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Macrophage-Derived LCN2 Promotes Methamphetamine-Induced Pulmonary Hypertension
Jie Zhou1, Zhenzhen Xu1, Dao-Bo Peng2
1Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, P.R. China (J.Z., Z.X., X.L., S.C., K.D., Y.J., C.G., X.P., W.-B.X.).
Lipocalin 2 (LCN2) plays a key role in methamphetamine-induced pulmonary hypertension (METH-PH). LCN2 deficiency protects against METH-PH by reducing inflammation and vascular remodeling, suggesting LCN2 as a therapeutic target.
Area of Science:
- Pulmonary vascular disease
- Inflammation and immunology
- Cellular and molecular mechanisms
Background:
- Methamphetamine (METH) use is linked to pulmonary hypertension (PH).
- Macrophage activation is critical in PH development, but METH-induced PH mechanisms are not fully understood.
Purpose of the Study:
- To investigate the role and mechanism of Lipocalin 2 (LCN2) in METH-induced PH (METH-PH).
Main Methods:
- Established a METH-PH mouse model using wild-type and LCN2 knockout (LCN2-/-) mice.
- Utilized a co-culture system of macrophages and pulmonary artery smooth muscle cells to explore mechanisms.
Main Results:
- LCN2 expression was elevated in lung macrophages of METH-PH mice.
- LCN2-/- mice showed protection against METH-PH, with reduced vascular remodeling and right ventricular pressure.
- LCN2 mediates IL-1β production via NLRP3 inflammasome activation and upregulates SLC7A11/GPX4 in smooth muscle cells, reducing reactive oxygen species and ferroptosis.
Conclusions:
- LCN2 is a key regulator of perivascular inflammation and vascular remodeling in METH-PH.
- Identified a novel mechanism involving LCN2, macrophages, inflammation, and intercellular signaling in METH-PH.
- LCN2 represents a potential therapeutic target for METH-induced PH.
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