Showing papers by "National Jewish Health published in 2004"

A Case Control Etiologic Study of Sarcoidosis: Environmental and Occupational Risk Factors

Abstract: Past research suggests that environmental factors may be associated with sarcoidosis risk. We conducted a case control study to test a priori hypotheses that environmental and occupational exposures are associated with sarcoidosis. Ten centers recruited 706 newly diagnosed patients with sarcoidosis and an equal number of age-, race-, and sex-matched control subjects. Interviewers administered questionnaires containing questions regarding occupational and nonoccupational exposures that we assessed in univariable and multivariable analyses. We observed positive associations between sarcoidosis and specific occupations (e.g., agricultural employment, odds ratio [OR] 1.46, confidence interval [CI] 1.13-1.89), exposures (e.g., insecticides at work, OR 1.52, CI 1.14-2.04, and work environments with mold/mildew exposures [environments with possible exposures to microbial bioaerosols], OR 1.61, CI 1.13-2.31). A history of ever smoking cigarettes was less frequent among cases than control subjects (OR 0.62, CI 0.50-0.77). In multivariable modeling, we observed elevated ORs for work in areas with musty odors (OR 1.62, CI 1.24-2.11) and with occupational exposure to insecticides (OR 1.61, CI 1.13-2.28), and a decreased OR related to ever smoking cigarettes (OR 0.65, CI 0.51-0.82). The study did not identify a single, predominant cause of sarcoidosis. We identified several exposures associated with sarcoidosis risk, including insecticides, agricultural employment, and microbial bioaerosols.

A Placebo-Controlled Trial of Interferon Gamma-1b in Patients with Idiopathic Pulmonary Fibrosis

Abstract: Background Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy. Methods In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo. Results Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported am...

CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus

Abstract: Angiotensin-converting enzyme 2 (ACE2) is a receptor for SARS-CoV, the novel coronavirus that causes severe acute respiratory syndrome [Li, W. Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., Somasundaran, M., Sullivan, J. L., Luzuriaga, K., Greenough, T. C., et al. (2003) Nature 426, 450–454]. We have identified a different human cellular glycoprotein that can serve as an alternative receptor for SARS-CoV. A human lung cDNA library in vesicular stomatitis virus G pseudotyped retrovirus was transduced into Chinese hamster ovary cells, and the cells were sorted for binding of soluble SARS-CoV spike (S) glycoproteins, S590 and S1180. Clones of transduced cells that bound SARS-CoV S glycoprotein were inoculated with SARS-CoV, and increases in subgenomic viral RNA from 1–16 h or more were detected by multiplex RT-PCR in four cloned cell lines. Sequencing of the human lung cDNA inserts showed that each of the cloned cell lines contained cDNA that encoded human CD209L, a C-type lectin (also called L-SIGN). When the cDNA encoding CD209L from clone 2.27 was cloned and transfected into Chinese hamster ovary cells, the cells expressed human CD209L glycoprotein and became susceptible to infection with SARS-CoV. Immunohistochemistry showed that CD209L is expressed in human lung in type II alveolar cells and endothelial cells, both potential targets for SARS-CoV. Several other enveloped viruses including Ebola and Sindbis also use CD209L as a portal of entry, and HIV and hepatitis C virus can bind to CD209L on cell membranes but do not use it to mediate virus entry. Our data suggest that the large S glycoprotein of SARS-CoV may use both ACE2 and CD209L in virus infection and pathogenesis.

Modeling pulmonary nitric oxide exchange

Abstract: Nitric oxide (NO) was first detected in the exhaled breath more than a decade ago and has since been investigated as a noninvasive means of assessing lung inflammation. Exhaled NO arises from the airway and alveolar compartments, and new analytical methods have been developed to characterize these sources. A simple two-compartment model can adequately represent many of the observed experimental observations of exhaled concentration, including the marked dependence on exhalation flow rate. The model characterizes NO exchange by using three flow-independent exchange parameters. Two of the parameters describe the airway compartment (airway NO diffusing capacity and either the maximum airway wall NO flux or the airway wall NO concentration), and the third parameter describes the alveolar region (steady-state alveolar NO concentration). A potential advantage of the two-compartment model is the ability to partition exhaled NO into an airway and alveolar source and thus improve the specificity of detecting altered NO exchange dynamics that differentially impact these regions of the lungs. Several analytical techniques have been developed to estimate the flow-independent parameters in both health and disease. Future studies will focus on improving our fundamental understanding of NO exchange dynamics, the analytical techniques used to characterize NO exchange dynamics, as well as the physiological interpretation and the clinical relevance of the flow-independent parameters.

Pigment epithelium-derived factor in idiopathic pulmonary fibrosis: a role in aberrant angiogenesis.

Abstract: Pigment epithelium-derived factor (PEDF) is a 50-kD protein with angiostatic and neurotrophic activities that regulates vascular development within the eye. PEDF expression was increased in the lungs of patients with idiopathic pulmonary fibrosis (IPF) based on microarray analyses. Angiogenesis has been implicated in the pathogenesis of fibrotic lung diseases, we therefore hypothesized that regional abnormalities in vascularization occur in IPF as a result of an imbalance between PEDF and vascular endothelial growth factor. We demonstrated that vascular density is regionally decreased in IPF within the fibroblastic foci, and that within these areas PEDF was increased, whereas vascular endothelial growth factor was decreased. PEDF colocalized with the fibrogenic cytokine, transforming growth factor (TGF)-β1, particularly within the fibrotic interstitium and the fibroblastic focus, and prominently within the epithelium directly overlying the fibroblastic focus. This suggested that TGF-β1 might regulate PEDF...

Helminth Antigens Modulate TLR-Initiated Dendritic Cell Activation

Abstract: There is increasing awareness that helminth infections can ameliorate proinflammatory conditions. In part, this is due to their inherent ability to induce Th2 and, perhaps, regulatory T cell responses. However, recent evidence indicates that helminths also have direct anti-inflammatory effects on innate immune responses. In this study, we address this issue and show that soluble molecules from the eggs of the helminth parasite Schistosoma mansoni (SEA) suppress LPS-induced activation of immature murine dendritic cells, including MHC class II, costimulatory molecule expression, and IL-12 production. SEA-augmented LPS-induced production of IL-10 is in part responsible for the observed reduction in LPS-induced IL-12 production. However, analyses of IL-10(-/-) DC revealed distinct IL-10-independent suppressive effects of SEA. IL-10-independent mechanisms are evident in the suppression of TLR ligand-induced MAPK and NF-kappaB signaling pathways. Microarray analyses demonstrate that SEA alone uniquely alters the expression of a small subset of genes that are not up-regulated during conventional TLR-induced DC maturation. In contrast, the effects of SEA on TLR ligand-induced DC activation were striking: when mixed with LPS, SEA significantly affects the expression of >100 LPS-regulated genes. These findings indicate that SEA exerts potent anti-inflammatory effects by directly regulating the ability of DC to respond to TLR ligands.

A consensus protocol for the determination of the threshold doses for allergenic foods: how much is too much?

Abstract: Background While the ingestion of small amounts of an offending food can elicit adverse reactions in individuals with IgE-mediated food allergies, little information is known regarding these threshold doses for specific allergenic foods. While low-dose challenge trials have been conducted on an appreciable number of allergic individuals, a variety of different clinical protocols were used making the estimation of the threshold dose very difficult. Objective A roundtable conference was convened to develop a consensus clinical protocol for low-dose challenge trials for the estimation of threshold doses for specific allergenic foods. Methods In May 2002, 20 clinical allergists and other interested parties were invited to participate in a roundtable conference to develop consensus of the key elements of a clinical protocol for low-dose challenge trials. Results A consensus protocol was developed. Patients with convincing histories of food allergies and supporting diagnostic evidence including past challenge trials or high CAP-RAST scores can be enrolled in low-dose challenge trials. Care must be taken with younger patients to assure that they have not outgrown their food allergy. An approach was developed for the medication status of patients entering such trials. Challenge materials must be standardized, for example, partially defatted peanut flour composed of equal amounts of the three major varieties of peanuts (Florunner, Virginia, Spanish). Challenge materials must be appropriately blinded with sensory evaluation used to confirm the adequacy of blinding. A double-blind, placebo-controlled design should be used for low-dose challenge trials. Low-dose challenge trials would begin at doses of 10 mug of the allergenic food and would continue with doses of 100 mug and 1 mg followed by specific higher doses up to 100 mg depending upon the expert judgement of the physician; even higher doses might be applied to assure that the patient is indeed reactive to the particular food. A 30-min time interval would be used between doses, and reactive doses would be expressed as both discrete and cumulative doses. The goal of each challenge would be to develop objective symptoms; trials should not be discontinued on the basis of subjective symptoms only. Statistically, a minimum of 29 patients would be enrolled in low-dose challenge trials for each allergenic food because 0 reactors out of 29 patients at a particular dose allow the conclusion that there is 95% certainty that 90% of allergic individuals will not react to that dose. Conclusion A consensus protocol was developed. Using this protocol, it will be possible to estimate threshold doses for allergenic foods, the lowest amount that elicits mild, objective symptoms in highly sensitive individuals.

Th2 response polarization during infection with the helminth parasite Schistosoma mansoni.

Abstract: Summary: T-helper 2 (Th2) cell responses play a critical role in protection against helminth infections. In the case of Schistosoma mansoni, an important helminth parasite of man, data from a mouse model of human disease have shown that Th2 responses are essential to allow host survival. In this infection, parasite eggs are the primary stimulus for Th2 response development. Recent work has shown that egg molecules exert multiple levels of control over the development of host interferon-γ-associated inflammatory responses. Soluble egg antigen inhibits the ability of dendritic cells to make interleukin-12 and induces Th2-polarized adaptive immune responses that in combination with regulatory T-cell responses effectively limit Th1 response development. In this article, we discuss the factors influencing Th2 response polarization during infection with S. mansoni.

Cystatin C antagonizes transforming growth factor beta signaling in normal and cancer cells.

Abstract: Cystatin C (CystC) is a secreted cysteine protease inhibitor that regulates bone resorption, neutrophil chemotaxis, and tissue inflammation, as well as resistance to bacterial and viral infections. CystC is ubiquitously expressed and present in most bodily fluids where it inhibits the activities of cathepsins, a family of cysteine proteases that can promote cancer cell invasion and metastasis. Transforming growth factor beta (TGF-beta) is a multifunctional cytokine endowed with both tumor-suppressing and tumor-promoting activities. We show herein that TGF-beta treatment up-regulated CystC transcript and protein in murine 3T3-L1 fibroblasts. Moreover, CystC mRNA expression was down-regulated in approximately 50% of human malignancies, particularly cancers of the stomach, uterus, colon, and kidney. Overexpression of CystC in human HT1080 fibrosarcoma cells antagonized their invasion through synthetic basement membranes in part via a cathepsin-dependent pathway. Independent of effects on cathepsin activity, CystC also reduced HT1080 cell gene expression stimulated by TGF-beta. Invasion of 3T3-L1 cells occurred through both cathepsin- and TGF-beta-dependent pathways. Both pathways were blocked by CystC, but only the TGF-beta-dependent pathway was blocked by a CystC mutant (i.e., delta14CystC) that is impaired in its ability to inhibit cathepsin activity. Moreover, CystC and delta14CystC both inhibited 3T3-L1 cell gene expression stimulated by TGF-beta. We further show that CystC antagonized TGF-beta binding to its cell surface receptors, doing so by interacting physically with the TGF-beta type II receptor and antagonizing its binding of TGF-beta. Collectively, our findings have identified CystC as a novel TGF-beta receptor antagonist, as well as a novel CystC-mediated feedback loop that inhibits TGF-beta signaling.

Contribution of Antigen-Primed CD8+ T Cells to the Development of Airway Hyperresponsiveness and Inflammation Is Associated with IL-13

Abstract: The role of Th2/CD4 T cells, which secrete IL-4, IL-5, and IL-13, in allergic disease is well established; however, the role of CD8+ T cells (allergen-induced airway hyperresponsiveness (AHR) and inflammation) is less clear. This study was conducted to define the role of Ag-primed CD8+ T cells in the development of these allergen-induced responses. CD8-deficient (CD8−/−) mice and wild-type mice were sensitized to OVA by i.p. injection and then challenged with OVA via the airways. Compared with wild-type mice, CD8−/− mice developed significantly lower airway responsiveness to inhaled methacholine and lung eosinophilia, and exhibited decreased IL-13 production both in vivo, in the bronchoalveolar lavage (BAL) fluid, and in vitro, following Ag stimulation of peribronchial lymph node (PBLN) cells in culture. Reconstitution of sensitized and challenged CD8−/− mice with allergen-sensitized CD8+ T cells fully restored the development of AHR, BAL eosinophilia, and IL-13 levels in BAL and in culture supernatants from PBLN cells. In contrast, transfer of naive CD8+ T cells or allergen-sensitized CD8+ T cells from IL-13-deficient donor mice failed to do so. Intracellular cytokine staining of lung as well as PBLN T cells revealed that CD8+ T cells were a source of IL-13. These data suggest that Ag-primed CD8+ T cells are required for the full development of AHR and airway inflammation, which appears to be associated with IL-13 production from these primed T cells.

Retinoic acid fails to reverse emphysema in adult mouse models

Abstract: Methods: The models used were an elastase induced emphysema model for acute alveolar destruction and a tumour necrosis factor (TNF)-α transgenic mouse which exhibits chronic air space enlargement, loss of elastic recoil, increased lung volume, and pulmonary hypertension comparable to human pulmonary emphysema. All-trans-retinoic acid (2 mg/kg) was injected for 12 successive days after the establishment of emphysema. The effects of treatment were evaluated using physiological and morphometric analyses. Results: In contrast to the rat, administration of all-trans-retinoic acid in these murine models did not improve the emphysema. Moreover, worsening of emphysema was observed in TNF-α transgenic mice treated with all-trans-retinoic acid. The level of keratinocyte chemoattractant (KC), a CXC chemokine, in bronchoalveolar lavage fluid was increased in TNF-α transgenic mice following retinoic acid treatment. These data raise the possibility that retinoic acid causes deterioration of emphysema by promoting inflammation in this model. Conclusions: In these models, retinoic acid did not show positive effects on emphysema. The effect of retinoic acid in the treatment of pulmonary emphysema remains controversial, and further studies are required to determine its physiological effects under a variety of experimental conditions.

Interleukin-1 Receptor Antagonist Attenuates Airway Hyperresponsiveness Following Exposure to Ozone

Abstract: The role of an interleukin (IL)-1 receptor antagonist (IL-1Ra) on the development of airway hyperresponsiveness (AHR) and airway inflammation following acute O(3) exposure in mice was investigated. Exposure of C57/BL6 mice to O(3) at a concentration of 2.0 ppm or filtered air for 3 h resulted in increases in airway responsiveness to inhaled methacholine (MCh) 8 and 16 h after the exposure, and an increase in neutrophils in the bronchoalveolar lavage (BAL) fluid. IL-1beta expression, assessed by gene microarray, was increased 2-fold 4 h after O(3) exposure, and returned to baseline levels by 24 h. Levels of IL-1beta in lung homogenates were also increased 8 h after O(3) exposure. Administration of (human) IL-1Ra before and after O(3) exposure prevented development of AHR and decreased BAL fluid neutrophilia. Increases in chemokine levels in lung homogenates, tumor necrosis factor-alpha, MIP-2, and keratinocyte chemoattractant following O(3) exposure were prevented by IL-1Ra. Inhalation of dexamethasone, an inhibitor of IL-1 production, blocked the development of AHR, BAL fluid neutrophilia, and decreased levels of IL-1 following O(3) exposure. In summary, acute exposure to O(3) induces AHR, neutrophilic inflammation, epithelial damage, and IL-1. An IL-1Ra effectively prevents the development of altered airway function, inflammation, and structural damage.

Wood smoke exposure and lung adenocarcinoma in non-smoking Mexican women.

Abstract: OBJECTIF: Mener une etude cas-controle pour determiner l'association entre une exposition au long cours a la fumee de bois provenant de la cuisson et l'adenocarcinome pulmonaire chez les femmes mexicaines non-fumeuses. METHODES : Nous avons revu les dossiers des patientes hospitalisees dans un hopital thoracique de reference de la ville de Mexico et identifie 113 cas d'adenocarcinome pulmonaire prouves par l'examen histologique chez les femmes non-fumeuses. Quatre groupes-controle de femmes non-fumeuses ont egalement ete selectionnes : 99 atteintes de tuberculose (TB) pulmonaire, 110 atteintes de maladies pulmonaires interstitielles (ILD), 64 souffrant d'affections pulmonaires diverses (MISC) et les trois groupes-controle combines (COMB) (n = 273). RESULTATS: L'exposition a ete evaluee sur la base de reponses a un questionnaire au moment de l'admission a l'hopital. L'exposition a la fumee de bois pendant plus de 50 ans, mais non pour des periodes plus courtes, est associee avec le cancer du poumon apres ajustement pour l'âge, le niveau d'education, le statut socio-economique et l'exposition a la fumee environnementale de tabac (ETS). Les odds ratios ajustes pour les modeles de regression logistique a variables multiples ont ete de 1,4 (IC 95% 0,6-2,0) pour les cas vs. les controles TB, de 1,9 (IC 95% 0,9-4,0) pour les cas vs. les controles ILD, de 2,6 (IC 95% 1,0-6,3) pour les cas vs. les controles MISC et de 1,9 (IC 95% 1,1-3,5) pour les cas vs. l'ensemble des controles COMB. CONCLUSION: Ces observations suggerent que l'exposition au long cours a la fumee de bois provenant de la cuisson peut contribuer au developpement des cancers pulmonaires.

Ribosome-inactivating proteins in plant biology.

Abstract: Ribosome-inactivating proteins (RIPs) are a group of cytotoxic Af-glycosidases that specifically cleave nucleo tide N-C glycosidic bonds. RIPs have been classified into three types: type I is composed of a single polypeptide chain, whereas type II is a heterodimer consisting of an A chain, functionally equivalent to a type I, which is attached to a sugar-binding B chain. Type III is a single chain containing an extended carboxyl-terminal domain with unknown function. Although RIPs were first identified more than 100 years ago, their biological function(s) still remains open to speculation. Besides their known activity of depurinating ribosomes at the

Complex and dynamic redistribution of NF-κB signaling intermediates in response to T cell receptor stimulation

Abstract: The central zone of the supramolecular activation cluster (c-SMAC) is a zone of T cell receptor (TCR) enrichment that forms at a T cell/antigen-presenting cell (APC) junction in response to antigen stimulation. We demonstrate that there is a surprisingly complex relocalization process that brings PKCθ and Bcl10, two intermediates in TCR activation of NF-κB, to the cytoplasmic face of the c-SMAC. TCR activation causes enrichment of PKCθ at the c-SMAC, followed by Bcl10 relocalization to punctate cytoplasmic structures, often at sites distant from the c-SMAC. These Bcl10 structures then undergo further relocalization, becoming enriched at the c-SMAC. TCR activation of NF-κB therefore involves the dynamic relocalization of multiple signaling intermediates, with distinct phases proximal to and distant from the c-SMAC.

Complement activation is critical to airway hyperresponsiveness after acute ozone exposure.

Abstract: Ozone (O3) can induce airway hyperresponsiveness (AHR) and neutrophilic inflammation. We evaluated the role of complement in development of AHR and inflammation after acute O3 exposure in mice. Mice were exposed to O3 at 2 ppm for 3 hours, and airway responsiveness to methacholine was measured 8 hours after O3 exposure. Complement was depleted or inhibited by intraperitoneal injection of cobra venom factor (CVF) or complement receptor-related gene y (Crry)-Ig, a potent C3 convertase inhibitor; neutrophils were depleted using an antineutrophil monoclonal antibody. CVF attenuated the development of AHR by O3. Administration of Crry-Ig also prevented the development of AHR. Bronchoalveolar lavage (BAL) fluid neutrophilia after O3 exposure was significantly decreased by administration of either CVF or Crry-Ig. Increased BAL fluid total protein after O3 exposure was lowered by depletion or inhibition of complement. In contrast to the effects of complement inhibition or depletion, depletion of BAL neutrophil counts by more than 90% with the monoclonal antibody did not affect the development of AHR after O3 exposure. These data indicated that activation of the complement system follows acute O3 exposure and is important to the development of AHR and airway neutrophilia. However, this neutrophil response does not appear necessary for the development of AHR.

Reduced Radiation Dose Helical Chest CT: Effect on Reader Evaluation of Structures and Lung Findings

Abstract: PURPOSE: To assess, by using computer simulation, the effect of the use of reduced computed tomographic (CT) tube current on reader evaluation of structures and lung findings on images obtained at clinically indicated chest CT examinations. MATERIALS AND METHODS: The noise level in the raw scan data of 150 clinically indicated conventional tube current (200–320-mA) chest CT examinations was modified to simulate tube current reduction to 100 and to 40 mA. A total of 450 image sets were thus available. Four radiologists blinded to the tube current used assessed the image sets in random order for 14 structures and lung findings and ranked subjective image quality by using a five-point scale (1 = nondiagnostic, 2 = inferior, 3 = adequate, 4 = good, 5 = excellent). After a 3-week interval, the 150 conventional tube current image sets were rescored so that intraobserver agreement could be assessed. The McNemar statistic was used to determine whether there were more scoring disagreements between interpretations ...

The role of virus-specific immunoglobulin E in airway hyperresponsiveness.

Abstract: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis during infancy and is associated with subsequent wheezing and asthma, but the nature of this association is not fully understood. We investigated the role of RSV-specific IgE antibodies in the pathophysiology of virus-induced airway dysfunction in a mouse model. Lung infection with RSV resulted in significant increases in mRNA expression for IgE and both of its high- and low-affinity receptors. In serum, virus-specific IgE antibodies reached peak levels by Day 21 after infection. Data from in vitro experiments show that RSV can induce mast cell degranulation, but only if these cells are sensitized with specific IgE. When passively sensitized in vivo with virus-specific IgE, mice developed exaggerated airway responsiveness to methacholine on airway infection, an effect that required the high-affinity receptor of IgE. These data suggest that RSV-specific IgE may contribute to the pathophysiology of airway dysfunction in children who develop this class of specific antibody.

Inhibition of early airway neutrophilia does not affect development of airway hyperresponsiveness

Abstract: The effect of modifying early neutrophil-mediated inflammation on the development of airway hyperresponsiveness (AHR) was investigated using an interleukin (IL)-1 receptor antagonist (IL-1Ra), an anti–IL-18 antibody (anti–IL-18) or a p38 mitogen-activated protein kinase (MAPK) inhibitor (M39). Balb/c mice were sensitized to ovalbumin (OVA) and challenged with a single intranasal dose of OVA. Treatment with the IL-1Ra or anti–IL-18 was initiated 20 min before challenge, whereas M39 was administered 4 h before the challenge. Eight hours after challenge, sensitized mice showed significantly higher numbers of neutrophils in bronchoalveolar lavage (BAL) fluid; treatment with IL-1Ra, anti–IL-18, or M39 significantly decreased the influx of neutrophils. At 48 h, none of the treatments affected eosinophil inflammation in BAL fluid and lung tissue, goblet cell hyperplasia, or cytokine levels (IL-4, IL-5, IL-12, IL-13, interferon-γ) in BAL fluid. Anti–IL-18 or IL-1Ra had no effect on the development of AHR, whereas...

Cloning of a novel signaling molecule, AMSH-2, that potentiates transforming growth factor β signaling

Abstract: Transforming growth factor-βs (TGF-βs), bone morphogenetic proteins (BMPs) and activins are important regulators of developmental cell growth and differentiation Signaling by these factors is mediated chiefly by the Smad family of latent transcription factors There are a large number of uncharacterized cDNA clones that code for novel proteins with homology to known signaling molecules We have identified a novel molecule from the HUGE database that is related to a previously known molecule, AMSH (a ssociated m olecule with the SH 3 domain of STAM), an adapter shown to be involved in BMP signaling Both of these molecules contain a coiled-coil domain located within the amino-terminus region and a JAB (Domain in J un kinase a ctivation domain b inding protein and proteasomal subunits) domain at the carboxy-terminus We show that this novel molecule, which we have designated AMSH-2, is widely expressed and its overexpression potentiates activation of TGF-β-dependent promoters Coimmunoprecipitation studies indicated that Smad7 and Smad2, but not Smad3 or 4, interact with AMSH-2 We show that overexpression of AMSH-2 decreases the inhibitory effect of Smad7 on TGF-β signaling Finally, we demonstrate that knocking down AMSH-2 expression by RNA interference decreases the activation of 3TP-lux reporter in response to TGF-β This report implicates AMSH and AMSH-2 as a novel family of molecules that positively regulate the TGF-β signaling pathway Our results suggest that this effect could be partially explained by AMSH-2 mediated decrease of the action of Smad7 on TGF-β signaling pathway

Targeted over-expression of mPGES-1 and elevated PGE2 production is not sufficient for lung tumorigenesis in mice

Abstract: There is a significant body of evidence suggesting that enzymes involved in arachidonic acid metabolism and their eicosanoid products play a role in various cancers, having both pro- and antitumorigenic effects. The goal of this study was to further define the role microsomal prostaglandin E synthases (mPGES-1) play in lung tumorigenesis. Transgenic mice were created with targeted over-expression of human mPGES-1 in the alveolar and airway epithelial cells using an SP-C promoter driven construct. Transgene positive (mPGES-1 + ) mice were shown to significantly over-express functional mPGES-1 in the lung and more specifically in alveolar type II cells. To study the effects of mPGES-1 over-expression in lung tumor formation, mice were exposed to a complete carcinogen protocol with a single injection of urethane or an initiation/promotion model with a single injection of 3-methyl-cholanthrene (MCA) followed by multiple injections of butylated hydroxytoluene (BHT). mPGES-1 + mice did not show a significant difference in tumor multiplicity or tumor size at 10, 16, 19 or 30 weeks after urethane injection compared with mPGES-1 - mice. No significant difference was seen in tumor incidence, multiplicity or size at 19 weeks after treatment with MCA/BHT. Western blots verified that mPGES-1 expression was increased in tumors versus uninvolved tissue of both mPGES-1 + and mPGES-1 - mice with overall expression being significantly higher in mPGES-1 + mice. Cyclooxygenase-2 levels were elevated in tumors in both groups. From these studies we conclude that over-expression of mPGES-1 and highly elevated PGE 2 production are not sufficient to induce lung tumors.

Thioredoxin liquefies and decreases the viscoelasticity of cystic fibrosis sputum.

Abstract: The persistent and viscous nature of airway secretions in cystic fibrosis (CF) disease leads to airway obstruction, opportunistic infection, and deterioration of lung function. Thioredoxin (Trx) is...

Potential Role for Antiangiogenic Proteins in the Evolution of Bronchopulmonary Dysplasia

Abstract: Impaired neovascularization is associated with the pathologic presentation of bronchopulmonary dysplasia (BPD). To determine if neovascularization and factors that negatively influence blood vessel formation play a role in the evolution of BPD, we examined the temporospatial distribution of a protein known to inhibit fetal lung neovascularization with associated dysplastic lung formation, endothelial-monocyte activating polypeptide (EMAP) II. Immunohistochemical analysis of EMAP II in lung tissues of human infants with BPD indicated an elevation in EMAP II abundance as compared with control. Utilizing a baboon model, western analysis indicated that EMAP II was increased twofold in those baboons with pathologic signs of BPD as compared with gestational controls. Consistent with our findings in human tissues, immunohistochemistry and in situ hybridization demonstrate that EMAP II is highly expressed in the perivascular stroma and dysplastic lung periphery in neonatal baboons with BPD as compared with controls. Lastly, there is a premature acceleration in EMAP II's perivascular distribution in term newborn baboon as compared with gestational control. The marked increase in EMAP II's temporal expression, its distribution in the perivascular and dysplastic alveolar regions of the lungs, and the interruption in vasculogenesis in BPD suggest that neovascularization and factors that negatively influence blood vessel formation may play a role in BPD evolution.