Citations

Background— Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-β type II receptor gene, BMPR2 , predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. Methods and Results— We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations ( P =0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. Conclusions— Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

ABSTRACTSeveral studies have demonstrated roles for eosinophils during innate and adaptive immune responses to helminth infections. However, evidence that eosinophils are capable of initiating an immune response to parasite antigens is lacking. The goal of the present in vitro study was to investigate the potential of eosinophils to serve as antigen-presenting cells (APC) and initiate an immune response to parasite antigens. Purified eosinophils were exposed to solubleStrongyloides stercoralisantigens, and the expression of various surface markers involved in cell activation was examined. Antigen-exposed eosinophils showed a sixfold increase in expression levels of CD69 and major histocompatibility complex (MHC) class II, a fourfold increase in levels of T-cell costimulatory molecule CD86, and a twofold decrease in levels of CD62L compared to eosinophils cultured in medium containing granulocyte-macrophage colony-stimulating factor. The ability of eosinophils to present antigen to T cells was determined by culturing them with T cells in vitro. Eosinophils pulsed with antigen stimulated antigen-specific primed T cells and CD4+T cells to increase interleukin-5 (IL-5) production. The blocking of MHC class II expression on eosinophils inhibited their ability to induce IL-5 production by CD4+T cells in culture. Antigen-pulsed eosinophils were able to prime naïve T cells and CD4+T cells in culture and polarized them into Th2 cells producing IL-5 similar to that induced by antigen-loaded dendritic cells. These results demonstrate that eosinophils are capable of activating antigen-specific Th2 cells inducing the release of cytokines and assist in the priming of naïve T cells to initiate Th2 responses against infection. This study highlights the potential of eosinophils to actively induce immune responses against infection by amplifying antigen-specific Th2-cell responses.

Objective— We tested the hypothesis that in early hypertension (HT), increased oxidative stress leads to myocardial microvascular remodeling. Methods and Results— Pigs were studied after a 12-week observation: normal (n=8), untreated renovascular HT (n=8), or HT+chronic antioxidant supplementation (HT+A, n=6). Left ventricular muscle mass (LVMM) and myocardial blood flow (MBF) reserve were determined using electron beam computer tomography (CT), and the spatial density and tortuousity of myocardial microvessels (<500 μm) was then measured in myocardial samples with micro-CT. Myocardial microvascular morphology, oxidative stress, inflammation, and growth factor expression were determined in vitro. HT and HT+A had similarly increased arterial pressure and LVMM, but only HT showed impaired MBF response to adenosine. Compared with normal, HT had increased spatial density of myocardial microvessels, which was preserved in HT+A (111.8±7.8, 166.3±15.7, and 106.4±6.1 vessels per cm 2 , respectively). HT also showed microvascular wall thickening, increased systemic and tissue oxidative stress, inflammation, and expression of vascular endothelial growth factor and its receptor Flk-1, most of which were attenuated by antioxidants. Conclusions— Myocardial microvascular remodeling in early HT is accompanied by tissue oxidative stress, inflammation, and altered growth factor expression, and attenuated by antioxidant intervention. This study underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early HT.