Connective Tissue Formation in Wound Healing - E-thesis

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post-transcriptional level. The most prominent cell types to express MMP-9 mRNA were macrophage-like cells. Connective tissue growth factor (CTGF) is downstream mediator of transforming growth factor-β (TGF-β) in fibroblasts. For the elucidation of its role in normal wound healing, its gene expression and protein localization, together with other fibrogenic growth factors, TGF- β1, and platelet-derived growth factors (PDGF), were studied. All these growth factors were found to be expressed throughout the wound healing process but CTGF had a more restricted expression pattern. CTGF mRNA had maximum expression at two weeks and the expressing cells were mostly fibroblasts, but in the early phase of wound healing also the blood vessel cells expressed CTGF at the gene and protein levels, suggesting that it is involved in angiogenesis. In conclusion, successful wound healing is accompanied by tightly scheduled expression of fibrillar collagens, matrix metalloproteinases and growth factors. The close association of type V collagen and CTGF in blood vessels during wound healing suggests their role in angiogenesis. MMP-2 is important during the prolonged remodeling phase, whereas the MMP- 9 gene is up-regulated when the granulation tissue matures. MMP-2 and MMP-9 might facilitate an essential event of wound healing, such as cell migration, angiogenesis and tissue remodeling. 8
INTRODUCTION The regulation of extracellular matrix (ECM) deposition is a key event in many physiological and pathological conditions. It is required for normal wound healing where ECM molecules need to be rapidly synthesized during the formation of early granulation tissue and also during the final replacement by mature connective tissue and tissue remodeling. A tight balance between connective tissue synthesis and breakdown is therefore required for the normal functioning of all tissues. The formation of new and regenerating tissue requires the coordinate regulation of various genes, which encode for both structural and regulatory molecules that participate in cell growth and tissue organization. Collagens are the major macromolecules of connective tissues and the most abundant proteins in the human body. Besides their structural role in numerous tissue and organs, collagens have a number of other important biological functions, such as cell attachment, chemotaxis and platelet aggregation. Fibril-forming collagens in soft tissues are type I, III and V. Type I collagen is the major collagen in most tissues. Type III collagen occurs in tissues exhibiting elastic properties, such as skin and blood vessels. Type V collagen is a quantitatively minor fibrillar collagen with a broad tissue distribution. Degradation of ECM proteins is essential in tissue repair where cell migration is an important event. The matrix metalloproteinase (MMP) family is a group of proteases with different ECM substrate specificities. Of these, MMP-2 and MMP-9 form the gelatinase sub-family. These enzymes have the capacity to degrade types IV and V collagen and the degradation products of collagens and elastin. Metalloproteinases are secreted as pro-enzymes, which undergo extracellular activation. The extracellular activity of these enzymes is modulated also by interaction with the specific tissue inhibitors of metalloproteinases (TIMP), and microenvironmental factors. Growth factors are essential for regulating the molecular and cellular events involved in the formation of granulation tissue and in wound healing. Growth factors affect the different phases in wound healing differently. Various growth factors induce their own synthesis in positive autocrine feedback loops, as well as of other growth factors. Thus, a plethora of factors is likely to be present at the site of the wound, which assures efficient enhancement of the different phases of wound healing. The most important granulation modulating growth factors known so far are platelet-derived growth factors (PDGF’s), transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF). 9
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: ABSTRACT A tight balance between co
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 and 42: inflammatory cells (283). MMP-9 may
Page 43 and 44: TG F-β ligand Receptor II Receptor
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
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89. Lohi J, Lehti K, Valtanen H, Pa
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124. Wiestner M, Krieg T, Horlein D
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159. Gay S, Vijanto J, Raekallio J,
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196. Saelman EU, Nieuwenhuis HK, He
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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
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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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Connective Tissue Formation in Wound Healing - E-thesis

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