CHAPTER 3 : TISSUE REPAIR:

REGENERATION, HEALING & FIBROSIS

Perbaikan (reparasi) jaringan:
1. REGENERASI : penggantian jaringan yg
kena jejas dgn sel jenis yg sama.
2. PENYEMBUHAN. Dapat mengganti
struktur asli, tetapi melibatkan
penimbunan kolagen & pembentukan
jaringan parut (scar)
3. FIBROSIS : Penggantian oleh jaringan
ikat.
jimmy - fk uwks 1
 Tissue response to injury. Repair after injury can occur by regeneration,
Figure 3-1

which restores normal tissue, or by healing, which leads to scar formation and
jimmy - fk uwks 2
fibrosis.
)
2005 Elsevier
 Kontrol proliferasi sel normal & pertumbuhan
jaringan

Pada jaringan dewasa, populasi sel

ditentukan oleh kecepatan prolifersi
sel, diferensiasi dan kematian sel oleh
apoptosis.

jimmy - fk uwks 3
 Mechanisms regulating cell populations. Cell numbers can be altered by
Figure 3-2

increased or decreased rates of stem cell input, by cell death due to apoptosis,
or by changes in the rates of proliferation or differentiation. (Modified from McCarthy NJ et al:
Apoptosis in the development of the immune system: growth factors, clonal selection and bcl-2. Cancer Metastasis Rev 11:157, 1992.)
jimmy - fk uwks 4
REGENERASI : Berdasar kemampuan sel untuk regenerasi,
sel tubuh dibagi dlm 3 kelompok sel :
Sel labil; Sel stabil & Sel permanen

Sel labil : berproliferasi terus menerus &

mengganti sel yg lepas atau mati. : sel epitel
permukaan tubuh: epidermis, epitel pelapis rongga
mulut, saluran pernapasan & pencernaan, dll.
Sel stabil : mampu regenerasi, tapi dlm
keadaan normal tidak bertambah banyak secara
aktif. Contoh: sel hati, pankreas, kel. Liur, endokrin,
tubuli ginjal, kelenjar adnexa kulit dll.
Sel permanen : Sel neuron & sel otot jantung.

jimmy - fk uwks 5
Cell-cycle landmarks. The figure shows the cell-cycle phases (G0,
G1,G2, S, and M), the location of the G1 restriction point, and the G1/S and
G2/M cell-cycle checkpoints. Cells from labile tissues such as the epidermis
and the gastrointestinal tract may cycle continuously; stable cells such as
hepatocytes are quiescent but can enter the cell cycle; permanent cells such
as neurons and cardiac myocytes havejimmy
lost- fkthe
uwks capacity to proliferate. (Modified from 6
Pollard TD and Earnshaw WC: Cell Biology. Philadelphia, Saunders, 2002.)
 Stem cells : mempunyai kemampuan penyembuhan
diri secara terus menerus & ber- replikasi secara
asimetrik.
Stem sells:
Embryonic stem cells
Adult stem cells.

Stem cells terdapat di lokasi yg disebut:

niches, yg letaknya berbeda pada
berbagai jaringan.

jimmy - fk uwks 7
 Stem-cell niches in various tissues. A, Epidermal stem cells
Figure 3-5

located in the bulge area of the hair follicle serve as a stem cells
for the hair follicle and the epidermis.

jimmy - fk uwks 8

2005 Elsevier
Figure 3-5 Stem-cell niches in various tissues.. B,
Intestinal stem cells are located at the
base of a colon crypt, above Paneth cells.
jimmy - fk uwks 9

2005 Elsevier
 C, Liver stem cells (commonly known as oval cells) are located in
Figure 3-5

the canals of Hering (thick arrow), structures that connect bile

ductules (thin arrow) with parenchymal hepatocytes (bile duct and
Hering canals are stained for cytokeratin 7;
jimmy - fk uwks 10

2005 Elsevier
, Figure D, Corneal stem cells are located in the limbus region, between
3-5

the conjunctiva and the cornea. (Courtesy of T-T Sun, New York
University, New York, NY.)
jimmy - fk uwks 11
Figure 3-6 Differentiation
pathways for pluripotent
bone marrow stromal cells.
Activation of key regulatory
proteins by growth factors,
cytokines, or matrix
components leads to
commitment of stem cells to
differentiate into specific
cellular lineages.
Differentiation of myotubes
requires the combined
action of several factors
(e.g., myoD, myogenin); fat
cells require PPARγ,
the osteogenic lineage
requires CBFA1 (also
known as RUNX2), cartilage
formation requires Sox9,
and endothelial cells require
VEGF and FGF-2. (Adapted and jimmy - fk uwks 12
redrawn from Rodan GA, Harada S: The missing
bone. Cell 89:677, 1997.) 2005 Elsevier
 Liver regeneration after partial hepatectomy. Upper panel, The lobes of
Figure 3-11

the liver of a rat are shown (M, median; RL and LL, right and left lateral lobes;
C, caudate lobe). Partial hepatectomy removes two thirds of the liver (median
and left lateral lobes), and only the right lateral and caudate lobes remain. After
3 weeks, the right lateral and caudate lobes enlarge to reach a mass equivalent
to that of the original liver. Note that there is no regrowth of the median and left
lateral lobes removed after partial hepatectomy.
jimmy - fk uwks 13

2005 Elsevier
Reparasi dgn Penyembuhan, Pembentukan
jaringan parut/scar & fibrosis
Proses reparasi & penyembuhan jaringan
mempunyai gambaran umum sbb.:
1. Tujuan dari reparasi adalah
penyembuhan seperti jaringan asal.
Terjadi reaksi radang eliminasi stimuli
yg merugikan membuang jaringan yg
rusak pembentukan extracellular matrix
& kolagen.

jimmy - fk uwks 14
Proses reparasi & penyembuhan jaringan mempunyai gambaran umum sbb.:
===========================================================

2. Bbrp jaringan sembuh total. Bila

regenerasi tidak terjadi deposisi
jaringan ikat, scar
3. Bila kerusakan berlangsung terus
timbul radang khronik fibrosis.
Reparasi mulai sejak awal radang, kadang
24 jam stlh jejas. Bila resolusi tidak terjadi
JARINGAN GRANULASI.
dgn gambaran: proliferasi pemb.darah kecil
(angiogenesis) & proliferasi fibroblast.
jimmy - fk uwks 15
 Granulation tissue showing numerous blood vessels,
Figure 3-17 A,

edema, and a loose ECM containing occasional inflammatory

cells. This is a trichrome stain that stains collagen blue; minimal mature
collagen can be seen at this point. B, Trichrome stain of mature scar, showing
dense collagen, with only scattered vascular channels.

jimmy - fk uwks 16

2005 Elsevier
 Angiogenesis by mobilization of endothelial precursor cells (EPCs) from
Figure 3-18

the bone marrow and from pre-existing vessels (capillary growth). EPCs are
mobilized from the bone marrow and may migrate to a site of injury or tumor
growth (upper panel). The homing mechanisms have not yet been defined. At
these sites, EPCs differentiate and form a mature network by linking with
existing vessels. In angiogenesis from pre-existing vessels, endothelial cells from these vessels become motile and proliferate
to form capillary sprouts (lower panel). Regardless of the initiating mechanism, vessel maturation (stabilization) involves the recruitment of
pericytes and smooth muscle cells to form the periendothelial layer. (Modified from Conway EM, Collen D, Carmeliet P: Molecular
mechanisms of blood vessel growth. Cardiovasc Res 49:507, 2001.)
jimmy - fk uwks 17

2005 Elsevier
Angiogenesis by mobilization of endothelial precursor cells (EPCs) from
the bone marrow and from pre-existing vessels (capillary growth). EPCs are mobilized from the bone marrow and may migrate to a site of
injury or tumor growth (upper panel). The homing mechanisms have not yet been defined. At these sites, EPCs differentiate and form a
. In angiogenesis from pre-existing vessels,
mature network by linking with existing vessels

endothelial cells from these vessels become motile and proliferate to

form capillary sprouts (lower panel). Regardless of the initiating
mechanism, vessel maturation (stabilization) involves the recruitment of
pericytes and smooth muscle cells to form the periendothelial layer. (Modified from
Conway EM, Collen D, Carmeliet P: Molecular mechanisms of blood vessel growth. Cardiovasc Res 49:507, 2001.)

jimmy - fk uwks 18

2005 Elsevier
PENYEMBUHAN
LUKA
Phases of
wound healing:
ada 3 fase :
1. Inflamasi;
2. Pembentukan
jaringan
granulasi;
3. Kontraksi
luka.

jimmy - fk uwks 19

2005 Elsevier
 Penyembuhan luka:
Penyembuhan primer (primary union or healing by first
intention)
0 jam Luka terisi bekuan darah
3-24 jam Neutrofil dari tepi luka menginfiltrasi
bekuan darah. Mitosis tampak pd sel basal
epitel.
Hari ke 3: Neutrofil diganti makrofag. Tampak
jaringan granulasi.
Hari ke 5: Rongga luka terisi jar. Granulasi,
neovaskularisasi maksimal. Mulai tampak
serabut kolagen & proliferasi sel epitel maksimal
Minggu II - IV: Proliferasi fibroblast & akumulasi
kolagen, mulai terjadi fibrosis/scar.
Bulan 2: Fibrosis tanpa radang.

jimmy - fk uwks 20
 Penyembuhan luka:
Penyembuhan sekunder (healing by second intention)

Bila terjadi sangat banyak kerusakan &

kehilangan sel/jaringan, mis. luka pada
kulit/permukaan proses reparasi menjadi
kompleks. regenerasi tidak sempurna jar
granulasi sangat banyak disebut
penyembuhan sekunder.
Beda penyembuhan sekunder vs peny primer:
Reaksi radang lebih hebat
Jar. Granulasi terbentuk sangat lebih luas
Kontraksi luka (woud contraction)
Timbul jaringan parut (scar) & epidermis menipis.

jimmy - fk uwks 21
 Steps in wound healing by first intention (left) and second intention
Figure 3-21

(right). Note large amounts of granulation tissue and wound contraction in

healing by second intention.
jimmy - fk uwks 22

2005 Elsevier
 Healing of skin ulcers. A, Pressure ulcer of the
Figure 3-22

skin, commonly found in diabetic patients. The histology slides show B, a

skin ulcer with a large gap between the edges of the lesion; C, a thin layer of epidermal reepithelialization and extensive granulation tissue formation in the dermis; and
D, continuing reepithelialization of the epidermis and wound contraction. (Courtesy of Z. Argenyi, M.D., University of Washington.)

jimmy - fk uwks 23

2005 Elsevier
 Healing of skin ulcers. A, Pressure ulcer of the skin, commonly
Figure 3-22

found in diabetic patients. The histology slides show B, a skin

ulcer with a large gap between the edges of the lesion; C, a thin
layer of epidermal reepithelialization and extensive granulation
tissue formation in the dermis;jimmy
and D, continuing reepithelialization
- fk uwks 24

of the epidermis and wound contraction. (Courtesy of Z. Argenyi, M.D., University of

2005 Elsevier
 Healing of skin ulcers. A, Pressure ulcer of the skin, commonly
Figure 3-22

found in diabetic patients. The histology slides show B, a skin ulcer

with a large gap between the edges of the lesion; C, a thin layer of
epidermal reepithelialization and extensive granulation tissue
jimmy - fk uwks 25
formation in the dermis; and D, continuing reepithelialization of the
epidermis and wound contraction. 2005 Elsevier
Figure 3-22 Healing of skin ulcers. A, Pressure ulcer of the skin,
commonly found in diabetic patients. The histology slides show B, a skin
ulcer with a large gap between the edges of the lesion; C, a thin layer of
epidermal reepithelialization and extensive granulation tissue formation in
the dermis; and D, continuing reepithelialization of the epidermis and
jimmy - fk uwks 26
wound contraction.
2005 Elsevier
 Keloid. Excess collagen deposition in the skin forming a
Figure 3-23 A,

raised scar known as keloid. B, Note the thick connective tissue deposition in the dermis.
(Slide courtesy of Z. Argenyi, M.D., University of Washington, Seattle, WA.)

jimmy - fk uwks 27

2005 Elsevier
 , Keloid. B, Note the thick connective tissue deposition in
Figure 3-23 A

the dermis. (Slide courtesy of Z. Argenyi, M.D., University of Washington,

Seattle, WA.)
jimmy - fk uwks 28

2005 Elsevier
 Development of fibrosis in chronic inflammation. The persistent stimulus
Figure 3-24

of chronic inflammation activates macrophages and lymphocytes, leading to

the production of growth factors and cytokines, which increase the synthesis
of collagen. Deposition of collagen is enhanced by decreased activity of
metalloproteinases. jimmy - fk uwks 29

2005 Elsevier
Figure 3-25 Repair responses after injury and inflammation. Repair after
acute injury has several outcomes, including normal tissue restitution and
healing with scar formation. Healingjimmy
in chronic
- fk uwks injury involves scar formation 30

and fibrosis (see text). 2005 Elsevier

terimakasih

jimmy - fk uwks 31