2-O, 3-O-desulfated heparin inhibits neutrophil elastase-induced HMGB-1 secretion and airway inflammation.

Abstract:

:Neutrophil elastase (NE) is a major inflammatory mediator in cystic fibrosis (CF) that is a robust predictor of lung disease progression. NE directly causes airway injury via protease activity, and propagates persistent neutrophilic inflammation by up-regulation of neutrophil chemokine expression. Despite its key role in the pathogenesis of CF lung disease, there are currently no effective antiprotease therapies available to patients with CF. Although heparin is an effective antiprotease and anti-inflammatory agent, its anticoagulant activity prohibits its use in CF, due to risk of pulmonary hemorrhage. In this report, we demonstrate the efficacy of a 2-O, 3-O-desulfated heparin (ODSH), a modified heparin with minimal anticoagulant activity, to inhibit NE activity and to block NE-induced airway inflammation. Using an established murine model of intratracheal NE-induced airway inflammation, we tested the efficacy of intratracheal ODSH to block NE-generated neutrophil chemoattractants and NE-triggered airway neutrophilic inflammation. ODSH inhibited NE-induced keratinocyte-derived chemoattractant and high-mobility group box 1 release in bronchoalveolar lavage. ODSH also blocked NE-stimulated high-mobility group box 1 release from murine macrophages in vitro, and inhibited NE activity in functional assays consistent with prior reports of antiprotease activity. In summary, this report suggests that ODSH is a promising antiprotease and anti-inflammatory agent that may be useful as an airway therapy in CF.

authors

Griffin KL,Fischer BM,Kummarapurugu AB,Zheng S,Kennedy TP,Rao NV,Foster WM,Voynow JA

doi

10.1165/rcmb.2013-0338RC

subject

Has Abstract

pub_date

2014-04-01 00:00:00

pages

684-9

issue

4

eissn

1044-1549

issn

1535-4989

journal_volume

50

pub_type

杂志文章
  • Human ciliated bronchial epithelial cells: expression of the HLA-DR antigens and of the HLA-DR alpha gene, modulation of the HLA-DR antigens by gamma-interferon and antigen-presenting function in the mixed leukocyte reaction.

    abstract::HLA-DR class II molecules are expressed by a variety of nonlymphoid cells, including the respiratory epithelium. However, it is not known if ciliated bronchial epithelial cells express the HLA-DR genes, if the expression of class II molecules on their surface can be modulated by immune mediators and, finally, if these...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/3.5.431

    authors: Rossi GA,Sacco O,Balbi B,Oddera S,Mattioni T,Corte G,Ravazzoni C,Allegra L

    更新日期:1990-11-01 00:00:00

  • 2-O, 3-O Desulfated Heparin Blocks High Mobility Group Box 1 Release by Inhibition of p300 Acetyltransferase Activity.

    abstract::High mobility group box 1 (HMGB1) is an alarmin released from macrophages after infection or inflammation and is a biomarker of lung disease progression in patients with cystic fibrosis. We reported that 2-O, 3-O desulfated heparin (ODSH) inhibits the release of HMGB1 from murine macrophages triggered by neutrophil el...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2016-0069OC

    authors: Zheng S,Kummarapurugu AB,Afosah DK,Sankaranarayanan NV,Boothello RS,Desai UR,Kennedy T,Voynow JA

    更新日期:2017-01-01 00:00:00

  • Expression and regulation of a molecular marker, SPR1, in multistep bronchial carcinogenesis.

    abstract::A small proline-rich protein, SPR1, is overexpressed in squamous metaplasia of bronchial epithelium. We studied the expression and regulation of SPR1 in a series of human bronchial epithelial cell lines representing a model of multistep bronchial carcinogenesis. These cell lines included a primary culture of tracheobr...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.22.1.3637

    authors: Lau D,Xue L,Hu R,Liaw T,Wu R,Reddy S

    更新日期:2000-01-01 00:00:00

  • Effects of nitrogen dioxide exposure on bronchoalveolar lavage proteins in humans.

    abstract::Nitrogen dioxide (NO2) is a pollutant of both outdoor and indoor atmospheres that has the potential to alter alveolar epithelial permeability. In order to assess alterations in the protein content of alveolar lining fluid induced by brief (3-h) exposures to low-level NO2, normal volunteers were exposed sequentially to...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/1.6.499

    authors: Frampton MW,Finkelstein JN,Roberts NJ Jr,Smeglin AM,Morrow PE,Utell MJ

    更新日期:1989-12-01 00:00:00

  • Immobilized IgG immune complex induces secretion of tumor necrosis factor-alpha by porcine alveolar macrophages.

    abstract::Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory mediator produced by activated monocytes and macrophages. We have previously shown that porcine alveolar macrophages (PAM) mediate bystander cytotoxicity through hydrogen peroxide production following activation with immobilized IgG immune complex (I...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/5.3.249

    authors: Kim JW,Wierda WG,Kim YB

    更新日期:1991-09-01 00:00:00

  • Hypoxia-inducible factor-1 stimulates postnatal lung development but does not prevent O2-induced alveolar injury.

    abstract::This study investigated whether hypoxia-inducible factor (HIF)-1 influences postnatal vascularization and alveologenesis in mice and whether stable (constitutive-active) HIF could prevent hyperoxia-induced lung injury. We assessed postnatal vessel and alveolar formation in transgenic mice, expressing a stable, constit...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2014-0037OC

    authors: Tibboel J,Groenman FA,Selvaratnam J,Wang J,Tseu I,Huang Z,Caniggia I,Luo D,van Tuyl M,Ackerley C,de Jongste JC,Tibboel D,Post M

    更新日期:2015-04-01 00:00:00

  • The Transient Receptor Potential Channel Vanilloid 1 Is Critical in Innate Airway Epithelial Responses to Protease Allergens.

    abstract::The airway epithelium plays a critical role in innate responses to airborne allergens by secreting IL-1 family cytokines such as IL-1α and IL-33 as alarmins that subsequently orchestrate appropriate immune responses. Previous studies revealed that epithelial IL-33 secretion by allergens such as Alternaria alternata or...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2019-0170OC

    authors: Schiffers C,Hristova M,Habibovic A,Dustin CM,Danyal K,Reynaert NL,Wouters EFM,van der Vliet A

    更新日期:2020-08-01 00:00:00

  • Plasminogen activation induced pericellular fibronectin proteolysis promotes fibroblast apoptosis.

    abstract::Apoptosis of fibroblasts/myofibroblasts is a critical event in the resolution of tissue repair responses; however, mechanisms for the regulation of (myo)fibroblast apoptosis/survival remain unclear. In this study, we demonstrate counter-regulatory interactions between the plasminogen activation system and transforming...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2007-0174OC

    authors: Horowitz JC,Rogers DS,Simon RH,Sisson TH,Thannickal VJ

    更新日期:2008-01-01 00:00:00

  • Three-dimensional mapping of ozone-induced acute cytotoxicity in tracheobronchial airways of isolated perfused rat lung.

    abstract::Acute lung injury induced by reactive oxygen gases such as ozone (O(3)) is focal and site-selective. To define patterns of acute epithelial injury along intrapulmonary airways, we developed a new analytic approach incorporating labeling of permeable cells, airway microdissection, and laser scanning confocal microscopy...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.22.2.3674

    authors: Postlethwait EM,Joad JP,Hyde DM,Schelegle ES,Bric JM,Weir AJ,Putney LF,Wong VJ,Velsor LW,Plopper CG

    更新日期:2000-02-01 00:00:00

  • Interleukin-9 upregulates mucus expression in the airways.

    abstract::Interleukin (IL)-9 has recently been shown to play an important role in allergic disease because its expression is strongly associated with the degree of airway responsiveness and the asthmatic-like phenotype. IL-9 is a pleiotropic cytokine that is active on many cell types involved in the allergic immune response. Mu...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.22.6.3927

    authors: Louahed J,Toda M,Jen J,Hamid Q,Renauld JC,Levitt RC,Nicolaides NC

    更新日期:2000-06-01 00:00:00

  • German cockroach proteases regulate interleukin-8 expression via nuclear factor for interleukin-6 in human bronchial epithelial cells.

    abstract::German cockroach extract synergistically regulates tumor necrosis factor-alpha (TNF-alpha)-induced interleukin (IL)-8 expression in human airway epithelial cells. The IL-8 promoter contains nuclear factor (NF)-kappaB, activating protein (AP)-1, and NF for IL-6 (NF-IL6) transcription factor binding regions. Because coc...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2004-0231OC

    authors: Page K,Hughes VS,Odoms KK,Dunsmore KE,Hershenson MB

    更新日期:2005-03-01 00:00:00

  • The matrix metalloproteinases and their inhibitors.

    abstract::A number of metalloproteinases that degrade the extracellular matrix of connective tissues and two specific tissue inhibitors of metalloproteinases (TIMPs) have now been isolated, characterized, and cloned. Comparison of the enzyme sequences has allowed the delineation of domain structures, and initial studies have be...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章,评审

    doi:10.1165/ajrcmb/7.2.120

    authors: Murphy G,Docherty AJ

    更新日期:1992-08-01 00:00:00

  • Reduction of glutathione is associated with growth restriction and enlargement of bovine pulmonary artery endothelial cells produced by transforming growth factor-beta 1.

    abstract::In addition to inhibiting proliferation and causing enlargement of bovine pulmonary artery endothelial cells in culture, porcine platelet transforming growth factor-beta 1 (TGF-beta 1) (2 ng/ml) lowered glutathione (GSH) of these cells by 48% after 96 h in culture when GSH levels were normalized for cell counts. This ...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/6.4.364

    authors: White AC,Das SK,Fanburg BL

    更新日期:1992-04-01 00:00:00

  • Characterization of the substance P receptor in guinea pig lung tissues.

    abstract::The biologic activity of substance P has been demonstrated to be limited both in in vivo and in vitro by a membrane-bound protease, neutral endopeptidase (EC 3.4.24.11). The interaction of substance P with its receptor on guinea pig lung tissues was studied in the presence of an inhibitor of neutral endopeptidase unde...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/1.4.269

    authors: Coats SR,Gerard NP

    更新日期:1989-10-01 00:00:00

  • Physiological Mechanisms of Airway Hyperresponsiveness in Obese Asthma.

    abstract::Obesity affects the incidence and severity of asthma in at least two major phenotypes: an early-onset allergic (EOA) form that is complicated by obesity and a late-onset nonallergic (LONA) form that occurs only in the setting of obesity. Both groups exhibit airway hyperresponsiveness to methacholine challenge but exhi...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章,评审

    doi:10.1165/rcmb.2016-0019PS

    authors: Bates JH

    更新日期:2016-05-01 00:00:00

  • Effect of inhibition of nitric oxide synthase on Pseudomonas aeruginosa infection of respiratory mucosa in vitro.

    abstract::We studied the effect of the nitric oxide synthase (NOS) inhibitor asymmetric dimethyl arginine (ADMA) and the inactive enantiomer N G-methyl-D-arginine (D-NMMA) on Pseudomonas aeruginosa infection of the respiratory mucosa in nasal turbinate organ cultures. We also investigated the effect of P. aeruginosa culture fil...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.19.6.2904

    authors: Dowling RB,Newton R,Robichaud A,Cole PJ,Barnes PJ,Wilson R

    更新日期:1998-12-01 00:00:00

  • Interleukin-8 and leukotriene-B(4), but not formylmethionyl leucylphenylalanine, stimulate CD18-independent migration of neutrophils across human pulmonary endothelial cells in vitro.

    abstract::Although neutrophil migration from the systemic circulation involves the beta2- (or CD18) integrin family, the existence of an alternative, CD18-independent route of neutrophil extravasation to tissues has been demonstrated in animal models. The molecular interactions involved in this alternative migratory route have ...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.23.2.3853

    authors: Mackarel AJ,Russell KJ,Brady CS,FitzGerald MX,O'Connor CM

    更新日期:2000-08-01 00:00:00

  • Carbonic anhydrase II expression in rat type II pneumocytes.

    abstract::Pulmonary carbonic anhydrase (CA) activity plays important roles in carbon dioxide exchange, fluid secretion, and pH regulation. This study reports the use of molecular and immunologic techniques to characterize expression of the high-activity cytosolic isoenzyme CA II in rat lung tissue. Northern blot analysis of RNA...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.10.5.7514010

    authors: Fleming RE,Moxley MA,Waheed A,Crouch EC,Sly WS,Longmore WJ

    更新日期:1994-05-01 00:00:00

  • Dissection of the hyperadhesive phenotype of airway eosinophils in asthma.

    abstract::Asthma is characterized by appearance of eosinophils in the airway. Eosinophils purified from the airway 48 h after segmental antigen challenge are described as exhibiting greater adhesion to albumin-coated surfaces via an unidentified beta2 integrin and increased expression of alphaMbeta2 (CD11b/18) compared with pur...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2006-0027OC

    authors: Barthel SR,Jarjour NN,Mosher DF,Johansson MW

    更新日期:2006-09-01 00:00:00

  • Corticosteroids inhibit sphingosine 1-phosphate-induced interleukin-6 secretion from human airway smooth muscle via mitogen-activated protein kinase phosphatase 1-mediated repression of mitogen and stress-activated protein kinase 1.

    abstract::Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid that plays an important proinflammatory role in asthmatic airways. Corticosteroids are first-line antiinflammatories in asthma; however, their repressive effects on S1P-induced cytokine secretion have not been investigated. To address this, our in vitro study r...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2013-0208OC

    authors: Che W,Parmentier J,Seidel P,Manetsch M,Ramsay EE,Alkhouri H,Ge Q,Armour CL,Ammit AJ

    更新日期:2014-02-01 00:00:00

  • Airway Progenitor Clone Formation Is Enhanced by Y-27632-Dependent Changes in the Transcriptome.

    abstract::The application of conditional reprogramming culture (CRC) methods to nasal airway epithelial cells would allow more wide-spread incorporation of primary airway epithelial culture models into complex lung disease research. In this study, we adapted the CRC method to nasal airway epithelial cells, investigated the grow...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2015-0274MA

    authors: Reynolds SD,Rios C,Wesolowska-Andersen A,Zhuang Y,Pinter M,Happoldt C,Hill CL,Lallier SW,Cosgrove GP,Solomon GM,Nichols DP,Seibold MA

    更新日期:2016-09-01 00:00:00

  • Apical and basolateral ATP-induced anion secretion in polarized human airway epithelia.

    abstract::The present study investigated mechanisms underlying apical and basolateral P2Y(1)-mediated Cl(-) secretion in human airway epithelial cells. Apical and basolateral ATP induced short-circuit currents (I(sc)) with different properties via P2Y(1) receptors. The former comprised an immediate rise followed by a slow atten...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2003-0183OC

    authors: Son M,Ito Y,Sato S,Ishikawa T,Kondo M,Nakayama S,Shimokata K,Kume H

    更新日期:2004-03-01 00:00:00

  • Mechanisms of the potentiation by adenosine of adenosine triphosphate-induced calcium release in tracheal smooth-muscle cells.

    abstract::The effects of concomitant P1-receptor stimulation on peak intracellular Ca2+ release by extracellular adenosine 5'-triphosphate (ATP) and 5-hydroxytryptamine (5-HT) were investigated in cultured airway smooth-muscle (ASM) cells. The results show that peak Ca2+ release to ATP is enhanced by preincubation with adenosin...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.21.1.3425

    authors: Michoud MC,Tao FC,Pradhan AA,Martin JG

    更新日期:1999-07-01 00:00:00

  • A549 lung epithelial cells synthesize anticoagulant molecules on the cell surface and matrix and in conditioned media.

    abstract::To investigate mechanisms regulating intra-alveolar coagulation, we studied monolayers of the A549 human lung epithelial cell line. The surface of A549 cells delayed the onset of prothrombin-to-thrombin conversion and prevented total prothrombin consumption in normal plasma compared to plastic cell-free wells. Similar...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/4.4.338

    authors: Berry L,Andrew M,Post M,Ofosu F,O'Brodovich H

    更新日期:1991-04-01 00:00:00

  • The Induction of Pattern-Recognition Receptor Expression against Influenza A Virus through Duox2-Derived Reactive Oxygen Species in Nasal Mucosa.

    abstract::We studied the relative roles of Duox2-derived reactive oxygen species (ROS) in host defense against influenza A virus (IAV) infection in normal human nasal epithelial cells and mouse nasal mucosa. We found that Duox2 primarily generated ROS rapidly after IAV infection in normal human nasal epithelial cells and that k...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2014-0334OC

    authors: Kim HJ,Kim CH,Kim MJ,Ryu JH,Seong SY,Kim S,Lim SJ,Holtzman MJ,Yoon JH

    更新日期:2015-10-01 00:00:00

  • Persistence of serotonergic enhancement of airway response in a model of childhood asthma.

    abstract::The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O3) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O3 plus allergen induces functional...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2013-0387OC

    authors: Moore BD,Hyde DM,Miller LA,Wong EM,Schelegle ES

    更新日期:2014-07-01 00:00:00

  • Inhibition of pulmonary artery smooth muscle cell growth by hypoxanthine, xanthine, and uric acid.

    abstract::We have previously reported that medium conditioned by hypoxic pulmonary artery endothelial cells (ECCM) contains a factor of small molecular weight that inhibits the growth of pulmonary artery smooth muscle cells (SMC). We postulated that this factor might be a breakdown product of ATP and, therefore, measured the le...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb/6.6.617

    authors: Hassoun PM,Shedd AL,Lanzillo JJ,Thappa V,Landman MJ,Fanburg BL

    更新日期:1992-06-01 00:00:00

  • Critical role of serum response factor in pulmonary myofibroblast differentiation induced by TGF-beta.

    abstract::Transforming growth factor-beta (TGF-beta) is a cytokine implicated in wound healing and in the pathogenesis of pulmonary fibrosis. TGF-beta stimulates myofibroblast differentiation characterized by expression of contractile smooth muscle (SM)-specific proteins such as SM-alpha-actin. In the present study, we examined...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/rcmb.2008-0288OC

    authors: Sandbo N,Kregel S,Taurin S,Bhorade S,Dulin NO

    更新日期:2009-09-01 00:00:00

  • Calcitriol and its synthetic analogue MC 903 inhibit the interleukin-2-induced migration of human lymphocytes.

    abstract::Sarcoidosis is characterized by the accumulation of activated lymphocytes in the lungs and other organs and by the spontaneous production of the active form of vitamin D, calcitriol. We hypothesized that calcitriol may modulate the responsiveness of human lymphocytes to the relevant biologic mediator, interleukin-2 (I...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章

    doi:10.1165/ajrcmb.12.6.7766430

    authors: Fraher LJ,Caveney AN,McFadden RG

    更新日期:1995-06-01 00:00:00

  • Heme oxygenase-1: the "emerging molecule" has arrived.

    abstract::Organisms on our planet have evolved in an oxidizing environment that is intrinsically inimical to life, and cells have been forced to devise means of protecting themselves. One of the defenses used most widely in nature is the enzyme heme oxygenase-1 (HO-1). This enzyme performs the seemingly lackluster function of c...

    journal_title:American journal of respiratory cell and molecular biology

    pub_type: 杂志文章,评审

    doi:10.1165/ajrcmb.27.1.4862

    authors: Morse D,Choi AM

    更新日期:2002-07-01 00:00:00