Paclitaxel Alleviates Pulmonary Arterial Hypertension by Modulating Macrophage M2a Polarization via the NF-κB Pathway

Abstract

BackgroundPulmonary arterial hypertension (PAH) is primarily associated with vascular remodeling, in which macrophage polarization is considered to play a major role. Paclitaxel(PTX) has been shown to modulate macrophage polarization in tumors. We investigated whether PTX could alleviate PAH by altering macrophage polarization, particularly M2a macrophages. MethodsTo establish PAH, rats underwent left pneumonectomy followed by monocrotaline (MCT) injection. In vitro, THP-1 cells were differentiated into macrophages using PMA and polarized with LPS+IFN-{gamma} (M1), IL-4 (M2a), or IL-10 (M2c), followed by PTX intervention. Hemodynamic parameters (mPAP) and right ventricular hypertrophy index (RVHI) were measured. Pathological changes were assessed via HE staining. Single-cell RNA sequencing analyzed macrophage subsets in lung tissues. Macrophage polarization and NF-{kappa}B pathway activity were evaluated using immunohistochemistry, qPCR, cytokine profiling and Western blot. ResultsIn a severe PAH model induced by left pneumonectomy plus monocrotaline, pulmonary interstitial macrophages initially exhibited a predominant M1-polarized phenotype in the early stage, which transitioned to an M2a-polarized phenotype in the later stage and eventually stabilized. Low-dose PTX alleviated severe PAH by reducing perivascular macrophage infiltration. Cytological studies confirmed that PTX inhibited M2a polarization via suppression of NF-{kappa}B, thereby attenuating its proliferative effects on pulmonary arterial smooth muscle cells (PASMCs). ConclusionM2a macrophages play a crucial role in PAH progression. PTX may alleviate PAH by suppressing M2a polarization via the NF-{kappa}B pathway.