Connective Tissue Formation in Wound Healing - E-thesis

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especially monocytes and fibroblasts (6). In addition to the three mammalian TGF-β isomers (TGF-β1, -β2 and -β3), the TGF-β superfamily comprises the activins, and bone morphogenetic proteins, as well as many other factors that are all thought to play major roles in differentiation and tissue morphogenesis (293). Table V Growth factor signals at the wound site. Modified from (Martin, 1997) Growth factor Source Primary target cells and effect Refs. EGF Platelets Keratinocyte motogen and mitogen (3) TGF-α Macrophages; keratinocytes Keratinocyte motogen and mitogen (3, 8) HB-EGF Macrophages Keratinocyte and fibroblast mitogen (15) FGFs 1, 2, and 4 Macrophages and damaged endothelial cells Angiogenic and fibroblast mitogen (4) FGF7 (KGF) Dermal fibroblasts Keratinocyte motogen and mitogen (4, 294) PDGF Platelets; Chemotactic for macrophages, (5) macrophages; fibroblasts; macrophage activation, keratinocytes fibroblast mitogen, and matrix production IGF-1 Plasma; platelets Endothelial cell and fibroblast mitogen (8, 295) VEGF Keratinocytes; macrophages Angiogenesis (19) TGF-β1 and -β2 Platelets; macrophages Keratinocyte migration; chemotactic for macrophages and fibroblasts; fibroblast matrix synthesis and remodeling (6) TGF-β3 Macrophages Antiscarring (6) CTGF Fibroblasts; endothelia Fibroblasts; downstream of TGF-1 (287) Activin Fibroblasts; keratinocytes Currently unknown (296) IL-1αand -β Neutrophils Early activators of growth factor expression in macrophages, keratinocytes, and fibroblasts (13) TNF-α Neutrophils Similar to the IL-1s (13) HGF Fibroblasts Epidermal cell proliferation and migration (16) 42
TG F-β ligand Receptor II Receptor I Smad activation Smad dim erization New transcription Proteinase sensitve “hinge” A B C TGF-β latency associated protein (LAP) ECM Latent TGF-β binding protein (LTBP) N Figure 9. The Smad pathway activated by TGF-β superfamily ligands. (A) An activation complex is formed by the binding of the ligand by the type I and type II receptors. This allows the type II receptor to phosphorylate the type I receptor on particular serine or threonine residues. (B) Those receptors that bind TGF-β family proteins or members of the activin family phosphorylate Smads 2 and 3. These Smads can complex with Smad 4 to form active transcription factors. A simplified version of the pathway is shown at the left. Modified from (Zhu et al., 2001). (C) The structure of the large latent TGF-β complex. Modified from (Saharinen et al., 1996) (297). 43 C N A ctive T G F-β EGF-like repeat 8-Cys repeat C
Page 1 and 2: Connective Tissue Formation in Woun
Page 3 and 4: CONTENTS ORIGINAL PUBLICATIONS 5 AB
Page 5 and 6: ORIGINAL PUBLICATIONS This thesis i
Page 7 and 8: ABSTRACT A tight balance between co
Page 9 and 10: INTRODUCTION The regulation of extr
Page 11 and 12: REVIEW OF THE LITERATURE WOUND HEAL
Page 13 and 14: days, and neutrophils are themselve
Page 15 and 16: Formation of Granulation Tissue New
Page 17 and 18: emodeled by contraction of the woun
Page 19 and 20: Table I Collagen types, their genes
Page 21 and 22: Structure and biosynthesis of colla
Page 23 and 24: A B COL1A1 COL3A1 COL5A1 C COL1A1 C
Page 25 and 26: TATA box GC box (Sp1/Sp3 binding el
Page 27 and 28: y sequences in their 3’ untransla
Page 29 and 30: espectively (160). Liver has as muc
Page 31 and 32: in the matrix as compared to type I
Page 33 and 34: is the need to generate mechanical
Page 35 and 36: and the catalytic domain, which con
Page 37 and 38: specific binding and cleavage of th
Page 39 and 40: constitutively expressed and contro
Page 41: inflammatory cells (283). MMP-9 may
Page 45 and 46: and the core proteins of the ECM pr
Page 47 and 48: hydrophobic stretch of the C-termin
Page 49 and 50: similarities to insulin-like growth
Page 51 and 52: CTGF and TGF-β distinguishes them
Page 53 and 54: OUTLINE OF THE PRESENT STUDIES The
Page 55 and 56: were determined: reduced hemoglobin
Page 57 and 58: (Minneapolis, MN, USA). Anti-PDGF A
Page 59 and 60: solution, 10% dextran sulphate and
Page 61 and 62: sequencer, Model 373A (Applied Bios
Page 63 and 64: histology. The hemoglobin content o
Page 65 and 66: especially at the later stages. The
Page 67 and 68: owing to the high standard deviatio
Page 69 and 70: A Staining index A 50 45 40 35 30 2
Page 71 and 72: the proliferative phase of wound re
Page 73 and 74: type V collagen expression is assoc
Page 75 and 76: healing model presented here lacks
Page 77 and 78: PDGF-A and -B protein was observed
Page 79 and 80: CTGF functions as a downstream medi
Page 81 and 82: I am also grateful for all my frien
Page 83 and 84: 19. Brown LF, Yeo KT, Berse B, et a
Page 85 and 86: 56. Phillips C, Wenstrup RJ. Biosyn
Page 87 and 88: 89. Lohi J, Lehti K, Valtanen H, Pa
Page 89 and 90: 124. Wiestner M, Krieg T, Horlein D
Page 91 and 92: 159. Gay S, Vijanto J, Raekallio J,
Page 93 and 94:
196. Saelman EU, Nieuwenhuis HK, He
Page 95 and 96:
237. Knäuper V, Cowell S, Smith B,
Page 97 and 98:
273. Rajavashisth TB, Liao JK, Gali
Page 99 and 100:
307. Geng Y, Weinberg RA. Transform
Page 101 and 102:
346. Heldin CH, Östman A, Rönnstr
Page 103 and 104:
382. Frazier KS, Grotendorst GR. Ex
Page 105 and 106:
416. Glumoff V, Mäkelä JK, Vuorio
Page 107:
454. Pierce GF, Tarpley JE, Tseng J
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