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Pathology 1.2b Dr. Teresita P.

Inflammation and Repair June 13&17, 2013

OUTLINE - Regurgitation  incomplete fusion of the membrane of
the lysosome and the membrane of the phagosome
I. Definition of terms
which causes lysosomal enzymes to escape
II. Control of Normal Cell Proliferation and Tissue Growth
III. Tissue Proliferation Activity - After destruction of microbes by the lysosomal enzymes,
A. Labile this is now followed by repair.
B. Stable
IV. Stem Cells o Regeneration
A. Embryonic Stem Cells  Growth of cells and tissues to replace lost structures, such
B. Adult Stem Cells  as the growth of an amputated limb of amphibians
C. Induced Pluripotent stem Cells o Healing
D. Transit Amplifying Cells  Usually a tissue response:
E. Developmental Plasticity - To a wound (commonly in the skin)
F. Stem Cells in Bone Marrow - To cell necrosis in organs incapable of regeneration
V. Cell Cycle and Regulation of cell replication - To inflammatory processes in internal organs
VI. Factors of Cell Proliferation o Two Processes of Healing
A. Platelet-derived Growth Factor  Regeneration
B. Epidermal Growth Factor - proliferation of surviving cells to replace lost tissue
C. Fibroblast Growth Factor - migration of surviving cells into vacant space
D. Hepatocyte Growth Factor - leaving no residual tissue of previous injury
E. Transforming Growth Factor  Repair
F. Macrophage-derived Growth Factors - Replacement by CT
VII. Signalling mechanism in Cell Growth - Also called Scar Formation (Fibrosis/Fibroplasia)
A. Autocrine - Scar formation is the predominant healing process that
B. Paracrine occurs when the extracellular matrix (ECM)framework is
C. Endocrine damaged by severe injury
VIII. Receptors and Signal Transduction Pathway - Restore some original structures but can cause structural
IX. Transcription factors Derangements
X. Extracellular Matrix and Cell-matrix Interaction - Most often consists of a combination of regeneration and
A. Function scar formation by the deposition of collagen
B. Composition - Although repair is a healing process, it may itself dysfunction,
C. 2 Basic Forms as, for instance, in the development of atherosclerosis
XI. Collagen
XIII. Cell Adhesion Molecules and its 4 Classifications o In adult tissues, the size of the cell is determined by:
XIV. Glycosaminoglycans (GAGS) and its 4 Families A. Rate of stem cell input
XV. Healing by Repair, Scar Formation and Fibrosis B. Rate of cell proliferation - eg. Estrogen during menstrual cycle
XVI. Three Phases of Cutaneous Wound Healing C. Rate of cell differentiation
XVII. Types of Healing D. Death by apoptosis
XIII. Sequence of Events in Wound Healing o Restoration of normal architecture, there should be:
XIX. Factors That Influence Wound Healing
OBJECTIVES  intact ECM framework
XX. Complications of Wound Healing
 Regenerative capacity of surviving affected parenchymal cells
1. Recognize and list the signs and symptoms 
2. Define terms used in healing and repair III. TISSUE PROLIFERATION ACTIVITY
2.1 Regeneration o Tissues of the body are divided in 3 groups on the basis of their
2.2 Granulation tissue proliferative activity of their cells: Labile, Stable and Permanent
2.3 Angiogenesis
2.4 Healing by first intention (give examples) A. CONTINUOUSLY DIVIDING (LABILE TISSUES)
2.5 Healing by second intention (give examples) o Cells that proliferate throughout life, replacing those that are
2.6 Organization destroyed
3. State the different types of cells according to their regenerative o They regenerate following injury if stem cells are not destroyed
capacity and give examples of each o Examples:
4. Describe the gross and microscopic tissue changes resulting from - Stratified squamous epithelia of skin, oral cavity, vagina, cervix
reparative processes: - Lining mucosa of all excretory ducts of the glands of the body
4.1 Regeneration - Columnar epithelium of the GI tract and uterus
4.2 Replacement by connective tissue - Transitional epithelium of urinary tract
5. Describe the sequence of events in the inflammatory reparative - Cells of bone marrow and hematopoietic tissues
process and the mechanism underlying these events - In most of these tissues mature cells are derived from adult stem
6. Enumerate the growth factors and the functions of each cells
7. Enumerate the factors that modify the quality of the
inflammatory-reparative response *ALWAYS DIVIDING*
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o Normally have a low level of replication; however, cells from these
tissues can undergo rapid division in response to stimuli when
needed(e.g. Injury)
o Capable of reconstituting the original tissue
o Considered to be in G0 stage but under a stimulus can enter G1
o Examples:
- Parenchymal cells of liver (hepatocytes), kidneys (renal tubular
cells), pancreatic glands
- Mesenchymal cells (fibroblasts, smooth muscle, cartilage,
osteoblasts, CT, endothelium)
- Lymphocytes and other leukocytes



o Contain cells that have left the cell cycle and can no longer undergo
mitotic division in postnatal life
o When damaged, replaced by scar tissue
o Examples:
- Majority of Neurons –Replaced by glial cells (Typically fibrosis;
Gliosis in the CNS)
- Skeletal muscles –Have some regenerative capacity through
differentiation of satellite cells which are attached to the
endomysial sheaths
- Cardiac muscle has very limited, if any, regenerative capacity, and an
injury to the heart muscle would be followed by scar formation Figure 1. Generation of embryonic stem cells and induced pluripotent stem cells.
IV. STEM CELLS o Differentiated cells of adult tissues can be reprogrammed to become
o Characterized by : pluripotent by transferring their nucleus to an anucleated oocyte.
 prolonged self-renewal capacity o Research has now demonstrated that differentiated cells of humans
 Their capacity to generate differentiated cell lineages. can be reprogrammed into pluripotent cells, similar to ES (embryonic
o Transdifferentiation stem) cells, by the transduction of genes encoding ES cell transcription
 Indicative of change in the lineage commitment or differentiation factors
of a stem cell from one type to another o An example of which is the reproductive cloning of Dolly the sheep
o Developmental Plasticity – cell’s capacity to transdifferentiate
o Core of regenerative medicine TRANSIT AMPLIFYING CELLS
o 2 Types: Embryonic and Adult o rapidly dividing cells generated by SS cells
o Lose capacity of self-perpetuationprogenitor cells (cells with
EMBRYONIC STEM CELLS restricted developmental potential).
o Embryos contain pluripotent ES cells, which can give rise to all the
tissues of the human body. STEM CELLS IN BONE MARROW
o isolated from normal blastocysts ○ Hematopoietic stem cells (HSCs)
o pluripotency related to expression of unique transcription factors (e.g.  generate all blood cells & reconstitute bone marrow depleted by
Nanog) disease or irradiation (e.g. multiple myeloma, leukemia)
o Used in therapeutic cloning (e.g. repopulate damaged organs)  can differentiate into other cell types such as hepatocytes, myocytes
o give rise to multipotent cell and neurons
 produce approximately 1,500,000 blood cells/second
ADULT (SOMATIC) STEM CELLS o Marrow / multipotent / mesenchymal stromal cells (MSC)
o more restricted differentiation capacity;  Multipotent
o lineage- specific  generate chondrocytes, osteoblasts, adipocytes, myoblasts,
o usually present in labile tissues endothelial cell precursors depending on the tissue to which they
o tissue stem cell= stem cells outside of the bone marrow migrate
o Reside in special microenvironments called niches  do not seem to participate in normal tissue homeostasis
 Niches - location/sites of stem cells niche cells generate or o Multipotent adult progenitor cells (MAPCs)
transmit stimuli that regulate SC self-renewal and generation of  Differentiate into mesodermal, endodermal & neuroectodermal cell
progeny cells types
 Present in tissues that continuously divide (bone marrow, skin, GI  found in skin, muscle and brain
 Present also in liver, pancreas, and adipose tissue, in which, under
normal conditions they do not actively produce differentiated cell
o Lining of gut, cornea, and hematopoietic tissue

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V. CELL CYCLE & REGULATION OF CELL REPLICATION o Exert their effects by binding to 2 cell surface receptors (PDGFR alpha
o Cell replication is stimulated by GFs or by signalling from ECM and beta)
components through integrins. o Stored in platelet granules and is released on platelet activation
o Because of its central role in maintaining tissue homeostasis and o Produced by activated macrophages, endothelial cells, smooth muscle
regulating physiologic growth processes, the cell cycle has multiple cells, and many tumor cells
controls and redundancies, particularly during the transition between o Causes migration and proliferation of fibroblasts, smooth muscle cells,
G1 and S phases and monocytes to sites of inflammation and healing skin wounds

Not mentioned by the lecturer, but in the book: EPIDERMAL GROWTH FACTOR (EGF)
o Each cycle is dependent on the activation and completion of the o Together with TGF alpha, they belong to EGF family with EGFR as
previous one common receptor.
o Progression of cell cycle is tightly regulated by proteins called o promotes the growth of fibroblasts, epithelial cells, hepatocytes
cylcins and associated enzymes called cyclin-dependent kinases o EGF receptor (family of 4 membrane receptors with intrinsic tyrosine
(CDK) kinase activity)
o Activated CKs drive the cell cycle by phosphorylating proteins o EGF receptors:
that are critical for cell cycle transition  EGFR1 (ERB B1 or EGFR)
o Activity of cyclin-CDK complexes is tightly regulated by CDK ○ its mutation and amplification is detected in cancers of lung,
inhibitors head & neck, breasts, glioblastoma
 ERB B2 receptor (HER-2 or HER2/Neu)
o G1/S transition is the restriction point ○ overexpressed in breast Ca treatment target
o Checkpoints ensure that cells with damaged DNA or chromosomes do o also called progression factor
not complete replication
 Monitors DNA integrity before replication o Wound repair- FGF-2 (basic), FGF-7 (KGF)
 G2/M checkpoint o Angiogenesis- FGF-2
 Checks DNA after replication and monitors whether the cell o Hematopoiesis- blood cell diff. & dev. of bone marrow stroma
can safely enter mitosis, detects whether DNA is damaged o Development- skeletal and cardiac muscle, lung maturation,
specification of liver from endodermal cells
 G0 –Physiologic state HEPATOCYTE GROWTH FACTOR (HGF)
 G1 –Presynthetic stage when DNA integrity monitoring before o Mitogenic to hepatocytes and most epithelial cells (biliary epithelium,
replication occurs lungs, kidney, mammary gland, and skin)
 S –DNA synthesis o Acts as a morphogen in embryonic development
 G2 –Premitotic stage o Promotes cell scattering and migration
 M –Mitotic stage o Enhances survival of hepatocytes
o Produced by fibroblasts and most mesenchymal cells, endothelial cells,
and liver parenchymal cells
o Produced as an inactive single-chain form (pro-HGF) that is activated by
serine proteases released in damaged tissues
o C-Met (HGF receptor) is often highly expressed in human tumors,
especially in renal and thyroid papillary carcinomas
o Isolated from platelets and serum
o HGF signaling is necessary during embryonic development

 Fibronectin - glycoprotein with the following characteristics:

(a) Chemotactic for fibroblasts and endothelial cells
(b) Promotes angiogenesis
(c) Links other extracellular matrix components (e.g.,collagen,
proteoglycans) and macromolecules (e.g., fibrin, heparin) to cell-
surface receptors called integrins. Integrins mediate interactions
between cells and extracellular matrix.
Figure 2. Cell cycle landmarks. The figure shows the cell cycle phases (G 0 , G 1 G 2 , S,
and M), the location of the G 1 restriction point, and the G 1 /S and G 2 /M cell cycle TRANSFORMING GROWTH FACTORS (TGFS)
checkpoints. Cells from labile tissues such as the epidermis and the GI tract may cycle o Share a common receptor with EGF, EGF receptor (EGFR)
continuously; stable cells such as hepatocytes are quiescent but can enter the cell o TGF-:
cycle; permanent cells such as neurons and cardiac myocytes have lost the capacity to  functions similar to EGF;
proliferate.  involved in epithelial cell proliferation in embryos and adults, and
in malignant transformation of normal cells to cancer
o mediated by an assemblage of growth factors  Produced by platelets, endothelial cells, lymphocytes and
 Growth inhibitor of most epithelial cells
o synthesized by platelets and other cells
 Can promote invasion and metastasis of cancer growth

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 Potent fibrogenic agent- stimulates fibroblast chemotaxis;

enhance production of collagen, fibronectin, proteoglycans;
inhibits collagen degradation
 strong anti-inflammatory effect- enhance some immune functions;
enhances development of interleukin-17 producing T cells that
may be involved in autoimmune injury
 practically always involved as an important fibrogenic agent


o Mediators of inflammation and immune response
o promote proliferation of fibroblasts, smooth muscle cells, & endothelial
o IL-1 & TNF for wound healing
o IL-6 & TNF in initiation of liver regeneration

*Study Table in appendix: Growth Factors and Cytokines Involved in

Regeneration and Wound Healing*


o receptor-mediated signal transduction is activated by binding of ligands
(e.g. growth factors and cytokines) to specific receptors
o 3 modes of signaling

o Cells respond to the signalling molecules that they themselves secrete,
thus establishing an autocrine loop
o Plays a role in liver regeneration and the proliferation of antigen- Figure 3. General patterns of intercellular signaling demonstrating autocrine,
stimulated lymphocytes paracrine, and endocrine signaling.
o Tumors frequently overproduce growth factors and their receptors,
thus stimulating their own proliferation through an autocrine loop VIII. RECEPTORS AND SIGNAL TRANSDUCTION PATHWAYS
o Receptors with intrinsic tyrosine kinase activity
PARACRINE o Receptors lacking intrinsic tyrosine kinase activity that recruit kinases
o One cell type produces the ligand, which then acts on adjacent target o G protein-coupled receptors
cells that express the appropriate receptor o Steroid hormone receptors
o Common in connective tissue repair of healing wounds, in which a
factor produced by one cell type (e.g. macrophage) has a growth effect
on adjacent cells (e.g. fibroblast)
o Necessary for hepatocyte replication during liver regeneration and for
Notch effects in embryonic development, wound healing, and renewing

o hormones synthesized by cells of endocrine organs act on target cells
distant from their site of synthesis, being usually carried by the blood
o growth factors may also circulate and act at distant sites, as is the case
for HGF
o several cytokines, such as those associated with the systemic aspects of
inflammation also act as an endocrine agents

Figure 4. Signal Transduction System: Shown are receptors with intrinsic tyrosine
kinase activity, seven transmembrane G-protein-coupled receptors, and receptors
without intrinsic tyrosine kinase activity. The figure also shows important signaling
pathways transduced by the activation of these receptors through ligand binding

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o Most signal transduction systems used by growth factors transfer
information to nucleus and modulate gene transcription through the
activity of TFs: GFs induce synthesis or activity of TFs.
o TFs that regulate cell proliferation are products of:
 growth-promoting genes ( c-MYC, c-JUN)
 cell cycle-inhibiting genes (p53)


o Tissue repair and regeneration depend on activity of soluble factors

and interactions between cells and the components of ECM
o ECM regulates growth, proliferation, movement and differentiation of
cells living within it; constantly remodeling

o Mechanical support
 For cell anchorage, cell migration, maintenance of cell polarity Figure 5. Main components of the extracellular matrix (ECM), including collagens,
proteoglycans, and adhesive glycoproteins. Both epithelial and mesenchymal cells
o Control of cell growth
(e.g., fibroblasts) interact with ECM via integrins. Basement membranes and
 Regulate cell proliferation by signaling through cellular receptors interstitial ECM have different architecture and general composition, although there
on the integrin family is some overlap in their constituents. For the sake of simplification, many ECM
o Maintenance of cell differentiation components (e.g., elastin, fibrillin, hyaluronan, and syndecan) are not included.
 Type of ECM proteins can affect the degree of differentiation
of the cells in the tissue XI. COLLAGEN
o Scaffolding of tissue renewal o The most common protein in the animal world providing the
 Integrity of basement membrane or the stroma of parenchymal extracellular framework for all multicellular organisms
cells is critical for organized regeneration of tissues; injury to these o Type IV collagen and Laminin are the main components of the
tissues results in restitution of normal structure only if the ECM is basement membrane
not damaged o Each collagen is composed of 3 chains that form a trimer in the shape
 Disruption of these structures leads to collagen deposition and of a triple helix
scar formation o Vitamin C is needed for procollagen hydroxylation
o Establishment of tissue microenvironments o genetic defects in collagen production Ehlers-Danlos syndrome &
 Basement membrane acts as a boundary between epithelium and osteogenesis imperfecta
underlying connective tissue
o Storage and presentation of regulatory molecules XII. ELASTIN, FIBRILIN AND ELASTIC STRUCTURES
 Growth factors like FGF and HGF are secreted and stored in the
ECM in some tissues, thus, allowing rapid deployment of growth o Elastic fibers provide the ability of tissues (blood vessels, skin, uterus,
factors after local injury lung) to expand and recoil (compliance)
o Fibers can stretch and return to original size after release of tension
o Fibrous structural proteins  Makes up the central core that is surrounded by the peripheral
 collagens and elastins for tensile strength and recoil network of microfibrils
o Adhesive glycoproteins  Sustained amounts are found in large blood vessels (aorta), uterus,
 connects matrix elements to one another and to cells skin, and ligaments
o Proteoglycans and hyaluronan o Fibrilin
 for resilience and lubrication  Peripheral microfibrillar network that surround the elastin core
 Associates either with itself or with other ECM components
TWO BASIC FORMS OF ECM: o Marfan Syndrome
o Interstitial matrix  Inherited defect in fibrillin resulting in formation of abnormal
 consists mostly of fibrillar and nonfibrillar collagen, elastin, elastic fibers
fibronectin, proteoglycan and hyaluronan  Manifested by changes in CVS and skeleton.
 Found in spaces between epithelial, endothelial, smooth muscle  Most famous person with Marfan Syndrome: Abraham Lincoln
cells, and connective tissue
 Consists of nonfibrillar collagen (mostly type IV), laminin, heparin o Function as transmembrane receptors but are sometimes stored in
sulfate, proteoglycans the cytoplasm
 laminin is most abundant glycoprotein in BM o Can bind to similar or different molecules in other cells, providing h
 Closely associated with cell surfaces omotypic (same cell) or heterotypic (different cell) interaction


 Calcium-dependent adherence protein participate in homotypic
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 Together with Integrins, they links cell surface with cytoskeleton o PROTEOGLYCANS
by binding to actin and intermediate filaments to provide a  integral membrane proteins
mechanism for transmission of mechanical force which activates  act as modulators of inflammation immune reactions, cell growth
intracellular transduction pathways and differentiation
 Forms the cell junctions zonula adherens (located at apical surface) 4 STRUCTURALLY DISTINCT FAMILIES OF GAGS:
and desmosomes (stronger and extensive junction) o Heparan sulfate
o INTEGRINS o Chondroitin/dermatan sulfate
 Binds to ECM proteins (fibronectin, laminin, osteopontin) o Keratan sulfate
providing a connection between cells and ECM  Heparan, chondroitin, keratin- are all synthesized and assembled
 Binds to adhesive proteins in other cells  cell to cell interaction in the Golgi apparatus and RER as proteoglycans
 Fibronectin o Hyaluronan
- binds to collagen, fibrin (stabilize blood clot in wound  binds to large amount of water  viscous hydrated  connective
gaps and acts as substrate for ECM deposition & tissue resist compression fracture
formation of provisional matrix during wound healing),  provide resilience and lubrication to many types of CT (cartilage in
proteoglycans joints)
- binds to cell surface receptors  Produced at the plasma membrane by enzymes called hyaluronan
 Laminin synthases and is not linked to a protein backbone
- themost abundant glycoprotein in BM  Abundant in heart valves, skin, skeletal tissues, synovial fluid,
- has binding domains for both ECM & cell surface vitreous humor of the eye, umbilical cord
receptors. Laminin & collagen type IV are tightly bound  Shock absorber
in BM
 Leukocyte/endothelial interactions during inflammatory o Basic features of repair by connective tissue deposition:
response  Inflammation
o Integrin-cytoskeleton complexes function as activated receptors and  Angiogenesis
trigger a number of signal transduction pathways  Migration & proliferation of fibroblasts
 Scar formation
 Connective tissue remodeling


o Inflammation
 injury  platelet adhesion and aggregation clot in wound
surface  inflammation
o Proliferation
 granulation tissue, proliferation & migration of CT cells re-
epithelialization of wound surface
o Maturation
 ECM deposition, tissue remodeling, wound contraction


 Simplest type of cutaneous wound repair
 clean, incised wounds with good apposition of edges
 re-epithelization occurs with formation of a thin scar
○ Ex. Surgical wounds
 Occurs in excisional wounds that create large defects on the skin
surface, causing extensive loss of cells and tissue
Figure 6. Mechanisms by which ECM components and growth factors interact and  open wounds with significant tissue loss, necrosis, wound
activate signaling pathways. Integrins bind ECM components and interact with the contraction (main differentiation), more intense inflammatory
cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin, a- reaction, more granulation, extensive collagen deposition, leading
actin, and talin). This can initiate the production of intracellular messengers or can to substantial scar.
directly mediate nuclear signals. Cell surface receptors for growth factors may
activate signal transduction pathways that overlap with those activated by integrins.
Signaling from ECM components and growth factors is integrated by the cell to
produce various responses, including changes in cell proliferation, locomotion, and


 Consist of long repeating polymers of specific disaccharides
 Except for hyaluronan, GAGs are linked to a core protein forms

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 Gross appearance: pink, soft, granular appearance on wound

 Histological appearance: presence of new small blood vessels or
angiogenesis (characteristic feature) and proliferation of
 Characterized as leaky due to the immaturity of new blood vessels
thus there is passage of proteins and fluid; exudative.
 The larger the wound and the greater the inflammatory response,
the more granulation tissue is present/needed to fill wound dead
space. The more distance between healing wound edges, the
more granulation tissue fills the gap.  secondary intention
wounds present with more granulation tissue.
o Day 5 to 7 – Cell proliferation and Collagen deposition
 granulation tissue fills area
 maximal neovascularization
 Celullar proliferation and collagen deposition by 48 to 96 hours,
macrophages replace neutrophils
 macrophages
- key cells of tissue repair
- clear extracellular debris, fibrin& foreign matter at repair site
- promote angiogenesis & ECM deposition

Figure 7. Wound healing and scar formation. A, Healing of wound that caused little
loss of tissue: note the small amount of granulation tissue, and formation of a thin
scar with minimal contraction. B, Healing of large wound: note large amounts of
granulation tissue and scar tissue, and wound contraction.


o Day 1 – Formation of Clot through primary and secondary hemostasis
 Wound  activation of coagulation pathways  clot - RBCs,fibrin,
fibronectin, complement components are contained in the clot
 MAIN FUNCTION: Stop bleeding and serves as scaffold for
migrating cells attracted by GFs, cytokines and chemokines
released into injured site
 dehydration at external surface  scab
 Within 24 hrs  neutrophils at incision margins
o Day 3 – granulation tissue

Figure 9. Roles of macrophage in wound healing

Table 1. GFs and Cytokines affecting various steps in wound healing

Monocyte chemotaxis Chemokines, TNF, PDGF, FGF, TGF-
Fibroblast migration/replication PDGF, EGF, FGF, TGF-ß, TNF, IL-1
Keratinocyte replication HB-EGF, FGF-7, HGF

Angiogenesis VEGF, angiopoietins, FGF

Collagen synthesis TGF-ß, PDGF

Figure 8. Granulation Tissue in the early phase wherein there is angiogenesis or
proliferation of capillaries (arrows). These capillaries are leaky and edema will occur
Collagenase secretion PDGF, FGF, TNF, TGF-ßinhibits
in the interstitial tissue. Chronic inflammatory cells are present like lymphocytes,
macrophages and few fibroblasts. As it becomes older, it becomes less vascularised
with more fibroblasts and fibrosis. Old granulation tissue appears different from new
granulation tissue.
 Granulation tissue  hallmark of tissue repair debris.
 Different from “Granuloma”  form of chronic inflammation
characterized by nodular accumulation of modified macrophages
known of epitheloid cells

 Formed by the proliferation of fibroblasts and vascular endothelial

cells 24-72hrs post injury.

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o 7 days – 1 month – Scar formation  keloid- excessive deposition of collagen; common among African
 exhuberant granulation- proud flesh
 desmoid- aggressive fibromatoses

Figure 10. Scar (arrow) at the end of the first month with progressive wound
Figure 11. Histology of a keloid. Ecessive collagen (ARROW) is deposited.
contraction made of collagen

 Leukocyte infiltrate, edema, and increased vascularity disappear. o Contracture- causes deformity of wound and the surrounding tissues;
prone to develop on the palms, soles, anterior aspect of thorax
 Increased collagen accumulation.
 Granulation tissue  pale, avascular scar (composed of: spindle
shaped fibroblasts, dense collagen, elastic tissue fragments, ECM
 Dermal appendages (i.e hair follicles) disappear.
 After 1 month : Scar is made up of acellular connective tissue
devoid of inflammatory infiltrate, covered by intact dermis.
o Wound ontraction
 Decrease wound surface area by closing the gap between the
dermal edges
 Made possible by myofibroblast which express a-actin and


o A Systemic Factors:
 Nutrition – protein deficiency, vitamin C deficiency, inhibit
collagen synthesis
Figure 12. Development of fibrosis in chronic inflmmation
 Metabolic status – Diabetic microangiopathy
 Circulatory status – inadequate blood supply delays wound o Excessive deposition of collagen and other ECM components in a
healing tissue
 Hormones – glucocorticoids inhibit collagen synthesis o Injurious stimulus caused by infections and other types of tissue injury
o Local Factors: persists in chronic diseases, causing organ dysfunction and often organ
 Infection – most important factor; Results in persistent tissue failure; the persistence of these injuries leads to chronic inflammation,
injury and delayed healing which is associated with the proliferation and activation of
 Mechanical Factors – early wound movement would delay healing macrophages and lymphocytes, and the production of plethora of
 Foreign bodies - Unnecessary sutures or fragments of steel glass, inflammatory and fibrogenic GFs and cytokines
or even bone, constitute impediments to healing o In kidney and lung fibrosis, myofibroblasts are the main source of
 Size, location & type of wound – richly vascularized areas heal collagen
o stellate cells are the major source of collagen producers in liver
faster than poorly vascularized areas; small versus large wound.
Small wounds heal faster


o Deficient scar formation  wound dehiscence and ulceration Edited by: Tes
o Excessive formation of repair components 
 hypertrophic scar-raised scar due to excessive accumulation of

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Appendix A

Figure 13. Repair respnses after injury and inflammation. An Overview of the relationships between these processes.

Appendix B
Reading Assignment:

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