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Basic Composition and Alterations in Chronic Lung Disease

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Basic Composition and Alterations in Chronic Lung Disease 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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