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Basic Composition and Alterations in Chronic Lung Disease

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BACK TO BASICS | LUNG DISEASE The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease Gerald Burgstaller1, Bettina Oehrle1, Michael Gerckens1, Eric S. White 2, Herbert B. Schiller1 and Oliver Eickelberg 3 Affiliations: 1Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich and Helmholtz Zentrum München, Member of the German Center for Lung Research, Munich, Germany. 2Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA. 3Division of Respiratory Sciences and Critical Care Medicine, University of Colorado, Denver, CO, USA. Correspondence: Gerald Burgstaller, Comprehensive Pneumology Center, Helmholtz Center Munich, Ludwig Maximilians University Munich, University Hospital Grosshadern, Max-Lebsche-Platz 31, Munich, Germany. E-mail: [email protected] @ERSpublications Molecular/biomechanical alterations within ECM in chronic lung diseases direct cellular function/ differentiation http://ow.ly/9GrY30c0LJG Cite this article as: Burgstaller G, Oehrle B, Gerckens M, et al. The instructive extracellular matrix of the lung: basic composition and alterations in chronic lung disease. Eur Respir J 2017; 50: 1601805 [https://doi. org/10.1183/13993003.01805-2016]. ABSTRACT The pulmonary extracellular matrix (ECM) determines the tissue architecture of the lung, and provides mechanical stability and elastic recoil, which are essential for physiological lung function. Biochemical and biomechanical signals initiated by the ECM direct cellular function and differentiation, and thus play a decisive role in lung development, tissue remodelling processes and maintenance of adult homeostasis. Recent proteomic studies have demonstrated that at least 150 different ECM proteins, glycosaminoglycans and modifying enzymes are expressed in the lung, and these assemble into intricate composite biomaterials. These highly insoluble assemblies of interacting ECM proteins and their glycan modifications can act as a solid phase-binding interface for hundreds of secreted proteins, which creates an information-rich signalling template for cell function and differentiation. Dynamic changes within the ECM that occur upon injury or with ageing are associated with several chronic lung diseases. In this review, we summarise the available data about the structure and function of the pulmonary ECM, and highlight changes that occur in idiopathic pulmonary fibrosis (IPF), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma and lung cancer. We discuss potential mechanisms of ECM remodelling and modification, which we believe are relevant for future diagnosis and treatment of chronic lung disease. Received: Sept 12 2016 | Accepted after revision: March 29 2017 Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com Copyright ©ERS 2017 https://doi.org/10.1183/13993003.01805-2016 Eur Respir J 2017; 50: 1601805 LUNG DISEASE | G. BURGSTALLER ET AL. Part A: the pulmonary ECM The evolution of complex tissues in higher organisms is accompanied by an expansion in protein diversity and structural organisation in the ECM [1], as well as an expansion of diversity of ECM receptors on cells. As in all other organ systems, the pulmonary ECM is organised into two main structural types: 1) basement membranes, which are thin sheets of glycoproteins that cover the basal side of epithelia and endothelia, and surround muscle, fat and peripheral nerve cells; and 2) interstitial matrices, which form a loose and fibril-like meshwork that interconnects structural cell types within tissues, and thereby maintains the three-dimensional (3D) cohesiveness and biomechanical characteristics of the lung [2]. Both basement membranes and interstitial matrices form tissue-specific “niches” that influence the stemness a) Matrisome Mass spectrometry d) ECM Glycoproteins Gene iBAQ Protein name name (log10) Mfap4 9.59 Microfibril-associated glycoprotein 4 Lamc1 9.53 Laminin subunit gamma-1 Lamb2 9.46 Laminin subunit beta-2 Nid1 9.44 Nidogen-1 Postn 9.44 Periostin Fbln5 9.39 Fibulin-5 Lamb3 9.27 Laminin subunit beta-3 Lama5 9.21 Laminin subunit alpha-5 Lamc2 9.18 Laminin subunit gamma-2 Lama3 9.08 Laminin subunit alpha-3 Fga 9.07 Fibrinogen, alpha polypeptide Dpt 8.94 Dermatopontin Emilin1 8.90 EMILIN-1 Fn1 8.85 Fibronectin Fgb 8.84 Fibrinogen beta chain Relative protein mass fraction (MS-data) Nid2 8.83 Nidogen-2 Npnt 8.79 Nephronectin Core matrisome Fgg 8.78 Fibrinogen gamma chain Matrisome associated Lama4 8.71 Laminin subunit alpha-4 Adipoq 8.57 Adiponectin Cell membrane Tinagl1 8.55 Tubulointerstitial nephritis antigen-like Cytoplasm Agrn 8.52 Agrin Cytoskeleton Mgp 8.49 Matrix Gla protein Vwa5a 8.48 von Willebrand factor A domain-containing protein 5A Nucleus Vtn 8.45 Vitronectin Eln 8.44 Elastin Tgfbi 8.40 Transforming growth factor-beta-induced protein ig-h3 Efemp1 8.39 EGF-containing fibulin-like extracellular matrix protein 1 Igfbp7 8.39 Insulin-like growth factor-binding protein 7 Sparc 8.30 SPARC Vwf 8.29 von Willebrand factor Mfge8 8.25 Lactadherin Mfap2 8.24 Microfibrillar-associated protein 2 Lama2 8.22 Laminin subunit alpha-2 Spon1 8.15 Spondin-1 Fbn1 8.06 Fibrillin-1 Ltbp1 7.88 Latent-transforming growth factor beta-binding protein 1 Emid1 7.86 EMI domain-containing protein 1 Thbs1 7.81 Thrombospondin 1 Mfap5 7.80 Microfibrillar-associated protein 5 Wisp2 7.78 WNT1-inducible signaling pathway protein 2 Tnxb 7.78 Protein Tnxb Sparcl1 7.77 SPARC-like protein 1 Tinag 7.71 Protein Tinag Lrg1 7.68 Leucine-rich HEV glycoprotein (Precursor) b) Collagens Ntn4 7.67 Netrin-4 Mmrn2 7.62 Multimerin-2 Gene iBAQ Protein name Ecm1 7.60 Extracellular matrix protein 1 name (log10) Pxdn 7.60 Peroxidasin homolog Ntn1 7.58 Netrin-1 Papln 7.57 Papilin Col6a1 9.36 Collagen alpha-1(VI) chain Abi3bp 7.52 Protein Abi3bp Col6a3 9.31 Protein Col6a3 Fbln1 7.45 Fibulin-1 Col6a2 9.16 Collagen alpha-2(VI) chain Pcolce 7.44 Procollagen C-endopeptidase enhancer 1 Col4a1 8.63 Collagen alpha-1(IV) chain Fbln1 7.43 Fibulin-1 Col4a2 8.58 Collagen alpha-2(IV) chain Ltbp2 7.40 Latent-transforming growth factor beta-binding protein 2 Col1a2 4.48 Collagen alpha-2(I) chain Vwa1 7.37 von Willebrand factor A domain-containing protein 1 Col1a1 8.18 Collagen alpha-1(I) chain Fbln2 7.29 Fibulin-2 Col4a5 8.03 Col4a5 protein Creld2 7.29 Cysteine-rich with EGF-like domain protein 2 Col12a1 7.98 Collagen alpha-1(XII) chain Sned1 7.26 Sushi, nidogen and EGF-like domain-containing protein 1 Col18a1 7.96 Collagen alpha-1(XVIII) chain Matn4 7.26 Matrilin-4 Col14a1 7.94 Collagen alpha-1(XIV) chain Thbs3 7.25 Thrombospondin-3 Col4a3 7.92 Collagen alpha-3(IV) chain Ltbp4 7.21 Latent-tranforming growth factor beta-binding protein 4 Col3a1 7.47 Collagen alpha-1(III) chain Tnc 7.20 Tenascin Col5a1 7.46 Collagen alpha-1(V) chain Igfbp5 7.17 Insulin-like growth factor-binding protein 5 Col15a1 7.38 Collagen alpha-1(XV) chain Slit3 7.16 Slit homolog 3 protein Col4a4 7.37 Collagen alpha-4(IV) chain Igfbp6 7.15 Insulin-like growth factor-binding protein 6 Col16a1 7.23 Collagen alpha-1(XVI) chain Pcolce2 7.10 Procollagen C-endopeptidase enhancer 2 Col4a6 7.16 Protein Col4a6 Aebp1 7.08 Adipocyte enhancer-binding protein 1 Col7a1 7.02 Collagen alpha-1(VII) chain Svep1 7.01 Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 Col8a1 6.97 Collagen alpha-1(VIII) chain Igfals 6.98 Insulin-like growth factor-binding protein complex acid labile subunit Col6a6 6.93 Collagen alpha-6(VI) chain Postn 6.94 Periostin Col5a2 6.60 Collagen alpha-2(V) chain Efemp2 9.88 EGF-containing fibulin-like extracellular matrix protein 2 Col6a4 6.39 Collagen alpha-4(VI) chain Colq 6.88 Acetylcholinesterase collagenic tail peptide Col11a1 6.31 Collagen alpha-1(XI) chain Hmnc1 6.86 Protein Hmcn1 Col14a1 6.16 Collagen alpha-1(XIV) chain Srpx2 6.85 Sushi repeat-containing protein SRPX2 Col10a1 6.07 Collagen alpha-1(X) chain Mmrn1 6.83 Multimerin-1 Col6a5 6.06 Collagen alpha-5(VI) chain Egflam 6.72 Pikachurin Col5a3 5.45 Collagen type V alpha 3 chain Bmper 6.72 BMP-binding endothelial regulator protein Col6a3 5.40 Protein Col 6a3 Lama1 6.71 Laminin subunit alpha-1 Col28a1 5.20 Collagen alpha-1(XXVIII) chain Emid1 6.56 EMI domain-containing protein 1 Col2a1 4.48 Collagen alpha-1(II) chain Lamc3 6.53 Laminin subunit gamma-3 Creld1 6.50 Cysteine-rich with EGF-like domain protein 1 Fras1 6.40 Extracellular matrix protein FRAS1 Spp1 6.38 Osteopontin c) ECM Proteoglycans Ctgf 6.30 Connective tissue growth factor Thsd4 6.18 Thrombospondin type-1 domain-containing protein 4 Gene iBAQ Protein name Cilp 6.10 Cartilage intermediate layer protein 1 name (log10) Emilin2 6.05 EMILIN-2 Fgl2 6.05 Fibroleukin Bgn 9.47 Biglycan Igsf10 6.02 Immunoglobulin superfamily member 10 Hspg2 9.41 Perlecan Kcp 5.98 Kielin/chordin-like protein Lum 9.29 Lumican Lama2 5.98 Laminin subunit alpha-2 Prelp 9.01 Prolargin Lgi3 5.90 Leucine-rich repeat LGI family member 3 Ogn 8.99 Mimecan Ltbp3 5.86 Latent-transforming growth factor beta-binding protein 3 Prg2 8.98 Bone marrow proteoglycan Ecm2 5.84 Extracellular matrix protein 2 Dcn 8.98 Decorin Crispld2 5.72 Cysteine-rich secretory protein LCCL domain-containing 2 Aspn 8.53 Asporin Ddx26b 5.70 Protein DDX26B Podn 7.51 Podocan Matn2 5.70 Matrilin-2 Prg3 7.51 Proteoglycan 3 Fgl1 5.61 Fibrinogen-like protein 1 Chad 7.10 Chondroadherin Fbn2 5.49 Fibrillin-2 Fmod 6.75 Fibromodulin Slit2 5.45 Slit homolog 2 protein Vcan 6.32 Versican Srpx 5.35 Sushi-repeat-containing protein SRPX Hapln1 6.25 Hyaluronan and proteoglycan link protein 1 Vwa3a 4.94 von Willebrand factor A domain-containing protein 3A Srgn 6.03 Serglycin Hmcn2 4.87 Hemicentin-2 Omd 5.89 Osteomodulin Thbs4 4.82 Thrombospondin-4 Acan 4.93 Aggrecan core protein Agm 4.63 Agrin Prg4 4.38 Proteoglycan 4 Cthrc1 4.57 Collagen tripe helix repeat-containing protein 1 FIGURE 1 Extracellular matrix (ECM) proteome of the adult healthy murine lung.
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    Supplemental Material Annexin A2-S100A10 Represents the Regulatory Component of Maxi-Cl Channel Dependent on Protein Tyrosine Dephosphorylation and Intracellular Ca2+ Md. Rafiqul Islama Toshiaki Okadaa Petr G. Merzlyaka,b Abduqodir H. Toychieva,c Yuhko Ando-Akatsukad Ravshan Z. Sabirova,b Yasunobu Okadaa,e aDivision of Cell Signaling, National Institute for Physiological Sciences (NIPS), Okazaki, Japan, bInstitute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent, Uzbekistan, cDepartment of Biological Sciences, State University of New York College of Optometry, New York, NY, USA, dDepartment of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan, eDepartment of Physiology, Kyoto Prefectural University of Medicine, Kyoto, Japan Supplementary Material Supplementary Fig. 1. Maxi-Cl currents in C127 cells were unaffected by siRNA- mediated silencing of three annexin family member genes, Anxa1, Anxa3 and Anxa11. Effects of knockdown mediated by Anxa1-specific siRNA (A), Anxa3-specific siRNA (B) and Anxa11-specific siRNA (C). Top panels: The effects on expression of ANXA mRNAs in C127 cells treated with non-targeting siRNA (cnt) or Anxa1/3/11-specific siRNA (si) detected by RT-PCR using Gapdh as a control. M: molecular size markers (100-bp ladder). These data represent triplicate experiments. Upper-middle panels: Representative time courses of Maxi-Cl current activation recorded at +25 mV after patch excision from C127 cells transfected with Anxa1/3/11-specific siRNA. Lower-middle panels: Voltage- dependent inactivation pattern of Maxi-Cl currents elicited by applying single voltage step pulses from 0 to 25 and 50 mV. Bottom panels: Summary of the effects of non-targeting siRNA (Control) and Anxa1/3/11-specific siRNA on the mean Maxi-Cl currents recorded at +25 mV.
  • The EMILIN/Multimerin Family

    The EMILIN/Multimerin Family

    View metadata, citation and similar papers at core.ac.uk brought to you by CORE REVIEW ARTICLE published: 06 Januaryprovided 2012 by Frontiers - Publisher Connector doi: 10.3389/fimmu.2011.00093 The EMILIN/multimerin family Alfonso Colombatti 1,2,3*, Paola Spessotto1, Roberto Doliana1, Maurizio Mongiat 1, Giorgio Maria Bressan4 and Gennaro Esposito2,3 1 Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico, Aviano, Italy 2 Department of Biomedical Science and Technology, University of Udine, Udine, Italy 3 Microgravity, Ageing, Training, Immobility Excellence Center, University of Udine, Udine, Italy 4 Department of Histology Microbiology and Medical Biotechnologies, University of Padova, Padova, Italy Edited by: Elastin microfibrillar interface proteins (EMILINs) and Multimerins (EMILIN1, EMILIN2, Uday Kishore, Brunel University, UK Multimerin1, and Multimerin2) constitute a four member family that in addition to the Reviewed by: shared C-terminus gC1q domain typical of the gC1q/TNF superfamily members contain a Uday Kishore, Brunel University, UK Kenneth Reid, Green Templeton N-terminus unique cysteine-rich EMI domain. These glycoproteins are homotrimeric and College University of Oxford, UK assemble into high molecular weight multimers. They are predominantly expressed in *Correspondence: the extracellular matrix and contribute to several cellular functions in part associated with Alfonso Colombatti, Division of the gC1q domain and in part not yet assigned nor linked to other specific regions of the Experimental Oncology 2, Centro di sequence. Among the latter is the control of arterial blood pressure, the inhibition of Bacil- Riferimento Oncologico, Istituto di Ricerca e Cura a Carattere Scientifico, lus anthracis cell cytotoxicity, the promotion of cell death, the proangiogenic function, and 33081 Aviano, Italy.
  • Supplementary Table 1: Adhesion Genes Data Set

    Supplementary Table 1: Adhesion Genes Data Set

    Supplementary Table 1: Adhesion genes data set PROBE Entrez Gene ID Celera Gene ID Gene_Symbol Gene_Name 160832 1 hCG201364.3 A1BG alpha-1-B glycoprotein 223658 1 hCG201364.3 A1BG alpha-1-B glycoprotein 212988 102 hCG40040.3 ADAM10 ADAM metallopeptidase domain 10 133411 4185 hCG28232.2 ADAM11 ADAM metallopeptidase domain 11 110695 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 195222 8038 hCG40937.4 ADAM12 ADAM metallopeptidase domain 12 (meltrin alpha) 165344 8751 hCG20021.3 ADAM15 ADAM metallopeptidase domain 15 (metargidin) 189065 6868 null ADAM17 ADAM metallopeptidase domain 17 (tumor necrosis factor, alpha, converting enzyme) 108119 8728 hCG15398.4 ADAM19 ADAM metallopeptidase domain 19 (meltrin beta) 117763 8748 hCG20675.3 ADAM20 ADAM metallopeptidase domain 20 126448 8747 hCG1785634.2 ADAM21 ADAM metallopeptidase domain 21 208981 8747 hCG1785634.2|hCG2042897 ADAM21 ADAM metallopeptidase domain 21 180903 53616 hCG17212.4 ADAM22 ADAM metallopeptidase domain 22 177272 8745 hCG1811623.1 ADAM23 ADAM metallopeptidase domain 23 102384 10863 hCG1818505.1 ADAM28 ADAM metallopeptidase domain 28 119968 11086 hCG1786734.2 ADAM29 ADAM metallopeptidase domain 29 205542 11085 hCG1997196.1 ADAM30 ADAM metallopeptidase domain 30 148417 80332 hCG39255.4 ADAM33 ADAM metallopeptidase domain 33 140492 8756 hCG1789002.2 ADAM7 ADAM metallopeptidase domain 7 122603 101 hCG1816947.1 ADAM8 ADAM metallopeptidase domain 8 183965 8754 hCG1996391 ADAM9 ADAM metallopeptidase domain 9 (meltrin gamma) 129974 27299 hCG15447.3 ADAMDEC1 ADAM-like,