Prevalence, Treatment, and Outcomes of Coexistent Pulmonary Hypertension and Interstitial Lung Disease in Systemic Sclerosis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150609/1/art40862.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150609/2/art40862_am.pd

Pulmonary Arterial Hypertension in Connective Tissue Diseases Beyond Systemic Sclerosis

Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) (CTD-PAH) is a devastating condition that may progress rapidly to cause right ventricular dysfunction, resulting in significant morbidity and mortality. The pathobiology, epidemiology, natural history, early diagnosis, and treatment response of PAH associated with scleroderma (SSc-PAH) have been the subjects of intense research efforts over the previous decade. The success of these efforts has resulted in increased awareness and earlier detection of SSc-PAH. Practitioners are less aware of the risk of PAH associated with other CTDs; the aim of this article is to discuss the broader scope of CTD-PAH

Suppression of nitrosative and oxidative stress to reduce cardiac allograft vasculopathy

Oxidant injury occurs when an organ is severed from its native blood supply and then reperfused and continues during subsequent periods of immune attack. Experiments here test the hypothesis that an antioxidant given only in the peri-reperfusion period protects against not only oxidative but also nitrosative stress, leading to reduced vasculopathy long after cardiac allotransplantation. Experiments were performed using a murine heterotopic cardiac transplantation model. An antioxidant, in the form of intraperitoneal high-dose riboflavin, was given to recipients during the initial 3 days after transplantation. Antioxidant-treated mice showed significantly longer graft survival than control mice. At 4 h after transplantation, antioxidant treatment significantly reduced graft lipid peroxidation and oxidized DNA and preserved antioxidant enzyme activity. At day 6 posttransplantation, the redox-sensitive transcription factor nuclear factor-κB and inducible nitric oxide synthase were significantly reduced following antioxidant treatment, with concomitant reduction of nitrotyrosine. Despite the limited duration of antioxidant treatment, both acute and chronic rejection were significantly suppressed. In vitro experiments confirmed suppression of nitrosative and oxidative stress and cardiomyocyte damage in antioxidant-treated cardiac allografts. Collectively, antioxidant administration during the initial 3 days after transplantation significantly reduces nitrosative and oxidative stress in cardiac allografts, modulates immune responses, and protects against vasculopathy

Performance of the DETECT Algorithm for Pulmonary Hypertension Screening in a Systemic Sclerosis Cohort

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/169315/1/art41732.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/169315/2/art41732_am.pd

Paradoxical exacerbation of neuronal injury in reperfused stroke despite improved blood flow and reduced inflammation in early growth response-1 gene-deleted mice

OBJECTIVES: Early growth response gene-1 (Egr-1) coordinates the rapid upregulation of diverse inflammatory and coagulation-related genes following ischemia/reperfusion. Genetic deletion of Egr-1 results in attenuated post-ischemic injury in diverse tissue systems. In the present study, we utilized a murine model of transient middle cerebral artery occlusion to probe the functional effects of Egr-1 deletion following cerebral ischemia/reperfusion. METHODS: The time course of Egr-1 expression was established by Northern/Western blot analysis, and immunocytochemistry localized Egr-1 to specific cell populations. Flow cytometry was then employed to characterize the ischemic cellular infiltrate of both wild-type (+/+) and Egr-1-null (-/-) mice. Next, the functional effect of Egr-1 deletion was investigated in Egr-1-deficient mice and their wild-type littermates subjected to middle cerebral artery occlusion. Infarct volumes, neurological scores, and reperfusion cerebral blood flow were compared between cohorts. RESULTS: Rapid upregulation of Egr-1 was observed in the ischemic hemisphere, and localized primarily to neurons and mononuclear cells. Egr-1 deletion led to a suppression of infiltrating neutrophils and activated microglia/macrophages (P\u3c0.001). Additionally, although Egr-1 deletion enhanced post-ischemic cerebral blood flow, Egr-1-deficient mice suffered larger infarcts (P=0.01) and demonstrated a trend towards worse neurological scores (P=0.06) than wild-type controls. DISCUSSION: Despite a reduction in the proportion of infiltrating inflammatory cells/activated microglia and improvement in post-ischemic reperfusion, Egr-1-deficient animals suffer larger infarcts in our model. Therefore, cerebral Egr-1 expression may function to protect neurons despite its adverse modulatory consequences for inflammation and thrombosis

Increased CD39 Nucleotidase Activity on Microparticles from Patients with Idiopathic Pulmonary Arterial Hypertension

<div><h3>Background</h3><p>Idiopathic pulmonary arterial hypertension (IPAH) is a devastating disease characterized by increased pulmonary vascular resistance, smooth muscle and endothelial cell proliferation, perivascular inflammatory infiltrates, and <em>in situ</em> thrombosis. Circulating intravascular ATP, ADP, AMP and adenosine activate purinergic cell signaling pathways and appear to induce many of the same pathologic processes that underlie IPAH. Extracellular dephosphorylation of ATP to ADP and AMP occurs primarily <em>via</em> CD39 (ENTPD1), an ectonucleotidase found on the surface of leukocytes, platelets, and endothelial cells <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040829#pone.0040829-Koziak1">[1]</a>. Microparticles are micron-sized phospholipid vesicles formed from the membranes of platelets and endothelial cells. <em>Objectives</em>: Studies here examine whether CD39 is an important microparticle surface nucleotidase, and whether patients with IPAH have altered microparticle-bound CD39 activity that may contribute to the pathophysiology of the disease.</p> <h3>Methodology/ Principal Findings</h3><p>Kinetic parameters, inhibitor blocking experiments, and immunogold labeling with electron microscopy support the role of CD39 as a major nucleotidase on the surface of microparticles. Comparison of microparticle surface CD39 expression and nucleotidase activity in 10 patients with advanced IPAH and 10 healthy controls using flow cytometry and thin layer chromatograph demonstrate the following: 1) circulating platelet (CD39⁺CD31⁺CD42b⁺) and endothelial (CD39⁺CD31⁺CD42b⁻) microparticle subpopulations in patients with IPAH show increased CD39 expression; 2) microparticle ATPase and ADPase activity in patients with IPAH is increased.</p> <h3>Conclusions/ Significance</h3><p>We demonstrate for the first time increased CD39 expression and function on circulating microparticles in patients with IPAH. Further research is needed to elucidate whether these findings identify an important trigger for the development of the disease, or reflect a physiologic response to IPAH.</p> </div

Clinical, Functional and Hemodynamic Characteristics of IPAH Patients (N = 10).

*<p>Thermodilution method used. All values are expressed as mean ± standard error of the mean.</p

Measurement of CD39 ATPase activity on microparticles from healthy controls compared with IPAH patients.

<p>Representative thin layer chromatography (A) shows increased dephosphorylation of 14C-labeled ATP to ADP in samples incubated with microparticles isolated from a patient with IPAH compared to a healthy control. Quantification of radiolabeled ATP and ADP in TLC samples from Controls (B) and IPAH patients (C) revealed a significant increase in the percentage of ATP dephosphorylated to ADP, as shown in (D).</p

Sample Characteristics.

<p>Sample Characteristics.</p

CD39 expression on platelet and endothelial microparticles.

<p>Flow cytometry revealed significantly increased surface CD39 expression on platelet (<b>CD31⁺CD42b⁺</b>) <b>and endothelial</b> (<b>CD31⁺CD42b⁻</b>) <b>microparticles.</b> PMP  =  platelet microparticles, EMP  =  endothelial microparticles.</p