Small-Molecule Activation of Protein Phosphatase 2A Counters Bleomycin-Induced Fibrosis in Mice.

The activity of protein phosphatase 2A (PP2A), a serine-threonine phosphatase, is reduced in the lung fibroblasts of idiopathic pulmonary fibrosis (IPF) patients. The objective of this study was to determine whether the reactivation of PP2A could reduce fibrosis and preserve the pulmonary function in a bleomycin (BLM) mouse model. Here, we present a new class of direct small-molecule PP2A activators, diarylmethyl-pyran-sulfonamide, exemplified by ATUX-1215. ATUX-1215 has improved metabolic stability and bioavailability compared to our previously described PP2A activators. Primary human lung fibroblasts were exposed to ATUX-1215 and an older generation PP2A activator in combination with TGFß. ATUX-1215 treatment enhanced the PP2A activity, reduced the phosphorylation of ERK and JNK, and reduced the TGFß-induced expression of ACTA2, FN1, COL1A1, and COL3A1. C57BL/6J mice were administered 5 mg/kg ATUX-1215 daily following intratracheal instillation of BLM. Three weeks later, forced oscillation and expiratory measurements were performed using the Scireq Flexivent System. ATUX-1215 prevented BLM-induced lung physiology changes, including the preservation of normal PV loop, compliance, tissue elastance, and forced vital capacity. PP2A activity was enhanced with ATUX-1215 and reduced collagen deposition within the lungs. ATUX-1215 also prevented the BLM induction of Acta2, Ccn2, and Fn1 gene expression. Treatment with ATUX-1215 reduced the phosphorylation of ERK, p38, JNK, and Akt and the secretion of IL-12p70, GM-CSF, and IL1α in BLM-treated animals. Delayed treatment with ATUX-1215 was also observed to slow the progression of lung fibrosis. In conclusion, our study indicates that the decrease in PP2A activity, which occurs in fibroblasts from the lungs of IPF subjects, could be restored with ATUX-1215 administration as an antifibrotic agent.

Septic Shock Secondary to Tricuspid Valve Vegetation Requiring Surgical Debulking.

Tricuspid valve endocarditis is increasing in incidence owing to the prevalent use of intravenous substances. Although most patients respond well to intravenous antibiotics over the course of six weeks, some patients require surgical intervention. A multilayered approach to diagnosis with both transthoracic and transesophageal echocardiography (TEE) is recommended for optimal diagnosis and management. In this article, we report a case of septic shock resulting from tricuspid valve infective endocarditis in a young woman with a history of intravenous drug use who ultimately required cardiothoracic surgical intervention for tricuspid valve vegetation. The sensitivity and specificity of TEE for vegetation on the native valves are about 96% and 90%, respectively. Timely surgical intervention may increase the likelihood of tricuspid valve repair by preventing further destruction of leaflet tissue. Transthoracic echocardiogram (TTE) and TEE have complementary roles in the diagnosis and evaluation of endocarditis. With this case report, we emphasize the importance of multimodality imaging and early surgical intervention to prevent further embolism and destruction of tricuspid valve leaflet tissue.

Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Emphysema.

The activity of PP2A (protein phosphatase 2A), a serine-threonine phosphatase, is reduced by chronic cigarette smoke (SM) exposure and α-1 antitrypsin (AAT) deficiency, and chemical activation of PP2A reduces the loss of lung function in SM-exposed mice. However, the previously studied PP2A-activator tricyclic sulfonamide compound DBK-1154 has low stability to oxidative metabolism, resulting in fast clearance and low systemic exposure. Here we compare the utility of a new more stable PP2A activator, ATUX-792, versus DBK-1154 for the treatment of SM-induced emphysema. ATUX-792 was also tested in human bronchial epithelial cells and a mouse model of AAT deficiency, Serpina1a-e-knockout mice. Human bronchial epithelial cells were treated with ATUX-792 or DBK-1154, and cell viability, PP2A activity, and MAP (mitogen-activated protein) kinase phosphorylation status were examined. Wild-type mice received vehicle, DBK-1154, or ATUX-792 orally in the last 2 months of 4 months of SM exposure, and 8-month-old Serpina1a-e-knockout mice received ATUX-792 daily for 4 months. Forced oscillation and expiratory measurements and histology analysis were performed. Treatment with ATUX-792 or DBK-1154 resulted in PP2A activation, reduced MAP kinase phosphorylation, immune cell infiltration, reduced airspace enlargements, and preserved lung function. Using protein arrays and multiplex assays, PP2A activation was observed to reduce AAT-deficient and SM-induced release of CXCL5, CCL17, and CXCL16 into the airways, which coincided with reduced neutrophil lung infiltration. Our study indicates that suppression of the PP2A activity in two models of emphysema could be restored by next-generation PP2A activators to impact lung function.

Thrombotic Thrombocytopenic Purpura due to Varicella-Zoster Virus Meningoencephalitis in an Immunocompetent Patient.

Varicella-zoster virus (VZV) can cause variable disease states in individuals with intact and compromised immune systems. Both meningoencephalitis and thrombotic thrombocytopenic purpura (TTP) are uncommon, life-threatening entities associated with VZV. There are few reported cases of TTP due to VZV and this may be the first case of TTP due to VZV meningoencephalitis confirmed through lumbar puncture. The literature tends to emphasize that this pathology mostly occurs in immunocompromised hosts. Here, we present a unique case of TTP due to VZV meningoencephalitis in a patient that was immunocompetent.