DOCSLIB.ORG

Activin a Contributes to the Development of Hyperoxia-Induced

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Activin a Contributes to the Development of Hyperoxia-Induced nature publishing group Basic Science Investigation Articles Activin A contributes to the development of ­ hyperoxia-induced lung injury in neonatal mice Rebecca Lim1,2, Ruth Muljadi1, Eugenia Koulaeva2, Patricia Vosdoganes2, Siow Teng Chan1, Rutu Acharya1, Seshini Gurusinghe1, Olli Ritvos3, Arja Pasternack3 and Euan M. Wallace1,2 BACKGROUND: Bronchopulmonary dysplasia (BPD) is one of There is currently no cure for BPD and asides from ventilatory the leading causes of morbidity and mortality in babies born support, clinical management involves the use of steroids, which prematurely, yet there is no curative treatment. In recent years, is associated with an increased incidence of cerebral palsy. There a number of inhibitors against TGFβ signaling have been tested is thus a need for new therapeutic approaches. for their potential to prevent neonatal injury associated with In the past decade, much light has been shed on the contri- hyperoxia, which is a contributing factor of BPD. In this study, bution of TGFβ signaling to neonatal lung development and we assessed the contribution of activin A—a member of the injury. TGFβ1 has been shown to be important for the sur- TGFβ superfamily—to the development of ­hyperoxia-induced vival and repair of type II alveolar epithelial cells (AEC2) (4). lung injury in neonatal mice. Specifically, TGFβ1 treatment of hyperoxia damaged AEC2 METHODS: We placed newborn C57Bl6 mouse pups in con- improved cell survival, migration, and secretion of proan- tinuous hyperoxia (85% O2) to mimic many aspects of BPD giogenic ligands such as vascular endothelial growth factor including alveolar simplification and pulmonary inflamma- (VEGF) and matrix proteins such as fibronectin. However, tion. The pups were administered activin A receptor type IIB-Fc inhibition of TGFβ signaling by curcumin and PPARγ agonist, antagonist (ActRIIB-Fc) at 5 mg/kg or follistatin at 0.1 mg/kg on rosiglitazone, were protective against hyperoxia-induced lung postnatal days 4, 7, 10, and 13. injury in neonatal rat models of BPD (5,6). These reports point RESULTS: Treatment with ActRIIB-Fc and follistatin protected to the need for better understanding of TGFβ signaling within against hyperoxia-induced growth retardation. ActRIIB-Fc also the context of BPD. reduced pulmonary leukocyte infiltration, normalized tissue: Activin A, a member of the TGFβ superfamily, has been airspace ratio and increased septal crest density. These findings reported to contribute to adult lung disease. In adult animals, were associated with reduced phosphorylation of Smad3 and overexpression of activin A in the lungs results in an alteration decreased matrix metalloproteinase (MMP)-9 activity. in the composition of the lung epithelial cell populations where CONCLUSION: This study suggests that activin A signal- ciliated cells dominate, with fewer AEC2 (7). These changes ing may contribute to the pathology of bronchopulmonary result in a compromise to lung compliance and a significant dysplasia. reduction in surfactant protein C-expressing AEC2. In another study, blocking activin A using follistatin following in bleomy- cin challenge, prevented lung inflammation and fibrosis (8). remature birth refers to birth before 37 wk of gestation. There While these studies support a role for activin A in adult inflam- Pare a large number of medical complications associated with matory and fibrotic lung injury, its role in neonatal lung injury, being born prematurely, many of which are a consequence of repair and development has never been previously studied. life-saving interventions, including bronchopulmonary dyspla- In this study, we exposed newborn mice to hyperoxia (85% sia (BPD). Historically, BPD was originally described in 1967, O2) and administered either soluble ActRIIB-Fc (5 mg/kg) or as a form of chronic lung disease observed in premature babies, follistatin (0.1 mg/kg) twice weekly to determine the contribu- resulting from the injurious effects of high oxygen tension and tion of activin A signaling to the pulmonary phenotype. We airway pressure used during mechanical ventilation (1). This assessed changes to lung remodeling, activin A levels, Smad form of lung disease is commonly referred to as “old BPD”. signaling and markers of lung injury including leukocyte infil- Today, this is rare due to gentler ventilation strategies and the tration, cell death, and proliferation. use of surfactant and antenatal steroids. Instead, a “new BPD” has emerged, defined as the requirement of supplemental oxy- RESULTS gen at 36 wk postconceptional age (2). The pathological hall- ActRIIB-Fc and Follistatin Treatment Improved Bodyweights marks are suggestive of arrested septation and alveolarisation Hyperoxia reduced bodyweights of pups as previously­ triggered by inflammation, corticosteroids, and hyperoxia (3). reported. The bodyweights of animals from the hyperoxia 1The Ritchie Centre, MIMR-PHI Institute of Medical Research, Victoria, Australia; 2Department of Obstetrics and Gynecology, Monash University, Victoria, Australia; 3Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. Correspondence: Rebecca Lim ([email protected]) Received 11 March 2014; accepted 22 November 2014; advance online publication 15 April 2015. doi:10.1038/pr.2015.46 Copyright © 2015 International Pediatric Research Foundation, Inc. Volume 77 | Number 6 | June 2015 Pediatric REsEarcH 749 Articles Lim et al. ab † 8 ‡ 800 ** * 6 600 4 400 Body weight (g) Activin A (pg/ml) 2 200 0 0 Saline ActRII-Fc FS288 Saline ActRII-Fc FS288 Saline ActRII-Fc FS288 Saline ActRII-Fc FS288 Normoxia Hyperoxia Normoxia Hyperoxia Figure 1. Hyperoxia reduced bodyweights of neonatal mouse pups. Hyperoxia reduced bodyweights of developing pups. They are significantly lighter at postnatal day day 14 compared to normoxia pups (a, *P < 0.05). Administration of ActRIIB-Fc and FS288 significantly increased bodyweights of ­hyperoxia-exposed pups (†P < 0.001, ‡P < 0.0001). Activin A levels were elevated in hyperoxia animals, which was reduced following FS288 treatment (b, *P < 0.05). + saline cohort were significantly lower compared to the a 2.0 ** normoxia + saline cohort at postnatal day 14 (Figure 1a). * Treatment with ActRIIB-Fc and follistatin significantly ** improved the bodyweights of pups subjected to hyperoxia such 1.5 that they were not significantly different to the normoxia treat- ment groups. Hyperoxia was associated with increased activin levels (Figure 1b, P < 0.05), which remained unchanged by 1.0 ActRIIB-Fc treatment but significantly reduced by follistatin (P < 0.05). pSmad3 vs total Smad 3 0.5 ActRIIB-Fc Treatment Improves Septation Hyperoxia increased Smad3 phosphorylation as previously reported by Dasgupta et al. (9) (Figure 2a, P < 0.05). This was 0.0 significantly reduced by ActRIIB-Fc and follistation (P < 0.01). Saline ActRII-Fc FS288 Saline ActRII-Fc FS288 Representative western blots are provided in Figure 2b. Typical Normoxia Hyperoxia of hyperoxia exposure, we saw a reduction in tissue: airspace b Normoxia Hyperoxia Normoxia Hyperoxia Normoxia Hyperoxia ratio (Figure 3a, P < 0.01) as increased oxygen tension induced + Saline + Saline + ActRII-Fc + ActRII-Fc + FS288 + FS288 alveolar simplification. Treatment with ActRIIB-Fc signifi- cantly increased tissue: airspace ratio in hyperoxia-treated ani- Total Smad 3 mals (P < 0.0001), suggesting that there was some prevention Phospho Smad 3 of alveolar simplification. Smad 2/3 signaling is increased in mouse models of Figure 2. Treatment with ActRIIB-Fc and follistatin reduced hyperoxia-induced lung injury (5) as well as sheep mod- ­hyperoxia-induced Smad 3 phosphorylation. Hyperoxia significantly els of antenatal inflammation-associated lung injury (10). increased Smad 3 phosphorylation (a, *P < 0.05). This was reduced in Given the effects of ActRIIB-Fc treatment on improving tis- ActRIIB-Fc- and FS288-treated animals (**P < 0.01). Representative western sue: airspace ratio and reducing phosphorylation of Smad 3, blots are shown (b). we sought to assess the effects of ActRIIB-Fc and follistatin on septation. Secondary septal crest density was thus deter- ActRIIB-Fc Treatment Reduced Pulmonary Leukocyte Infiltration mined by morphometric analysis. We confirmed that hyper- and IL-6 Production oxia significantly reduced septal crest density (Figure 3a, Unsurprisingly, hyperoxia increased the recruitment of leu- P < 0.001). Administration of ActRIIB-Fc increased septa- kocytes in the lungs as determined by CD45 immunohisto- tion in the hyperoxia-treated animals (P < 0.0001) while chemistry (Figure 4a, P < 0.05). This was significantly reduced follistatin treatment had no significant impact on septation. by ActRIIB-Fc treatment (P < 0.01) where the percentage of Representative images of septal crest imaging are shown in CD45+ cells was reduced to numbers comparable to that of Figure 3c. normoxia + saline animals. Given that ActRIIB-Fc treatment 750 Pediatric REsEarcH Volume 77 | Number 6 | June 2015 Copyright © 2015 International Pediatric Research Foundation, Inc. Activin contributes to hyperoxic injury Articles ab‡ 0.8 ** 0.20 0.6 † 0.15 ‡ 0.4 0.10 % Septal crests Tissue space: air space 0.2 0.05 0.0 0.00 Saline ActRII-Fc FS288 Saline ActRII-Fc FS288 FS288 ActRII-Fc Saline Saline ActRII-Fc FS288 Normoxia Hyperoxia Normoxia Hyperoxia c Saline ActRII-Fc FS288 Normoxia Hyperoxia Figure 3. Changes in tissue: airspace ratio and secondary septation. Tissue: airspace ratio was reduced by hyperoxia (a, **P
Load more

Recommended publications
  • Surfactant Protein-C in the Maintenance of Lung Integrity and Function Stephan W
    erg All y & of T l h a e n r r a Glasser, et al. J Aller Ther 2011, S7 p u y o J Journal of Allergy & Therapy DOI: 10.4172/2155-6121.S7-001 ISSN: 2155-6121 Review Article Open Access Surfactant Protein-C in the Maintenance of Lung Integrity and Function Stephan W. Glasser1*, John E. Baatz2 and Thomas R. Korfhagen1 1Department of Pediatrics, Cincinnati Children’s Hospital Medical Center , University of Cincinnati College of Medicine, Cincinnati, Ohio, USA 2Department of Pediatrics, Medical University of South Carolina and MUSC Children’s Hospital; Charleston, South Carolina, USA Abstract Surfactant protein-C (SP-C) is a lung cell specific protein whose expression is identified from the earliest stages of mammalian lung development in a subset of developing epithelial cells and in the alveolar type II cell in the mature lung. Although SP-C gene expression is not critical and protein function is not necessary for the normal developing morphological patterning of the lung, studies of SP-C protein mutations and SP-C deficiency have revealed critical roles of SP-C in the maintenance and function of the preterm and mature lung during various forms of intrinsic or extrinsic lung injury. This review summarizes studies using in vitro experimental approaches, in vivo modeling in transgenic mice, and analysis of human disease pathogenesis. Collected data reveal an essential role for SP-C singly and in combination with other lung proteins, in maintenance of lung structure and pulmonary function of the immature and mature lung. Introduction regulating lung development, function, and recovery from injury.
    [Show full text]
  • Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis
    bioRxiv preprint doi: https://doi.org/10.1101/2020.07.30.227892; this version posted July 30, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Single-Cell Transcriptomics Identifies Dysregulated Metabolic Programs of Aging Alveolar Progenitor Cells in Lung Fibrosis Jiurong Liang1,6, Guanling Huang1,6, Xue Liu1, Forough Taghavifar1, Ningshan Liu1, Changfu Yao1, Nan Deng2, Yizhou Wang3, Ankita Burman1, Ting Xie1, Simon Rowan1, 5 Peter Chen1, Cory Hogaboam1, Barry Stripp1, S. Samuel Weigt5, John Belperio5, William C. Parks1,4, Paul W. Noble1, and Dianhua Jiang1,4 1Department of Medicine and Women’s Guild Lung Institute, 2Samuel Oschin Comprehensive Cancer Institute, 3Genomics Core, 4Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. 5Department of Medicine 10 University of California, Los Angeles (UCLA), Los Angeles, CA 90048, USA. 6These authors contributed equally. Correspondence and requests for materials should be addressed to P.W.N. ([email protected]), D.J. ([email protected]). Running title: Metabolic defect of aging alveolar progenitor 15 One sentence summary: Metabolic defects of alveolar progenitors in aging and during lung injury impair their renewal. Data availability: The single cell RNA-seq are deposited Funding statement: This work was supported by NIH grants R35-HL150829, R01- HL060539, R01-AI052201, R01-HL077291, and R01-HL122068, and P01-HL108793. 20 Conflict of interest: The authors declare that there is no conflict of interest. Ethics approval statement: All mouse experimens were under the guidance of the IACUC008529 in accordance with institutional and regulatory guidelines.
    [Show full text]
  • Idiopathic Pulmonary Fibrosis: Pathogenesis and Management
    Sgalla et al. Respiratory Research (2018) 19:32 https://doi.org/10.1186/s12931-018-0730-2 REVIEW Open Access Idiopathic pulmonary fibrosis: pathogenesis and management Giacomo Sgalla1* , Bruno Iovene1, Mariarosaria Calvello1, Margherita Ori2, Francesco Varone1 and Luca Richeldi1 Abstract Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. This review will present the substantial advances achieved in the understanding of IPF pathogenesis and in the therapeutic options that can be offered to patients, and will address the issues regarding diagnosis and management that are still open. Main body: Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. Sustained alveolar epithelial micro-injury and activation has been recognised as the trigger of several biological events of disordered repair occurring in genetically susceptible ageing individuals. Despite multidisciplinary team discussion has demonstrated to increase diagnostic accuracy, patients can still remain unclassified when the current diagnostic criteria are strictly applied, requiring the identification of a Usual Interstitial Pattern either on high-resolution computed tomography scan or lung biopsy. Outstanding achievements have been made in the management of these patients, as nintedanib and pirfenidone consistently proved to reduce the rate of progression of the fibrotic process. However, many uncertainties still lie in the correct use of these drugs, ranging from the initial choice of the drug, the appropriate timing for treatment and the benefit-risk ratio of a combined treatment regimen.
    [Show full text]
  • Lung Stem Cells
    Cell Tissue Res DOI 10.1007/s00441-007-0479-2 REVIEW Lung stem cells Darrell N. Kotton & Alan Fine Received: 3 June 2007 /Accepted: 13 July 2007 # Springer-Verlag 2007 Abstract The lung is a relatively quiescent tissue com- comprising these structures face repeated insults from prised of infrequently proliferating epithelial, endothelial, inhaled microorganisms and toxicants, and potential inju- and interstitial cell populations. No classical stem cell ries from inflammatory mediators carried by the blood hierarchy has yet been described for the maintenance of this supply. Although much is known about lung structure and essential tissue; however, after injury, a number of lung cell function, an emerging literature is providing new insights types are able to proliferate and reconstitute the lung into the repair of the lung after injury. epithelium. Differentiated mature epithelial cells and newly Recent findings suggest that a variety of cell types recognized local epithelial progenitors residing in special- participate in the repair of the adult lung. Many mature, ized niches may participate in this repair process. This differentiated local cell types appear to play roles in review summarizes recent discoveries and controversies, in reconstituting lung structure after injury. In addition, newly the field of stem cell biology, that are not only challenging, recognized local epithelial progenitors and putative stem but also advancing an understanding of lung injury and cells residing in specialized niches may participate in this repair. Evidence supporting a role for the numerous cell process. This review introduces basic concepts of stem cell types believed to contribute to lung epithelial homeostasis is biology and presents a discussion of the way in which these reviewed, and initial studies employing cell-based therapies concepts are helping to challenge and advance our for lung disease are presented.
    [Show full text]
  • Systematic Review of Drug Effects in Humans and Models with Surfactant-Processing Disease
    REVIEW DRUG EFFECTS Systematic review of drug effects in humans and models with surfactant-processing disease Dymph Klay1, Thijs W. Hoffman1, Ankie M. Harmsze2, Jan C. Grutters1,3 and Coline H.M. van Moorsel1,3 Affiliations: 1Interstitial Lung Disease Center of Excellence, Dept of Pulmonology, St Antonius Hospital, Nieuwegein, The Netherlands. 2Dept of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands. 3Division of Heart and Lung, University Medical Center Utrecht, Utrecht, The Netherlands. Correspondence: Coline H.M. van Moorsel, Interstitial Lung Disease Center of Excellence, St Antonius Hospital, Koekoekslaan 1, Nieuwegein, 3435CM, The Netherlands. E-mail: [email protected] @ERSpublications Drug effects in disease models of surfactant-processing disease are highly dependent on mutation http://ow.ly/ZYZH30k3RkK Cite this article as: Klay D, Hoffman TW, Harmsze AM, et al. Systematic review of drug effects in humans and models with surfactant-processing disease. Eur Respir Rev 2018; 27: 170135 [https://doi.org/10.1183/ 16000617.0135-2017]. ABSTRACT Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky–Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations. We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation.
    [Show full text]
  • M(2-9), a Cecropin-Melittin Hybrid Peptide
    ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Sept. 2001, p. 2441–2449 Vol. 45, No. 9 0066-4804/01/$04.00ϩ0 DOI: 10.1128/AAC.45.9.2441–2449.2001 Copyright © 2001, American Society for Microbiology. All Rights Reserved. N-Terminal Fatty Acid Substitution Increases the Leishmanicidal Activity of CA(1-7)M(2-9), a Cecropin-Melittin Hybrid Peptide CRISTINA CHICHARRO,1 CESARE GRANATA,2† ROSARIO LOZANO,1 2 1 DAVID ANDREU, AND LUIS RIVAS * Centro de Investigaciones Biolo´gicas (CSIC), Vela´zquez 144, 28006 Madrid,1 and Departament de Quı´mica Orga`nica, Universitat de Barcelona, Martı´ i Franque`s 1, 08028 Barcelona,2 Spain Received 16 February 2001/Returned for modification 18 April 2001/Accepted 5 June 2001 In order to improve the leishmanicidal activity of the synthetic cecropin A-melittin hybrid peptide CA(1- 7)M(2-9) (KWKLFKKIGAVLKVL-NH2), a systematic study of its acylation with saturated linear fatty acids was carried out. Acylation of the N␧-7 lysine residue led to a drastic decrease in leishmanicidal activity, whereas ␣ ␧ acylation at lysine 1, in either the or the NH2 group, increased up to 3 times the activity of the peptide against promastigotes and increased up to 15 times the activity of the peptide against amastigotes. Leish- manicidal activity increased with the length of the fatty acid chain, reaching a maximum for the lauroyl analogue (12 carbons). According to the fast kinetics, dissipation of membrane potential, and parasite membrane permeability to the nucleic acid binding probe SYTOX green, the lethal mechanism was directly related to plasma membrane permeabilization. The protozoal mammalian parasite Leishmania is the caus- In contrast to frequent C-terminal amidation and to other ative agent of the set of clinical manifestations known as leish- less common posttranslational modifications such as glycosyl- maniasis, which afflicts 12 million to 14 million people world- ation or incorporation of D-amino acids or halogenated amino wide (24).
    [Show full text]
  • Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
    Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase
    [Show full text]
  • Isolating the Role of Corticosterone in the Hypothalamic-Pituitary-Gonadal Genomic Stress Response
    bioRxiv preprint doi: https://doi.org/10.1101/2020.10.08.330209; this version posted October 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1 Isolating the role of corticosterone in the hypothalamic-pituitary-gonadal 2 genomic stress response 3 4 By: Suzanne H. Austin1, *, Rayna Harris1, April M. Booth1, Andrew S. Lang2, Victoria S. Farrar1, 5 Jesse S. Krause1, 3, Tyler A. Hallman4, Matthew MacManes2, and Rebecca M. Calisi1 6 7 1Department of Neurobiology, Physiology, and Behavior, University of California Davis, 1 8 Shields Avenue, Davis, CA, USA, 95616 9 2 Department of Molecular, Cellular and Biomedical Sciences, The University of New 10 Hampshire, 434 Gregg Hall, Durham, NH, USA, 03824 11 3 Department of Biology, University of Nevada, Reno, 1664 N. Virginia Street, Reno, NV, USA, 12 89557-0314 13 4 Department of Fisheries and Wildlife, Oregon State University, 104 Nash Hall, Corvallis, OR 14 97331 15 16 *Current address: 17 Department of Integrative Biology, Oregon State University, 3029 Cordley Hall, Corvallis, OR, 18 USA, 97331; Department of Fisheries and Wildlife, Oregon State University, 104 Nash Hall, 19 Corvallis, OR 97331 20 21 22 23 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.10.08.330209; this version posted October 9, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Human IL-32 Expression Protects Mice Against a Hypervirulent Strain of Mycobacterium Tuberculosis
    Human IL-32 expression protects mice against a hypervirulent strain of Mycobacterium tuberculosis Xiyuan Baia,b,c,1,2, Shaobin Shangd,1, Marcela Henao-Tamayod, Randall J. Basarabad, Alida R. Ovrutskya,b,c, Jennifer L. Matsudab, Katsuyuki Takedae, Mallory M. Chanb, Azzeddine Dakhamae, William H. Kinneyb, Jessica Trostelb, An Baib, Jennifer R. Hondab,c, Rosane Achcarf, John Hartneyb, Leo A. B. Joosteng, Soo-Hyun Kimh, Ian Ormed, Charles A. Dinarellog,i,2, Diane J. Ordwayd, and Edward D. Chana,b,c,2 aDenver Veterans Affairs Medical Center, Denver, CO 80206; dDepartment of Microbiology, Immunology, and Pathology, Mycobacteria Research Laboratories, Colorado State University, Fort Collins, CO 80523; Departments of bMedicine and Academic Affairs, ePediatrics, and fPathology, National Jewish Health, Denver, CO 80206; gDepartment of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; hDepartment Biomedical Science and Technology, Konkuk University, Seoul, Korea; and Divisions of cPulmonary Sciences and Critical Care Medicine and iInfectious Diseases, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045-2539 Contributed by Charles Anthony Dinarello, December 24, 2014 (sent for review December 2, 2014) Silencing of interleukin-32 (IL-32) in a differentiated human pro- line, increased the intracellular burden of MTB, indicating that monocytic cell line impairs killing of Mycobacterium tuberculosis IL-32 plays a host-protective role (9). However, the role of IL-32 (MTB) but the role of IL-32 in vivo against MTB remains unknown. in the response to TB in vivo remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was gen- IL-32 is composed of six isoforms (α, β, γ, δ, e, and ζ) due to erated in which the human IL-32γ gene is expressed using alternatively spliced mRNA variants (3).
    [Show full text]
  • Lipid–Protein and Protein–Protein Interactions in the Pulmonary Surfactant System and Their Role in Lung Homeostasis
    International Journal of Molecular Sciences Review Lipid–Protein and Protein–Protein Interactions in the Pulmonary Surfactant System and Their Role in Lung Homeostasis Olga Cañadas 1,2,Bárbara Olmeda 1,2, Alejandro Alonso 1,2 and Jesús Pérez-Gil 1,2,* 1 Departament of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, 28040 Madrid, Spain; [email protected] (O.C.); [email protected] (B.O.); [email protected] (A.A.) 2 Research Institut “Hospital Doce de Octubre (imasdoce)”, 28040 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-913944994 Received: 9 May 2020; Accepted: 22 May 2020; Published: 25 May 2020 Abstract: Pulmonary surfactant is a lipid/protein complex synthesized by the alveolar epithelium and secreted into the airspaces, where it coats and protects the large respiratory air–liquid interface. Surfactant, assembled as a complex network of membranous structures, integrates elements in charge of reducing surface tension to a minimum along the breathing cycle, thus maintaining a large surface open to gas exchange and also protecting the lung and the body from the entrance of a myriad of potentially pathogenic entities. Different molecules in the surfactant establish a multivalent crosstalk with the epithelium, the immune system and the lung microbiota, constituting a crucial platform to sustain homeostasis, under health and disease. This review summarizes some of the most important molecules and interactions within lung surfactant and how multiple lipid–protein and protein–protein interactions contribute to the proper maintenance of an operative respiratory surface. Keywords: pulmonary surfactant film; surfactant metabolism; surface tension; respiratory air–liquid interface; inflammation; antimicrobial activity; apoptosis; efferocytosis; tissue repair 1.
    [Show full text]
  • Simple, Helical Peptoid Analogs of Lung Surfactant Protein B
    Chemistry & Biology, Vol. 12, 77–88, January, 2005, ©2005 Elsevier Ltd All rights reserved. DOI 10.1016/j.chembiol.2004.10.014 Simple, Helical Peptoid Analogs of Lung Surfactant Protein B Shannon L. Seurynck, James A. Patch, interface, (2) the ability to reach near-zero surface ten- and Annelise E. Barron* sion upon film compression, and (3) the ability to re- Department of Chemical and Biological Engineering spread upon multiple compressions and expansions of Northwestern University surface area with minimal loss of surfactant into the 2145 Sheridan Road subphase [10]. LS is composed of w90% lipids and Evanston, Illinois 60208 w10% surfactant proteins [5, 11–15]. The hydrophobic surfactant proteins, SP-B and SP-C, in particular are essential to the proper biophysical function of LS for Summary breathing and are thought to be involved in the organ- ization and fluidization of the lipid film [10]. The helical, amphipathic surfactant protein, SP-B, is Films of the main lipid component of LS, dipalmitoyl a critical element of pulmonary surfactant and hence phosphatidylcholine (DPPC), can reach near-zero sur- is an important therapeutic molecule. However, it is face tension upon compression in vitro; however, this difficult to isolate from natural sources in high purity. molecule is slow to adsorb to the interface and exhibits We have created and studied three different, nonnatu- poor respreadability [10]. With the addition of palmitoyl- ral analogs of a bioactive SP-B fragment (SP-B1-25), oleoyl phosphatidylglycerol (POPG) and/or palmitic using oligo-N-substituted glycines (peptoids) with acid (PA), there is an increased rate of surfactant ad- simple, repetitive sequences designed to favor the sorption and better respreadability than with DPPC formation of amphiphilic helices.
    [Show full text]
  • I WO 2015/019381 Al Fig. 2
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization I International Bureau (10) International Publication Number (43) International Publication Date WO 2015/019381 Al 12 February 2015 (12.02.2015) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C12Q 1/68 (2006.01) G01N 33/68 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/IT20 14/0002 14 KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (22) International Filing Date: MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, 8 August 2014 (08.08.2014) OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (25) Filing Language: Italian TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (26) Publication Language: English ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every RM2013A000465 8 August 2013 (08.08.2013) IT kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (72) Inventors; and UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicants : SALTINI, Cesare [IT/IT]; Via Valle Delia TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Noce, 10/B, 1-00046 Grottaferrata RM (IT).
    [Show full text]