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Inflammatory Mechanisms in the Pathogenesis of Pulmonary Arterial Hypertension

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Abstract

Inflammation is a prominent feature of human and experimental pulmonary hypertension (PH) as suggested by infiltration of various inflammatory cells and increased expression of certain cytokines in remodeled pulmonary vessels. Macrophages, T and B lymphocytes, and dendritic cells are found in the vascular lesions of idiopathic pulmonary arterial hypertension (PAH) as well as in PAH associated with connective tissue diseases or infectious etiologies such as HIV. In addition, PAH is often characterized by the presence of circulating chemokines and cytokines, increased expression of growth (such as VEGF and PDGF) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors, and viral protein components (e.g., HIV‐1 Nef), which directly contribute to further recruitment of inflammatory cells and the pulmonary vascular remodeling process. These inflammatory pathways may thus serve as potential specific therapeutic targets. This article provides an overview of inflammatory pathways involving chemokines and cytokines as well as growth factors, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy. © 2011 American Physiological Society. Compr Physiol 1:1929‐1941, 2011.

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Figure 1. Figure 1.

Main inflammatory mediators in pulmonary vascular remodeling in pulmonary arterial hypertension. CX3CL1 (Fractalkine) causes upregulation of its receptor CX3CR1 on CD4+ and CD8+ T lymphocytes . CCL5 (RANTES) and nuclear factor of activated T cells (NFAT) attract T and B lymphocytes. IL‐6 (Interleukin‐6) binds to its soluble receptor (soluble IL‐6 Receptor) and the complex then binds to gp130 . Vascular endothelial growth factor (VEGF) acts through its receptor KDR, a receptor tyrosine kinase . Other growth factors involved in vascular remodeling include platelet‐derived growth factor (PDGF), epithelial growth factor (EGF), and fibroblast growth factor (FGF‐2). The receptor (5‐HTR) and transporter (5‐HTT) of serotonin (5‐HT), and VPAC [the receptors of vasoactive intestinal peptide (VIP)] are all coupled to G‐protein . Endothelin‐1 (ET‐1) is a potent vasoconstrictor and mitogen.

Figure 2. Figure 2.

Schematic inflammatory pathways involving growth factors, vasomodulators, and infectious stimuli in the pathogenesis of pulmonary arterial hypertension. Hypoxia increases influx of Ca2+, which binds to Calcineurin. The complex dephosphorylates NFAT (NFAT‐P), which can now translocate to the nucleus where it alters gene expression. Endothelin acts through Ca++ channels and ERK/Jun kinases . EGF (epidermal growth factor), TNF‐α, and PDGF (platelet‐derived growth factor) act through tyrosine kinase receptors and are partially transduced by intracellular reactive oxidant species (ROS) . The regulatory proteins, SMADs activate nuclear transcription factors through MAPK . 5‐HT promotes PASMC hyperplasia through the serotonin transporter via production of ROS and MAPK activation . ALK1 and BMPR1‐2 are receptors of the TGF‐β superfamily and BMP (bone morphogenetic protein) .



Figure 1.

Main inflammatory mediators in pulmonary vascular remodeling in pulmonary arterial hypertension. CX3CL1 (Fractalkine) causes upregulation of its receptor CX3CR1 on CD4+ and CD8+ T lymphocytes . CCL5 (RANTES) and nuclear factor of activated T cells (NFAT) attract T and B lymphocytes. IL‐6 (Interleukin‐6) binds to its soluble receptor (soluble IL‐6 Receptor) and the complex then binds to gp130 . Vascular endothelial growth factor (VEGF) acts through its receptor KDR, a receptor tyrosine kinase . Other growth factors involved in vascular remodeling include platelet‐derived growth factor (PDGF), epithelial growth factor (EGF), and fibroblast growth factor (FGF‐2). The receptor (5‐HTR) and transporter (5‐HTT) of serotonin (5‐HT), and VPAC [the receptors of vasoactive intestinal peptide (VIP)] are all coupled to G‐protein . Endothelin‐1 (ET‐1) is a potent vasoconstrictor and mitogen.



Figure 2.

Schematic inflammatory pathways involving growth factors, vasomodulators, and infectious stimuli in the pathogenesis of pulmonary arterial hypertension. Hypoxia increases influx of Ca2+, which binds to Calcineurin. The complex dephosphorylates NFAT (NFAT‐P), which can now translocate to the nucleus where it alters gene expression. Endothelin acts through Ca++ channels and ERK/Jun kinases . EGF (epidermal growth factor), TNF‐α, and PDGF (platelet‐derived growth factor) act through tyrosine kinase receptors and are partially transduced by intracellular reactive oxidant species (ROS) . The regulatory proteins, SMADs activate nuclear transcription factors through MAPK . 5‐HT promotes PASMC hyperplasia through the serotonin transporter via production of ROS and MAPK activation . ALK1 and BMPR1‐2 are receptors of the TGF‐β superfamily and BMP (bone morphogenetic protein) .

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Hala El Chami, Paul M. Hassoun. Inflammatory Mechanisms in the Pathogenesis of Pulmonary Arterial Hypertension. Compr Physiol 2011, 1: 1929-1941. doi: 10.1002/cphy.c100028