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Background: Vitamin D insufficiency has been associated with chronic inflammatory diseases. However, the underlying mechanisms remain unclear. Results: Vitamin D inhibits COX-2-mediated inflammatory response by modulating the Akt/NF-B signaling pathway via direct up-regulation of thioesterase superfamily member 4. Conclusion: Vitamin D plays novel roles in anti-inflammation. Significance: Supplemental vitamin D could protect against chronic inflammatory diseases by targeting THEM4/Akt/NF-B signaling.

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Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3CD4 T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2 bone marrow reconstitution and CRTH2 CD4 T cell adoptive transfer deteriorated hypoxia + ovalbumininduced PAH in CRTH2 mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.

Activation of RAGE facilitates the development of hypoxia-induced pulmonary hypertension by increase of ECM deposition in pulmonary arteries. Our results indicate that sRAGE may be a potential biomarker for PAH diagnosis and disease severity, and that RAGE may be a promising target for PAH treatment.

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Background-Pulmonary arterial remodeling characterized by increased vascular smooth muscle proliferation is commonly seen in life-threatening disease, pulmonary arterial hypertension (PAH). Clinical studies have suggested a correlation between osteoprotegerin serum levels and PAH severity. Here, we aimed to invhestigate vascular osteoprotegerin expression and its effects on pulmonary arterial smooth muscle cell proliferation in vitro and in vivo, as well as examine the signal transduction pathways mediating its activity. Methods and Results-Serum osteoprotegerin levels were significantly elevated in patients with PAH and correlated with disease severity as determined by the World Health Organization (WHO) functional classifications and 6-minute walking distance tests. Similarly, increased osteoprotegerin expression was observed in the pulmonary arteries of hypoxia plus SU5416-and monocrotaline-induced PAH animal models. Moreover, osteoprotegerin disruption attenuated hypoxia plus SU5416-induced PAH progression by reducing pulmonary vascular remodeling, whereas lentiviral osteoprotegerin reconstitution exacerbated PAH by increasing pulmonary arterial smooth muscle cell proliferation. Furthermore, pathway analysis revealed that osteoprotegerin induced pulmonary arterial smooth muscle cell proliferation by interacting with integrin α v β 3 to elicit downstream focal adhesion kinase and AKT pathway activation. Conclusions-Osteoprotegerin facilitates PAH pathogenesis by regulating pulmonary arterial smooth muscle cell proliferation, suggesting that it may be a potential biomarker and therapeutic target in this disease. Jia et al Osteoprotegerin in Pulmonary HypertensionIn addition, experimental results indicated that osteoprotegerin promotes the proliferation of various cancer cells and endothelial cells in a TRAIL-independent manner. 14,15 These data expand the functional significance of osteoprotegerin beyond its presumed role as a receptor activator of nuclear factor-κB ligand and TRAIL decoy receptor, and suggest that it may interact with integrins or fatty acid synthase. 8,14,15 This is greatly relevant because pulmonary arterial smooth muscle cells (PASMCs) express several integrin molecules that regulate pulmonary vascular remodeling and contribute to PAH progression. 16,17 Integrins are a large family of structurally related heterodimeric transmembrane receptors that regulate cell-cell and cell-matrix contacts. 18 Of the 18α and 8β subtypes identified, pulmonary vascular smooth muscles express α 1-5 , α 7 , α 8 , α v , β 1 , β 3 , and β 4 .17 On the basis of these observations, we hypothesize that osteoprotegerin may contribute to pulmonary vascular remodeling in an integrindependent manner.In this study, we demonstrated that osteoprotegerin expression was increased in both murine and human pulmonary arterial SMCs (mPASMCs and hPASMCs) in response to hypoxia and in the lung tissue and pulmonary arteries of hypoxia plus SU5416 (HySu)-induced PAH model mice. Moreover, integrin α 1 , α 8 , α v , and β 3 express...

Objective— Macrophages participate in the pathogenesis of pulmonary arterial hypertension (PAH). Lgmn (Legumain), a newly discovered cysteine proteinase belonging to the C13 peptidase family, is primarily expressed in macrophages; however, its roles in PAH remain unknown. Approach and Results— Herein, Lgmn was upregulated in lung tissues of PAH mice subjected to hypoxia plus SU5416 and PAH rats challenged with monocrotaline. Global Lgmn ablation and macrophage-specific ablation alleviated PAH compared with wild-type mice, evident from a reduction in right ventricular systolic pressure, the ratio of the right ventricular wall to the left ventricular wall plus the septum, the pulmonary vascular media thickness, and pulmonary vascular muscularization. Increased expression of ECM (extracellular matrix) proteins was correlated with MMP (matrix metalloproteinase)-2 activation and TGF (transforming growth factor)-β1 signaling in the PAs. Although Lgmn did not affect inflammatory cell infiltration and PA smooth muscle cell proliferation, it drove increased the synthesis of ECM proteins via MMP-2 activation. MMP-2 hydrolyzed the TGF-β1 precursor to the active form. An Lgmn-specific inhibitor markedly ameliorated PAH. Clinically, serum Lgmn levels were closely associated with the severity of idiopathic PAH. Conclusions— Our results indicate that Lgmn inhibition could be an effective strategy for preventing or delaying PAH.