Abstract
Previously we reported that silibinin ameliorated pulmonary arterial hypertension (PAH) in rat PAH models, possibly through the suppression of the CXCR4/SDF-1, until the point where PAH became a severe and irreversible condition. To further investigate how silibinin ameliorates PAH, we first attempted to clarify its effect on bone marrow cells (BMCs), since the CXCR4/SDF-1 axis is known to regulate stem cell migration and attachment in BM niches. Rat PAH models were established through a combination of a single subcutaneous injection of monocrotaline (MCT) and chronic hypoxic conditions (10% O2). BMCs were harvested and cultured, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and flow cytometry (FCM) were performed to investigate whether silibinin affected CXCR4 expression. Silibinin upregulated the gene expression of stem cell related markers CXCR4, SDF-1, SCF, and c-Kit, inflammatory markers IL-6 and TNFα, mesenchymal stem cell (MSC)-related markers CD44 and CD29, and the granulocyte/monocyte-macrophage marker CD14 in cultured BM in PAH rats, but not in normal rats, except CXCR4. FCM showed that silibinin increased the CXCR4-positive cell population in a granulocyte fraction of cultured BMCs. However, immunohistochemical (IHC) staining showed no significant change in CXCR4 expression in the BM of the tibias. These results suggest that silibinin increases the expression of CXCR4 in BM, and the increased CXCR4-positive cells could be granulocytes/monocyte-macrophages.
Highlights
Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome characterized by high blood pressure and vascular remodeling in the pulmonary arterioles
We focused on C-X-C chemokine receptor type 4 (CXCR4) and performed pharmacological analysis of a CXCR4 inhibitor, silibinin, to treat pulmonary arterial hypertension (PAH)
We previously reported that CXCR4 expression is significantly higher in the pulmonary arteries of PAH rats treated with monocrotaline (MCT) and hypoxia than in normal rats [14]
Summary
Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome characterized by high blood pressure and vascular remodeling in the pulmonary arterioles. Recent studies of PAH treatment have focused on gene and cell therapy in animal models, as these treatments are considered to attenuate pulmonary vascular remodeling [4,5]. We focused on C-X-C chemokine receptor type 4 (CXCR4) and performed pharmacological analysis of a CXCR4 inhibitor, silibinin, to treat PAH. CXCR4-positive cells have recently been implicated in the development of pulmonary arterial hypertension (PAH) [8,9,10,11,12,13]. We previously reported that CXCR4 expression is significantly higher in the pulmonary arteries of PAH rats treated with monocrotaline (MCT) and hypoxia than in normal rats [14]. We investigated the effect of silibinin on the BM cells of normal rats and PAH rat models
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