Vascular repair and regeneration as a therapeutic target for pulmonary arterial hypertension.

The last decade has seen substantial changes in our understanding of the pathobiology of pulmonary arterial hypertension (PAH), a severe and devastating disease without curative treatment. It is now accepted that injury to the endothelial cells of the pulmonary arteries is central for the subsequent development of lumen-obliterative lung vascular lesions. A variety of circulating and lung-resident progenitor and stem cells likely contribute to vascular integrity, and evidence for the presence of cells expressing stem and progenitor cell markers is found inside and in the immediate vicinity of pulmonary vascular lesions in PAH.

Natural occurrence of subjective aging experiences in community-dwelling older adults.

Objectives: The subjective experience of aging is a relevant correlate of developmental outcomes. However, traditional approaches fall short of capturing the inherent multidimensionality of subjective aging experiences (SAEs). Based on the concept of Awareness of Age-Related Change (AARC; Diehl, M.

Inhibition of HSP27 blocks fibrosis development and EMT features by promoting Snail degradation.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation. Transition of epithelial/mesothelial cells into myofibroblasts [epithelial-to-mesenchymal transition (EMT)] occurs under the influence of transforming growth factor (TGF)-β1, with Snail being a major transcription factor. We study here the role of the heat-shock protein HSP27 in fibrogenesis and EMT.

Inflammation and dysregulated fibroblast proliferation--new mechanisms?

Idiopathic pulmonary fibrosis (IPF) is a devastating, age-related lung disease of unknown cause that has few treatment options. Once thought to be a chronic inflammatory process, current evidence indicates that the fibrotic response may primarily be driven by abnormally activated alveolar epithelial cells and the underlying mesenchyme. The mediators produced and present in this microenvironment induce the formation of fibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of epithelial to mesenchymal transition.

Angiogenesis in pulmonary fibrosis: too much or not enough?

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal disease, based on a multifaceted and incompletely understood pathogenesis. Some of the cellular and molecular mechanisms of vascular remodeling have been experimentally explored, and it is obvious that alterations of microvessels are involved in IPF. These can, among others, lead to the development of pulmonary hypertension.

Markov models of aging: theory and practice.

We review and structure some of the mathematical and statistical models that have been developed over the past half century to grapple with theoretical and experimental questions about the stochastic development of aging over the life course. We suggest that the mathematical models are in large part addressing the problem of partitioning the randomness in aging: How does aging vary between individuals, and within an individual over the lifecourse? How much of the variation is inherently related to some qualities of the individual, and how much is entirely random? How much of the randomness is cumulative, and how much is merely short-term flutter? We propose that recent lines of statistical inquiry in survival analysis could usefully grapple with these questions, all the more so if they were more explicitly linked to the relevant mathematical and biological models of aging. To this end, we describe points of contact among the various lines of mathematical and statistical research.

Identification of RARRES1 as a core regulator in liver fibrosis.

Genetic factors contribute to progression and modulation of hepatic fibrosis. High throughput genomics/transcriptomics approaches aiming at identifying key regulators of fibrosis development are tainted with the difficulty of separating essential biological "driver" from modifier genes. We applied a comparative transcriptomics approach and investigated fibrosis development in different organs to identify overlapping expression changes, since these genes may be part of core pathways in fibrosis development.

Molecular mechanisms of MMP9 overexpression and its role in emphysema pathogenesis of Smad3-deficient mice.

Previous studies have found that inappropriate elevation of matrix metalloproteinase-9 (MMP9) expression and activity is coincident with early onset of emphysema in Smad3-null mice. Herein, we further investigated the role of increased MMP9 in emphysema pathogenesis and the related molecular regulatory mechanisms of elevated MMP9 in Smad3-null lung. Genetic blockade of MMP9 in Smad3-null mice significantly attenuated emphysema pathology but not hypoalveolarization during early postnatal lung development.

Transforming growth factor-β evokes Ca2+ waves and enhances gene expression in human pulmonary fibroblasts.

Fibroblasts maintain the structural framework of animal tissue by synthesizing extracellular matrix molecules. Chronic lung diseases are characterized in part by changes in fibroblast numbers, properties, and more. Fibroblasts respond to a variety of growth factors, cytokines, and proinflammatory mediators.

Adenovirus-mediated gene transfer of TGF-β1 to the renal glomeruli leads to proteinuria.

The mechanism of proteinuria in many common kidney diseases involves glomerular hemodynamic effects and local expression of angiogenic, fibrogenic, and vasoactive factors. Transforming growth factor (TGF)-β has been associated with many diseases involving proteinuria and renal fibrosis. TGF-β has been shown to induce podocyte dedifferentiation in vitro, but its in vivo effects on the glomerular filtration barrier are not well described.

Removal of monomer delignification products by laccase from Trametes versicolor.

The influence of a laccase from Trametes versicolor on the removal of phenolic monomers in liquid hot water pretreated wheat straw supernatants (LHW-S) was examined. Beside the total phenol content derived by Folin-Ciocalteu (FC-) assay, phenolic monomers were measured via headspace-solid phase micro-extraction (HS-SPME)/GC-MS. A notable decrease of the phenols was achieved using 0.

Pulmonary microcirculation in interstitial lung disease.

Vascular abnormalities are a common feature of interstitial lung diseases (ILD). The development of pulmonary hypertension has been recognized as a condition that determines the overall prognosis, particularly for patients with idiopathic pulmonary fibrosis and scleroderma-associated lung disease. The treatment of chronic ILD is challenging due to the lack of causal therapies, specifically of the fibroproliferative component of the disorders, but also due to the vascular abnormalities.

Local delivery of GM-CSF protects mice from lethal pneumococcal pneumonia.

The growth factor GM-CSF has an important role in pulmonary surfactant metabolism and the regulation of antibacterial activities of lung sentinel cells. However, the potential of intra-alveolar GM-CSF to augment lung protective immunity against inhaled bacterial pathogens has not been defined in preclinical infection models. We hypothesized that transient overexpression of GM-CSF in the lungs of mice by adenoviral gene transfer (Ad-GM-CSF) would protect mice from subsequent lethal pneumococcal pneumonia.

Fibrocytes in chronic lung disease--facts and controversies.

Fibrocytes are bone marrow-derived mesenchymal cell precursors, defined primarily by their ability to co-express markers of both haematopoietic (e.g. CD45 or CXCR4) and stromal (e.

Risk posed by chlorinated organic compounds in Abu Qir Bay, East Alexandria, Egypt.

Introduction: In Egypt, the picture of threats to humans and the environment from the exposure to organic pollutants is still incomplete. Thus the objectives of this study were to assess the occurrence and distribution of polychlorinated biphenyls (PCBs), organochlorine pesticides, and chlorpyrifos in sediments and mussels of Abu Qir Bay and their risks for environment and human health.

Materials And Methods: Twenty-three different compounds organochlorines were determined in 20 surfacial sediment and 10 mussel samples by gas chromatography-electron capture detector.

Cigarette smoke exposure aggravates air space enlargement and alveolar cell apoptosis in Smad3 knockout mice.

The concept of genetic susceptibility factors predisposing cigarette smokers to develop emphysema stems from the clinical observation that only a fraction of smokers develop clinically significant chronic obstructive pulmonary disease. We investigated whether Smad3 knockout mice, which develop spontaneous air space enlargement after birth because of a defect in transforming growth factor-β (TGF-β) signaling, develop enhanced alveolar cell apoptosis and air space enlargement following cigarette smoke exposure. We investigated Smad3(-/-) and Smad3(+/+) mice at different adult ages and determined air space enlargement, alveolar cell proliferation, and apoptosis.

Oxidative stress contributes to the induction and persistence of TGF-β1 induced pulmonary fibrosis.

Oxidative stress with reactive oxygen species (ROS) can contribute to the pathogenesis of idiopathic pulmonary fibrosis. Antioxidant enzymes, such as extracellular superoxide dismutase (ECSOD), may modulate the injury and repair components of the fibrogenic response. Here we determined whether ECSOD could attenuate experimental TGF-β1-induced persistent lung fibrosis.

Auxin triggers a genetic switch.

Cell specification in development requires robust gene-regulatory responses to transient signals. In plants, the small signalling molecule auxin has been implicated in diverse developmental processes. Auxin promotes the degradation of AUXIN/INDOLE-3-ACETIC ACID (AUX/IAA) inhibitors that prevent AUXIN RESPONSE FACTOR (ARF) transcription factors from regulating their target genes.

In vivo role of platelet-derived growth factor-BB in airway smooth muscle proliferation in mouse lung.

Airway smooth muscle (ASM) hyperplasia in asthma likely contributes considerably to functional changes. Investigating the mechanisms behind proliferation of these cells may lead to therapeutic benefit. Platelet-derived growth factor (PDGF)-BB is a well known ASM mitogen in vitro but has yet to be directly explored using in vivo mouse models in the context of ASM proliferation and airway responsiveness.

Micro-computed tomography of pulmonary fibrosis in mice induced by adenoviral gene transfer of biologically active transforming growth factor-β1.

Background: Micro-computed tomography (micro-CT) is a novel tool for monitoring acute and chronic disease states in small laboratory animals. Its value for assessing progressive lung fibrosis in mice has not been reported so far. Here we examined the importance of in vivo micro-CT as non-invasive tool to assess progression of pulmonary fibrosis in mice over time.

Early chemical development at Legacy Wyeth Research.

This article describes an approach to early process development in the context of the productivity model in legacy Wyeth (i.e. to deliver two New Drug Applications per year for New Molecular Entities).

Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors.

Idiopathic pulmonary fibrosis (IPF) is a disabling disease of the lung parenchyma, characterized by progressive accumulation of scar tissue and myofibroblast activation after repetitive epithelial microinjury. The therapeutic options are limited, and patients usually die within a few years after diagnosis. Pulmonary hypertension (PH) in IPF has been increasingly recognized as a condition with relevance for the overall prognosis.

Increased deposition of chondroitin/dermatan sulfate glycosaminoglycan and upregulation of β1,3-glucuronosyltransferase I in pulmonary fibrosis.

Pulmonary fibrosis (PF) is characterized by increased deposition of proteoglycans (PGs), in particular core proteins. Glycosaminoglycans (GAGs) are key players in tissue repair and fibrosis, and we investigated whether PF is associated with changes in the expression and structure of GAGs as well as in the expression of β1,3-glucuronosyltransferase I (GlcAT-I), a rate-limiting enzyme in GAG synthesis. Lung biopsies from idiopathic pulmonary fibrosis (IPF) patients and lung tissue from a rat model of bleomycin (BLM)-induced PF were immunostained for chondroitin sulfated-GAGs and GlcAT-I expression.