nonparametric data were compared using the Mann-Whitney U test. PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance.

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

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