Key result
Mast cells bidirectionally modulate hypoxic pulmonary hypertension through harmful degranulation and protective lipid mediators.
Why the study?
Hypoxic pulmonary hypertension is characterized by persistent pulmonary vascular remodeling and elevated pressure driven by immune microenvironment dysregulation, in which activated mast cells bidirectionally regulate vascular remodeling.
This review highlights the dual pro-inflammatory and protective regulatory roles of mast cells in hypoxic pulmonary hypertension, identifying mast cell stabilization, IgE blockade, and ω-3 epoxide lipid pathways as promising therapeutic targets.
Answers are grounded in this paper and cite their sources.
Mast cell stabilization and ω-3 epoxide pathways merit investigation in hypoxic pulmonary hypertension; leaves open clinical translation pending prospective trials.
Hypoxic pulmonary hypertension (HPH) is characterized by persistent pulmonary vascular remodeling and elevated pressure, with immune microenvironment dysregulation driving its progression. Mast cells (MCs), as key innate immune cells, are activated under hypoxia via multiple pathways including ROS/calcium signaling, PI3K, and HIF-1α. Through degranulation, they release pro-inflammatory mediators such as histamine, IL-6, and TNF-α, while also secreting protective lipid mediators like ω-3 epoxides via non-degranulation pathways, thereby bidirectionally regulating vascular remodeling. Activated MCs interact with fibroblasts, macrophages, T cells, endothelial cells, and smooth muscle cells, exacerbating inflammation, immune imbalance, and extracellular matrix deposition through key signaling axes including IL-6, IL-1R1/MyD88, and RhoA-ROCK, thus promoting disease progression. Experimental strategies targeting MC stabilization, IgE-FcϵRIα signaling blockade, and the PAF-AH2-ω-3 epoxide axis have shown therapeutic efficacy. Future studies should utilize single-cell and spatial omics to dissect the spatiotemporal heterogeneity of cellular crosstalk and establish immune-phenotype-guided precision intervention systems, offering new directions for HPH therapy.
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Zhai et al. (2026) conducted a review in Hypoxic pulmonary hypertension. Mast cell-targeted therapies (mast cell stabilization, IgE-FcϵRIα signaling blockade, and PAF-AH2-ω-3 epoxide axis modulation) was evaluated on Pulmonary vascular remodeling and immune microenvironment regulation. Mast cells bidirectionally regulate hypoxic pulmonary hypertension by promoting vascular remodeling via degranulation while exerting protective effects through ω-3 epoxide lipid mediators.
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