Tacrolimus ameliorates pulmonary hypertension associated with pulmonary fibrosis via modulation of vascular remodeling
- 1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai-Baiyang Joint R&D Center for Basic and Translational Medicine of Organ Fibroproliferation, Nankai University
- 2Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
- 3Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine
Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is frequently complicated by pulmonary hypertension (IPF-PH), a severe condition that worsens symptoms, reduces exercise capacity, and shortens survival. Current anti-fibrotic and PH-targeted therapies show limited efficacy in IPF-PH, and the therapeutic role of tacrolimus in this composite disease remains underexplored.
Methods: A bleomycin-induced IPF-PH rat model was established. Rats were randomized into control, bleomycin model, treprostinil (positive control), and tacrolimus (0.05 mg/kg/day, subcutaneous, 21 days) groups. Right ventricular systolic pressure (RVSP), echocardiography, right ventricular and lung histology, immunohistochemistry, qRT-PCR, and Western blot were assessed. In vitro, C166 endothelial cells and primary rat pulmonary arterial endothelial cells were stimulated with bleomycin with or without tacrolimus; MOVAS smooth muscle cells were stimulated with TGF-β1 with or without tacrolimus. Endpoints included cell viability, tube formation, ROS, SOD/GSH, apoptosis, proliferation/migration, and MAPK/PI3K/AKT signaling.
Results: Tacrolimus reduced RVSP, improved PAT/PET and right heart function, attenuated right ventricular hypertrophy and pulmonary fibrosis, and decreased vascular wall thickness and α-SMA expression. It also downregulated fibrosis markers Fn1 and Col1a1. In endothelial cells, tacrolimus restored P-VEGFR2/VEGFR2 and VE-cadherin expression, promoted tube formation, reduced apoptosis (Bax/Bcl-2, cleaved caspase-9/3), and alleviated oxidative stress (ROS, SOD/GSH, Keap1/HO-1). In smooth muscle cells, tacrolimus inhibited TGF-β1-induced proliferation and migration and reduced Ki67 expression. Mechanistically, tacrolimus suppressed MAPK (JNK, ERK, p38) and PI3K/AKT pathway activation in vivo and in vitro .
Discussion: Tacrolimus ameliorates bleomycin-induced IPF-PH through vascular remodeling-oriented, multi-target effects, including endothelial protection, suppression of oxidative stress and apoptosis, and inhibition of smooth muscle proliferation, partly via MAPK and PI3K/AKT signaling. These findings support tacrolimus as a potential therapeutic candidate for IPF-PH, especially in patients with prominent vascular remodeling, while highlighting the need for further dose-response, target-specific, immunomodulatory, and delivery optimization studies before clinical translation.
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BibTeX
@article{liu2026tacrolimus,
title = {{Tacrolimus ameliorates pulmonary hypertension associated with pulmonary fibrosis via modulation of vascular remodeling}},
author = {Xueze Liu and Qi Chen and Yayue Hu and Zhigang Liu and Zhongyi Yang and Jiayang Yu and Huihui Li and Ruxuan Chen and Chi Shao and Shiyang Wang and Cheng Yang and Xiaohe Li and Hui Huang},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1880903},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1880903/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Tacrolimus ameliorates pulmonary hypertension associated with pulmonary fibrosis via modulation of vascular remodeling
AU - Xueze Liu
AU - Qi Chen
AU - Yayue Hu
AU - Zhigang Liu
AU - Zhongyi Yang
AU - Jiayang Yu
AU - Huihui Li
AU - Ruxuan Chen
AU - Chi Shao
AU - Shiyang Wang
AU - Cheng Yang
AU - Xiaohe Li
AU - Hui Huang
PY - 2026
DA - 2026/10/26
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1880903
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1880903/full
AB - Introduction: Idiopathic pulmonary fibrosis (IPF) is frequently complicated by pulmonary hypertension (IPF-PH), a severe condition that worsens symptoms, reduces exercise capacity, and shortens survival. Current anti-fibrotic and PH-targeted therapies show limited efficacy in IPF-PH, and the therapeutic role of tacrolimus in this composite disease remains underexplored. Methods: A bleomycin-induced IPF-PH rat model was established. Rats were randomized into control, bleomycin model, treprostinil (positive control), and tacrolimus (0.05 mg/kg/day, subcutaneous, 21 days) groups. Right ventricular systolic pressure (RVSP), echocardiography, right ventricular and lung histology, immunohistochemistry, qRT-PCR, and Western blot were assessed. In vitro, C166 endothelial cells and primary rat pulmonary arterial endothelial cells were stimulated with bleomycin with or without tacrolimus; MOVAS smooth muscle cells were stimulated with TGF-β1 with or without tacrolimus. Endpoints included cell viability, tube formation, ROS, SOD/GSH, apoptosis, proliferation/migration, and MAPK/PI3K/AKT signaling. Results: Tacrolimus reduced RVSP, improved PAT/PET and right heart function, attenuated right ventricular hypertrophy and pulmonary fibrosis, and decreased vascular wall thickness and α-SMA expression. It also downregulated fibrosis markers Fn1 and Col1a1. In endothelial cells, tacrolimus restored P-VEGFR2/VEGFR2 and VE-cadherin expression, promoted tube formation, reduced apoptosis (Bax/Bcl-2, cleaved caspase-9/3), and alleviated oxidative stress (ROS, SOD/GSH, Keap1/HO-1). In smooth muscle cells, tacrolimus inhibited TGF-β1-induced proliferation and migration and reduced Ki67 expression. Mechanistically, tacrolimus suppressed MAPK (JNK, ERK, p38) and PI3K/AKT pathway activation in vivo and in vitro . Discussion: Tacrolimus ameliorates bleomycin-induced IPF-PH through vascular remodeling-oriented, multi-target effects, including endothelial protection, suppression of oxidative stress and apoptosis, and inhibition of smooth muscle proliferation, partly via MAPK and PI3K/AKT signaling. These findings support tacrolimus as a potential therapeutic candidate for IPF-PH, especially in patients with prominent vascular remodeling, while highlighting the need for further dose-response, target-specific, immunomodulatory, and delivery optimization studies before clinical translation.
SN - 1663-9812
ER -