Tadalafil for veterans with chronic obstructive pulmonary disease-pulmonary hypertension: A multicenter, placebo-controlled randomized trial.

Treating Veterans with chronic obstructive pulmonary disease complicated by pulmonary hypertension (COPD-PH) using phosphodiesterase type-5 inhibitor pharmacotherapy is common, but efficacy data are lacking. To address this further, patients with COPD-PH from five Department of Veterans Affairs hospitals were randomized (1∶1) to receive placebo or oral tadalafil (40 mg/day) for 12 months. The primary endpoint was changed from baseline in 6-min walk distance at 12 months.

Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases.

G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids.

The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension.

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague-Dawley (SD) rat model of hypoxic PH.

The Link between and Colon Cancer: a Fulminant Example and Review of the Evidence.

Systemic infections due to may originate in the tonsillar/internal jugular veins or from the abdomen. We encountered a patient who presented with bacteremia, fulminant septic shock, and extensive soft tissue pyogenic infection due to . In addition, there was widespread metastatic colon cancer with the unique finding of pre-mortem co-localization of and cancer cells at a site distant from the colon.

c-Jun, Foxo3a, and c-Myc Transcription Factors are Key Regulators of ATP-Mediated Angiogenic Responses in Pulmonary Artery Vasa Vasorum Endothelial Cells.

Angiogenic vasa vasorum (VV) expansion plays an essential role in the pathogenesis of hypoxia-induced pulmonary hypertension (PH), a cardiovascular disease. We previously showed that extracellular ATP released under hypoxic conditions is an autocrine/paracrine, the angiogenic factor for pulmonary artery (PA) VV endothelial cells (VVECs), acting via P2Y purinergic receptors (P2YR) and the Phosphoinositide 3-kinase (PI3K)-Akt-Mammalian Target of Rapamycin (mTOR) signaling. To further elucidate the molecular mechanisms of ATP-mediated VV angiogenesis, we determined the profile of ATP-inducible transcription factors (TFs) in VVECs using a TranSignal protein/DNA array.

Role of Inflammatory Cell Subtypes in Heart Failure.

Inflammation is a well-known feature of heart failure. Studies have shown that while some inflammation is required for repair during injury and is protective, prolonged inflammation leads to myocardial remodeling and apoptosis of cardiac myocytes. Various types of immune cells are implicated in myocardial inflammation and include neutrophils, macrophages, eosinophils, mast cells, natural killer cells, T cells, and B cells.

RhoGTPase in Vascular Disease.

Ras-homologous (Rho)A/Rho-kinase pathway plays an essential role in many cellular functions, including contraction, motility, proliferation, and apoptosis, inflammation, and its excessive activity induces oxidative stress and promotes the development of cardiovascular diseases. Given its role in many physiological and pathological functions, targeting can result in adverse effects and limit its use for therapy. In this review, we have summarized the role of RhoGTPases with an emphasis on RhoA in vascular disease and its impact on endothelial, smooth muscle, and heart and lung fibroblasts.

An Optimized Evans Blue Protocol to Assess Vascular Leak in the Mouse.

Vascular leak, or plasma extravasation, has a number of causes, and may be a serious consequence or symptom of an inflammatory response. This study may ultimately lead to new knowledge concerning the causes of or new ways to inhibit or treat plasma extravasation. It is important that researchers have the proper tools, including the best methods available, for studying plasma extravasation.

Sustained Activation of Rho GTPases Promotes a Synthetic Pulmonary Artery Smooth Muscle Cell Phenotype in Neprilysin Null Mice.

Objective: Pulmonary artery smooth muscle cells (PASMCs) from neprilysin (NEP) null mice exhibit a synthetic phenotype and increased activation of Rho GTPases compared with their wild-type counterparts. Although Rho GTPases are known to promote a contractile SMC phenotype, we hypothesize that their sustained activity decreases SM-protein expression in these cells.

Approach And Results: PASMCs isolated from wild-type and NEP mice were used to assess levels of SM-proteins (SM-actin, SM-myosin, SM22, and calponin) by Western blotting, and were lower in NEP PASMCs compared with wild-type.

Protection against vascular leak in neprilysin transgenic mice with complex overexpression pattern.

Neprilysin (NEP) is a cell surface metallopeptidase found in many tissues. Based mostly on pharmacological manipulations, NEP has been thought to protect blood vessels from plasma extravasation. We have suggested that NEP may protect against pulmonary vascular injury.

Neprilysin regulates pulmonary artery smooth muscle cell phenotype through a platelet-derived growth factor receptor-dependent mechanism.

Reduced neprilysin (NEP), a cell surface metallopeptidase, which cleaves and inactivates proinflammatory and vasoactive peptides, predisposes the lung vasculature to exaggerated remodeling in response to hypoxia. We hypothesize that loss of NEP in pulmonary artery smooth muscle cells results in increased migration and proliferation. Pulmonary artery smooth muscle cells isolated from NEP(-/-) mice exhibited enhanced migration and proliferation in response to serum and platelet-derived growth factor, which was attenuated by NEP replacement.

Alveolar hypoxia promotes murine lung tumor growth through a VEGFR-2/EGFR-dependent mechanism.

Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia.

Decreased neprilysin and pulmonary vascular remodeling in chronic obstructive pulmonary disease.

Rationale: Studies with genetically engineered mice showed that decreased expression of the transmembrane peptidase neprilysin (NEP) increases susceptibility to hypoxic pulmonary vascular remodeling and hypertension; in hypoxic wild-type mice, expression is decreased early in distal pulmonary arteries, where prominent vascular remodeling occurs. Therefore, in humans with smoke- and hypoxia-induced vascular remodeling, as in chronic obstructive pulmonary disease (COPD), pulmonary activity/expression of NEP may likewise be decreased.

Objectives: To test whether NEP activity and expression are reduced in COPD lungs and pulmonary arterial smooth muscle cells (SMCs) exposed to cigarette smoke extract or hypoxia and begin to investigate mechanisms involved.

Vascular endothelial growth factor receptor 2-targeted chemoprevention of murine lung tumors.

No clinically effective chemoprevention for lung cancer has been found. Angiogenesis is an early feature of both adenocarcinoma and squamous cell lung cancer. We investigated the effects of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) inhibition on lung carcinogenesis in a murine model of adenocarcinoma.

A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer.

No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months.

Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia.

Neprilysin is a transmembrane metalloendopeptidase that degrades neuropeptides that are important for both growth and contraction. In addition to promoting carcinogenesis, decreased levels of neprilysin increases inflammation and neuroendocrine cell hyperplasia, which may predispose to vascular remodeling. Early pharmacological studies showed a decrease in chronic hypoxic pulmonary hypertension with neprilysin inhibition.

Lung disease and PKCs.

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types.

Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling.

Thiazolidinediones (TZDs) are insulin-sensitizing agents that also decrease systemic blood pressure, attenuate the formation of atherosclerotic lesions, and block remodeling of injured arterial walls. Recently, TZDs were shown to prevent pulmonary arterial (PA) remodeling in rats treated with monocrotaline. Presently we report studies testing the ability of the TZD rosiglitazone (ROSI) to attenuate pathological arterial remodeling in the lung and prevent the development of pulmonary hypertension (PH) in rats subjected to chronic hypoxia.

Chronic hypoxia diminishes the proliferative response of Guinea pig uterine artery vascular smooth muscle cells in vitro.

The pregnancy-related size enlargement of the guinea pig uterine artery is partially accomplished by hyperplasia in all layers of the vessel wall. We sought to determine the separate and combined effects of chronic hypoxia and pregnancy on the proliferative capacity of uterine artery vascular smooth muscle cells (UA VSMCs). We established primary UA VSMC cultures from a total of 13 guinea pigs using an enzymatic digestion technique.

Impact of customized videotape education on quality of life in patients with chronic obstructive pulmonary disease.

Purpose: To compare the impact of a library of pulmonary rehabilitation videotapes versus an older videotape and usual care on quality of life and ability to perform activities of daily living in persons with chronic obstructive pulmonary disease.

Methods: Two hundred fourteen patients diagnosed with chronic obstructive pulmonary disease, emphysema, or chronic bronchitis were recruited and randomized to receive customized videotapes, standard videotapes, or usual care. Outcome measures included the Fatigue Impact Scale, Seattle Obstructive Lung Disease Questionnaire, and the SF-36(R) Health Survey.

High prevalence of occult endobronchial malignancy in high risk patients with moderate sputum atypia.

Early stage radiographically occult lung cancer has a high cure rate, but comprises a small fraction of all lung cancer. Abnormal sputum cytology is one indication for bronchoscopy in patients with chest imaging that is not suspicious for lung cancer. While there is good evidence that sputum cytologic findings of carcinoma, carcinoma in situ or severe atypia predict high rates of diagnosis of lung cancer, less is known of the frequency in which lung cancer is diagnosed in bronchoscopies carried out for the indication of moderate sputum atypia.

Protein kinase C-epsilon-null mice have decreased hypoxic pulmonary vasoconstriction.

PKC contributes to regulation of pulmonary vascular reactivity in response to hypoxia. The role of individual PKC isozymes is less clear. We used a knockout (null, -/-) mouse to test the hypothesis that PKC-epsilon is important in acute hypoxic pulmonary vasoconstriction (HPV).