Baicalin attenuates bleomycin-induced pulmonary fibrosis via adenosine A2a receptor related TGF-β1-induced ERK1/2 signaling pathway

Abstract

BackgroundBaicalin has been reported to have anti-fibrosis effect; however, its mechanism still remains to be elucidated. Adenosine A2a receptor (A2aR) is a novel inflammation regulator, and transforming growth factor-β1 (TGF-β1)-induced extracellular signal regulated kinase1/2 (ERK1/2) signaling pathway plays an important role in idiopathic pulmonary fibrosis (IPF). This study was to explore the relationship of A2aR and TGF-β1-induced ERK1/2 in bleomycin (BLM)-induced pulmonary fibrosis in mice, and to investigate whether A2aR mediate the anti-fibrosis effect of Baicalin on BLM-induced pulmonary fibrosis.MethodsThe A2aR−/− and A2aR+/+ mice were respectively divided into three groups: control group, model group, baicalin group. Pulmonary fibrosis was induced in mice of model groups by intratracheal instillation of bleomycin, and baicalin was administered in mice of baicalin groups daily for 28 days. Histopathological and ultrastructural changes of lung tissues were evaluated. Lung coefficient and the levels of hydroxyproline (HYP) in lung tissues were measured at the same time. The levels of serum TGF-β1 were measured by ELISA. The expression of TGF-β1, ERK1/2, p-ERK1/2 and A2aR were detected by western blot and immunohistochemical staining techniques.ResultsSevere lung fibrosis was observed in the bleomycin-treated mice on day 28. The histopathological findings and collagen content of lung tissues were much severer/higher in A2aR−/− mice than in A2aR+/+ mice. We also showed that TGF-β1 and p-ERK1/2 were upregulated in bleomycin-treated mice and expressed higher in A2aR−/− mice compared to A2aR+/+ mice. Besides, bleomycin-treated A2aR+/+ mice had increased A2aR level in lungs. However, long-term treatment with baicalin in A2aR−/− and A2aR+/+ mice significantly ameliorated the histopathological changes in lungs. Moreover, Increased TGF-β1 and p-ERK1/2 expressions in bleomycin-treated A2aR−/− and A2aR+/+ mice were obviously diminished by baicalin. The baicalin-treated A2aR−/− mice had severer lung fibrosis and higher expressions of TGF-β1 and p-ERK1/2 than A2aR+/+ mice. Baicalin has also upregulated the expression of A2aR in A2aR+/+ mice.ConclusionsGenetic inactivation of A2aR exacerbated the pathological processes of bleomycin-induced pulmonary fibrosis. Together, baicalin could inhibit BLM-induced pulmonary fibrosis by upregulating A2aR, suggesting A2aR as a therapeutic target of baicalin for the treatment of pulmonary fibrosis.

Astragalus and Baicalein Regulate Inflammation of Mesenchymal Stem Cells (MSCs) by the Mitogen-Activated Protein Kinase (MAPK)/ERK Pathway

“…Also, Baicalin has an anti-fibrosis effect on bleomycin-induced pulmonary fibrosis [26]. Similar phenomena were also observed in our study.…”

Modulation of Glutathione Hemostasis by Inhibition of 12/15‐Lipoxygenase Prevents ROS‐Mediated Cell Death after Hepatic Ischemia and Reperfusion

“…at maximum solubility in DMSO in this proof-of-principle experiment. The applied dosage of Baicalein is well established as it has been used in previously described animal studies [ 73 , 74 ], and preliminary dosage finding experiments of our study group showed no significant impact at lower concentrations. Previous studies regarding the protective effects of DMSO on hepatic ischemia and reperfusion used significantly lower dosages (500 mg/kg b.w.…”

Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury

“…Inhibits CD8 + CTL and Th1 expansion to alloantigens. [ 110 ] 27 CD4 + T cells Inhibits TCR-mediated IFN-γ release [ 111 ] 28 CD4 + CD25 + FoxP3 + Tregs Increases number of Tregs and increases the expression of CTLA-4 receptor [ 112 ] 29 CD4 + CD25 + FoxP3 + Tregs Upregulates ecto-enzymes CD39 and CD73 expression accelerating adenosine generation from extracellular ATP [ 112 ] 30 AdoRA2A knockout mice Bleomycin-induced fibrosis is more severe and elevated TGF-β1 is higher than in wild-type mice [ 113 ] 31 AdoRA2A and AdorA2B Adenosine Macrophages Differentiation of monocytes towards M2 macrophages with VEGF and IL-10 release [ 114 – 118 ] 32 Macrophages Inhibits LPS-induced IL-6, MIP-2 and TNF-α release [ 119 , 120 ] 33 AdoRA2B Adenosine Neutrophils Inhibits neutrophil recruitment and transmigration, release of TNF-α, IL-6, MIF-1α and IL-8 [ 121 , 122 ] 34 Neutrophils Inhibits superoxide generation [ 123 ] 35 Neutrophils Inhibits TNF-α release [ 76 ] 36 Macrophages Stimulates IL-10 release [ 124 ] 37 …”