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Pathology 1st LE > Inflammation and Repair (trans 4) > Flashcards

Inflammation and Repair (trans 4) Flashcards

1
Q

REMEMBER
The normal cellular population is controlled by the:
o Regular division of actively dividing cells
o Rate of stem cell input
o Changes in proliferation and differentiation of cells
o Rate of apoptosis or cell death

A

2 requirements for the restoration of damaged tissue to normal
o Intact extracellular matrix
o Regenerative capacity of surrounding parenchyma cells

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2
Q

REMEMBER
Stem cells are characterized by their:
o Prolonged cell renewal
o Capacity to generate differentiated cell lineages (Transdifferentiation)

A

Transdifferentiation
o Differentiation from one cell type to another; change in cell lineage
o This capacity is also known as regenerative plasticity and hence is the core of regenerative medicine

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3
Q

TWO MAIN TYPES OF STEM CELLS

A
  1. Embryonic Stem Cells

2. Adult/Somatic Stem Cells

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4
Q

Embryonic Stem Cells
􀁸 Derived from cells in blastocyst
􀁸 Pluripotent: may give rise to tissues of different types
􀁸 The pluripotency of embryonic stem cells are related to the expression of growth and transcription factors
􀁸 Used for therapeutic cloning (regeneration of lost organ tissue; culturing of new organs)

A

Adult/Somatic Stem Cells
􀁸 Has more restricted capacity for differentiation
􀁸 Lineage-specific
􀁸 Usually found in labile (continuously dividing) tissues
􀁸 Also found in liver, pancreas and adipose tissue.
􀁸 Types:
a. Hematopoetic – inside bone marrow
b. Tissue stem cells – outside bone marrow
􀁸 Located in stem cell “niches”, which generate or transmit stimuli that regulate stem cell self-renewal and generation of progeny cells

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5
Q

Rapidly dividing cells generated by stem cells

A

TRANSIT AMPLIFYING CELLS

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6
Q

REMEMBER

progenitor cells are cells with restricted developmental potential

A

INDUCED PLURIPOTENT STEM CELLS (IPS)
􀁸 Differentiated cells of humans reprogrammed into pluripotent cells. Reprogramming is done by transferring their nucleus to an anucleated oocyte.
􀁸 Reprogamming occurs by the transduction of genes encoding embryonic stem cell transcription factors

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7
Q

STEM CELLS IN BONE MARROW

Hematopoetic Stem Cells (HSCs)

A

o Generate all blood cell types
o Reconstitute bone marrow depleted by disease or
irradiation (e.g. multiple myeloma, leukemia)
o Can differentiate into other cell types such as
hepatocytes, myocytes and neurons
o Produce approximately 1,500,000 blood cells/second

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8
Q

STEM CELLS IN BONE MARROW

Marrow/Multipotent/Mesenchymal Stromal Cells (MSC)

A

o Generate chondrocytes, osteoblasts, adipocytes, myoblasts, endothelial cell precursors depending on the tissue to which they migrate
o Do not seem to participate in normal tissue homeostasis

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9
Q

STEM CELLS IN BONE MARROW

Multipotent Adult Progenitor Cells (MAPCs)

A

o Differentiate into mesodermal, endodermal & neuroectodermal cell types
o Found in skin, muscle and brain

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10
Q

REMEMBER

The replication of cells is stimulated by growth factors (GF) or by signaling from ECM components through integrins

A

Four Phases Of Cell Cycle:

a. G1 – Presynthetic stage when DNA integrity monitoring before replication occurs
b. S – DNA synthesis (Replication)
c. G2 – Premitotic stage
d. M – Mitotic stage
* *Each cycle is dependent on the activation and completion of the previous one
* *Progression of cell cycle is tightly regulated by proteins called cyclins and associated enzymes called cyclindependent kinases (CDK).

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11
Q

Cell replication:

Activated CDKs drive the cell cycle by phosphorylating proteins that are critical for cell cycle transition

A

Activity of cyclin-CDK complexes is tightly regulated by CDK inhibitors.

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12
Q

Cell replication
Checkpoints
- Checkpoints ensure that cells with damaged DNA or chromosomes do not complete replication
- Checkpoint defects that allow cells with DNA strand breaks and chromosome abnormalities to divide produce mutations in daughter cells that may lead to neoplasia

A

o G1/S checkpoint: monitors DNA integrity before replication
􀂃 Tightly regulated by cyclins, CDK and CDK inhibitors
o G2/M checkpoint: checks DNA after replication and monitors whether the cell can safely enter mitosis
􀂃 If it senses DNA damage, checkpoint activation delays cell cycle and triggers DNA repair mechanism.

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13
Q

REMEMBER

- GF are polypeptides that promote cell survival, locomotion, contractility, differentiation, and angiogenesis

A
  • GF function as ligands that bind to specific receptors, delivering signals to the target cell that stimulate transcription genes
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14
Q

Growth Factors

Platelet-Derived Growth Factor (PDGF)

A

􀁸 Synthesized by platelets, stored in platelet granules, and is released on platelet activation
􀁸 Also produced by activated macrophages, endothelial cells, smooth muscle cells, and many tumor cells
􀁸 Binds to 2 cell surface receptors (PDGFR alpha and beta)
􀁸 Two newly identified isoforms PDGF (CC and DD) need extracellular proteolytic cleavage to release growth factors
􀁸 PDGF-B and C participate in activation of hepatic stellate cells in initial steps of liver fibrosis and stimulate wound contraction
􀁸 Causes migration and proliferation of fibroblasts, smooth muscle cells, and monocytes to sites of inflammation and wounds

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15
Q

Growth Factors
Epidermal Growth Factor (EGF)
􀁸 Also called progression factor
􀁸 EGF is produced by platelets and macrophages
􀁸 Promotes the growth of endothelial cells, fibroblasts, hepatocytes, and epithelial cells (cells involved in regeneration and repair)
􀁸 EGF and TGF-α share the same receptor, Epidermal Growth Factor Receptor (EGFR) which has an intrinsic tyrosine kinase activity

A

EGF receptors:

  1. EGFR1 (ERB B1 or EGFR)
    - Its mutation and amplification is detected in cancers of lung, head & neck, breasts, glioblastoma.
  2. ERB B2 receptor (HER-2 or HER2/Neu)
    - Over expressed in Breast Cancer; hence, targeted for its treatment.
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16
Q

Growth Factors

Fibroblast Growth Factor (FGF)

A

􀁸 Acidic (aFGF or FGF-1); basic (bFGF or FGF-2)
􀁸 Transduce signals through 4 tyrosine kinase receptors (FGFRs 1-4)
􀁸 Associate with heparin sulfate in the ECM and serve as a reservoir for storage of inactive factors
􀁸 Wound repair: FGF-2 and FGF-7 (aka Keratinocyte Growth Factor) help in re-epithelialization
􀁸 Angiogenesis: FGF-2
􀁸 Hematopoiesis: blood cell diff. & dev. of bone marrow stroma
􀁸 Development: skeletal and cardiac muscle development, lung maturation and specification of liver from endodermal cells

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17
Q

Growth Factors

Hepatocyte Growth Factor (HGF)

A

􀁸 Isolated from platelets and serum
􀁸 Mitogenic to hepatocytes and most epithelial cells (biliary epithelium, lungs, kidney, mammary gland, and skin)
􀁸 Acts as a morphogen in embryonic development
􀁸 Promotes cell scattering and migration
􀁸 Enhances survival of hepatocytes
􀁸 Produced by fibroblasts and most mesenchymal cells, endothelial cells, and liver parenchymal cells
􀁸 Produced as an inactive single-chain form (pro-HGF) that is activated by serine proteases in damaged tissues
􀁸 C-Met (HGF receptor) is often highly expressed in human tumors, especially in renal and thyroid papillary carcinomas
􀁸 HGF signalling is necessary during embryonic development
􀁸 HGF and c-Met inhibitors are being evaluated in cancer therapy trials

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18
Q 
Growth Factors
Transforming Growth (TGF): Transforming Growth Factor α (TGF-α)
A

􀂃 TGF-α is produced by keratinocytes, macrophages and other inflammatory cells that migrate into the area of healing wounds
􀂃 Involved in epithelial cell proliferation in embryos and adults, and in malignant transformation of normal cells to cancer
􀂃 EGF and TGF-α share the same receptor, Epidermal Growth Factor Receptor (EGFR), which has an intrinsic tyrosine kinase activity

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19
Q 
Growth Factors
Transforming Growth (TGF): Transforming Growth Factor B (TGF-B)
A
  • Most widespread distribution in mammals
  • produced by platelets, endothelial cells, lymphocytes, and macrophages
  • Growth inhibitor of most epithelial cells
  • Potent fibrogenic agent
  • Strong anti-inflammatory effect but enhances some immune functions
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20
Q 
Growth Factors
Transforming Growth (TGF): Transforming Growth Factor B (TGF-B) as growth inhibitor
A

o blocks the cell cycle by increasing the expression of cell cycle inhibitors
o can promote invasion and metastasis of cancer growth on mesenchymal cells

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21
Q 
Growth Factors
Transforming Growth (TGF): Transforming Growth Factor B (TGF-B) as Potent fibrogenic agent
A

o development of fibrosis in chronic inflammatory conditions particularly in lungs, kidney and liver
o stimulates fibroblast chemotaxis
o enhances production of collagen, fibronectin and proteoglycans
o inhibits collagen degradation by decreasing matrix proteases and increasing protease inhibitor activities

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22
Q

Growth Factors

Cytokines (Macrophage-Derived Growth Factors)

A

􀁸 Mediators of inflammation and immune responses
􀁸 Promote proliferation of fibroblasts, smooth muscle cells, and endothelial cells
􀁸 IL-1 & TNF (Tumor Necrosis Factor) participate in wound healing reactions
􀁸 IL-6 & TNF involved in the initiation of liver regeneration

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23
Q

Growth Factors

Vascular Endothelial Growth Factor (VEGF)

A

􀁸 Also called vascular permeability factor
􀁸 Family of homodimeric proteins including VEGF-A, -B, -C, -D and PIGF (Placental Growth Factor)
􀁸 Potent inducer of blood vessel formation in early development (vasculogenesis)
􀁸 Central role in the growth of new blood vessels in adults (angiogenesis) especially in chronic inflammations, wound healing and in tumors

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24
Q

Growth Factors
Vascular Endothelial Growth Factor (VEGF)
- Signal through three tyrosine kinase receptors:

A

o VEGFR 1 – has a role in inflammation and facilitate the mobilization of endothelial stem cells
o VEGFR 2 – located in endothelial cells and many other cell types; main receptor for vasculogenic and angiogenic effects
o VEGFR 3 – where VEGF-C and VEGF-D bind to act on lymphatic endothelial cells to induce lymphatic vessel production (Lymphangiogenesis)

25
Q

Principal Signaling Pathways Used by Cell Surface Receptors
Receptors with intrinsic tyrosine kinase activity
Ligands:
Signaling mechanisms:

A

Principal Signaling Pathways Used by Cell Surface Receptors
Receptors with intrinsic tyrosine kinase activity
Ligands: EGF, VEGF, FGF, HGF
Signaling mechanisms: Ligand binding to one chain of the receptor activates tyrosine kinase on the other chain, resulting in activation of multiple downstream signaling pathways (RAS-MAP kinase, PI-3 kinase, PLC-y) and activation of various transcription factors

26
Q

Principal Signaling Pathways Used by Cell Surface Receptors
GPCRs
Ligands:
Signaling mechanisms:

A

Principal Signaling Pathways Used by Cell Surface Receptors
GPCRs
Ligands: Multiple inflammatory mediators, hormones, all chemokines
Signaling mechanisms: Ligand binding induces switch from GDP-bound inactive form of ssociated G protein to GTP-bound active form; activates cAMP; Ca influx leading to increased cell motility

27
Q

Principal Signaling Pathways Used by Cell Surface Receptors
Receptors without intrinsic enzymatic activity
Ligands:
Signaling mechanisms:

A

Principal Signaling Pathways Used by Cell Surface Receptors
Receptors without intrinsic enzymatic activity
Ligands: Many cytokines including interferons, growth hormone, CSFs, EPO
Signaling mechanisms: Ligand binding recruits kinases (e.g. Janus kinases) that phosphorylate and activate transcription factors (e.g. signal transducers and activators of transcription)

28
Q

Mechanism of tissue and organ regeneration
- Liver regeneration is not true regeneration. The resection of tissues does not cause new growth of liver but instead triggers a process of compensatory hyperplasia in the remaining parts of the organ

A
  • End point of liver regeneration is the reconstitution of functional mass rather than the reconstitution of the original form
29
Q

Mechanism of tissue and organ regeneration
Liver regeneration
- Almost all hepatocytes replicate during liver regeneration after hepatectomy (all hepatocytes are quiescent cells), after which is followed by synchronous replication of the nonparenchymal cells (Kupffer cells, endothelial cells, stellate cells)

A
  • Hepatocyte proliferation is triggered by combined actions of cytokines and polypeptide growth factors
  • Hepatocyte replication depends on paracrine effects of GFs and cytokines (HGF &IL-6 produced by hepatic non-parenchymal cells)
  • *Intrahepatic stem or progenitor cells has no role in compensatory growth occurring after hepatectomy
30
Q

TWO BASIC FORMS OF EXTRACELLULAR MATRIX
Interstitial Matrix
o Found in spaces between epithelial, endothelial, smooth muscle cells, and connective tissue
o Consists mostly of fibrillar and nonfibrillar collagen, elastin, fibronectin, proteoglycan and hyaluronan

A

Basement Membrane
o Closely associated with cell surfaces
o Consist of nonfibrillar collagen (mostly type IV), laminin, heparin sulfate, proteoglycans (laminin is the most abundant glycoprotein in BM)

31
Q

The ECM functions for:
• Mechanical Support
o For cell anchorage and cell migration and maintenance of cell polarity
o The reason why cancer cells have lost mechanical support is due to an extracellular matrix defect
• Control of cell growth
o Regulate cell proliferation by signaling cellular receptors of the integrin family
• Maintenance of cell differentiation
o Types of ECM proteins can affect the degree of differentiation of the cells in the tissue

A

• Scaffolding of tissue renewal
o Integrity of basement membrane or the stroma of parenchymal cells is critical for organized regeneration of tissues; injury to these tissues results in restitution of normal structure only if the ECM is not damaged
o If the basement membrane is damaged or destroyed, it cannot anymore regenerate
o Disruption of these structures leads to collagen deposition and scar formation
• Establishment of tissue microenvironments
o Basement membrane acts as a boundary between epithelium and underlying connective tissue
• Storage and presentation of regulatory molecules
o Growth factors like FGF and HGF are secreted and stored in the ECM in some tissues, thus, allowing rapid deployment of growth factors after local injury

32
Q

COMPOSITION OF EXTRACELLULAR MATRIX

A 
• Fibrous structural proteins
o Collagen and Elastin
o Provides tensile strength and recoil
• Adhesive glycoproteins
o Connect the matrix elements to one another and to cells
• Proteoglycans and hyaluronan
o Provide resilience and lubrication
33
Q

COLLAGEN

Function: Provides extracellular framework for all multicellular organisms

A

The different types of collagen are:

  1. Fibrillar Collagen –Type I, II, III, V, IX
  2. Type IV Collagen
  3. Type VII Collagen
  4. Type IX Collagen
  5. Procollagen
34
Q

COMPOSITION OF EXTRACELLULAR MATRIX

COLLAGEN

A

Fibrillar Collagen –Type I, II, III, V, IX
􀂃 Found in extracellular fibrillar structures
􀂃 Comprise the major proportion of the connective tissue in healing wounds and particularly in scars
􀂃 Tensile strength derived from their cross-linking, which is the result of covalent bonds catalyzed by the enzyme lysyl-oxidase dependent on Vitamin C

35
Q

COMPOSITION OF EXTRACELLULAR MATRIX

COLLAGEN

A

Type IV Collagen
▪ Forms the anchoring fibrils between epithelial and mesenchymal structures, such as epidermaldermal junctions
▪ Main components of basement membrane, together with laminin

36
Q

COMPOSITION OF EXTRACELLULAR MATRIX

COLLAGEN

A

Type IX Collagen
▪ Component of intervertebral disks
Procollagen
▪ Secreted from the cell and cleaved by proteases to form the basic unit of the fibrils

37
Q

Collagen fibril formation
▪ Associated with oxidation of lysine and hydroxylysine residues by extracellular enzyme lysyl oxidase
▪ Results in the cross-linking between chains of adjacent molecules which stabilizes the array
▪ Major contributor to the tensile strength of collagen

A

Genetic defects in collagen production
▪ Ehlers-Danlos syndrome
▪ Osteogenesis imperfecta
**Vitamin C – is required for procollagen hydroxylation
**Scurvy – a condition of Vitamin C deficiency, showing signs of inadequate healing

38
Q

ELASTIN, FIBRILLIN, AND ELASTIC STRUCTURES

A
  • Elastic fibers has a central core of elastin and a peripheral fibrillin
  • Elastic fibers provide the ability of tissues (blood vessels, skin, uterus, lung) to expand and recoil (compliance) after conferring physical stress
  • Fibers can stretch and return to original size after release of tension
39
Q

Elastin
􀁸 Makes up the central core that is surrounded by the peripheral network of microfibrils
􀁸 Sustained amounts are found in large blood vessels (accommodate recurrent pulsatile flow), uterus, skin and ligaments

A

Fibrillin
􀁸 Peripheral microfibrillar network that surround the elastin core
􀁸 Associates either with itself or with the other ECM components

40
Q

Inherited defect in fibrillin resulting in formation of abnormal elastic fibers

A

Marfan syndrome

**Manifested by weakened aortic walls and skeletal abnormalities

41
Q

ADHESIVE GLYCOPROTEINS AND ADHESIVE RECEPTORS OR CELL ADHESION PROTEINS (CAMs)
• Function as transmembrane receptors but are sometimes stored in the cytoplasm
• Can bind to similar or different molecules in other cells, providing homotypic (same cell) or heterotypic (different cell) interaction
• Adhesion proteins act as transmembrane receptors

A 
Four main families:
o Ig family of CAMs
o Cadherins
o Integrins
o Selectin
42
Q

ADHESIVE GLYCOPROTEINS AND ADHESIVE RECEPTORS OR CELL ADHESION PROTEINS (CAMs)
Integrins
• Bind to ECM proteins (fibronectin, laminin, osteopontin) for cell and ECM interaction
• Bind to adhesive proteins in other cells for cell to cell interaction
• Present in plasma membrane of most cells except RBC

A
  1. Fibronectin

2. Laminin

43
Q

Integrins:
fibronectin
▪ Binds to collagen, proteoglycans, and fibrin (stabilize blood clot in wound gaps/acts as substratum for ECM deposition & formation of provisional matrix during wound healing)
▪ Binds to cell surface receptors
▪ Links other ECM components (e.g. collagen, proteoglycans) and macromolecules (e.g. fibrin, heparin) to cell-surface receptors called integrins (mediate interactions between cells and ECM)
▪ Chemotactic for fibroblasts and endothelial cells
▪ Promotes angiogenesis
▪ Tissue fibronectin forms fibrillar aggregates at wound healing sites
▪ Plasma fibronectin binds to fibrin within the blood clot that forms in a wound, providing the substratum for ECM deposition and reepithelialization

A

Laminin
▪ Most abundant glycoprotein in basement membrane
▪ Has binding domains for both ECM & cell surface receptors
▪ Laminin and collagen type IV are tightly bound in basement membrane

44
Q

ADHESIVE GLYCOPROTEINS AND ADHESIVE RECEPTORS OR CELL ADHESION PROTEINS (CAMs)
Cadherins

A
  • (Together with integrins) Links cell surface with cytoskeleton by binding to actin and intermediate filaments -> provide mechanism for transmission of mechanical force -> activate intracellular transduction pathways
  • Calcium-dependent adherence protein participate in hemolytic interactions
  • Forms the cell junctions zonula adherens (located at apical surface) and desmosomes (stronger and extensive junction)
45
Q

ADHESIVE GLYCOPROTEINS AND ADHESIVE RECEPTORS OR CELL ADHESION PROTEINS (CAMs)
Selectin

A

Leukocyte/endothelial interactions during inflammatory response

46
Q

GLYCOSAMINOGLYCANS (GAGS) & PROTEOGLYCANS
• Consist of long repeating polymers of specific disaccharides
• Can be integral membrane proteins
• Act as modulators of inflammation, immune response, and cell growth and differentiation
• Except for hyaluronan, GAGs are linked to a core protein to form proteoglycans

A

Four Families of GAGs:

  1. Heparan sulfate
  2. Chondroitin/dermatan sulfate
  3. Keratan sulfate
  4. Hyaluronan
    * *Heparin, chrondroitin, keratin – are all synthesized and assembled in the Golgi apparatus and RER as proteoglycans
47
Q

Hyaluronan (GAG)

A

o Abundant in heart valves, skin, skeletal tissues, synovial fluid, vitreous humor of the eye, umbilical cord
o Huge mucopolysaccharide without a protein core
o Binds a large amount of water (1000-fold its own weight) forming a viscous hydrated gel that gives connective tissues resilience and lubrication to many types of CT (cartilage in joints)
o Produce at a plasma membrane by enzymes called hyaluronan synthases and is not linked to a protein backbone
o Provide resilience and lubrication to many types of CT (cartilages in joints)
o Deficiency in hyaluronan may lead to osteoarthritis, commonly present among the elderly

48
Q

PROTEOGLYCANS

A
  • Integral membrane proteins
  • Act as modulators of inflammations, immune reactions, cell growth and differentiation
  • Form highly hydrated compressible gels conferring resilience and lubrication (such as in the cartilage in joints)
  • Consist of glycosaminoglycans or mucopolysaccharides linked to a protein backbone
  • Reservoirs for growth factors secreted into the ECM (e.g., fibroblast growth factor [FGF], HGF)
49
Q

Two processes of healing

A
  1. Regeneration

2. Repair

50
Q

two types of healing

A
  1. Healing by 1st Intention (Primary Union)

2. Healing by 2nd Intention (Secondary Union)

51
Q

Healing by 1st Intention (Primary Union)
􀁸 Simplest type of cutaneous wound repair
􀁸 Clean, incised wounds with good apposition of edges
o Wounds without infection or debris
􀁸 There is re-epithelization with formation of thin scar,
o i.e. surgical wounds

A

Healing by 2nd Intention (Secondary Union)
o Open wounds with significant tissue loss, necrosis, wound contraction (main differentiating point between 1st and 2nd intention), more intense inflammatory reaction, more granulation, extensive collagen deposition, leading to substantial scar
o Occurs in excisional wounds that create large defects on the skin surface, causing extensive loss of cells and tissue

52
Q

PHASES OF WOUND HEALING

DAY 1: Formation of Clot through Primary and Secondary Hemostasis

A
  • The main function of clot formation is to stop bleeding and to serve as a scaffold for migrating cells attracted by GFs, cytokines and chemokines released into the injured site
    o Damaged tissues release chemicals to stimulate platelet activating factor.
    o Kinin cascade shrinks endothelial cells and bradykinins cause pain.
    o Prostaglandins constrict smooth muscle.
    o Platelets release serotonin.
  • Scab is formed due to dehydration at external surface
  • Neutrophils are at the incision margins within 24 hours
53
Q

PHASES OF WOUND HEALING
DAY 3: Granulation Tissue
- Granulation tissue is the hallmark of tissue repair debris
**Different from GRANULOMA (form of chronic inflammation characterized by nodular accumulation of epithelloid cells)
**granulation tissue grows older, it becomes less vascular and more fibrotic

A

Gross appearance:
o Pink, soft, granular appearance on wound surface
Histologic appearance:
o Characteristic Feature: presence of new capillaries or angiogenesis
o Proliferation of fibroblasts and inflammatory cells (macrophages)
o Leaky and exudative due to immaturity of new blood vessels which allows passage of proteins and fluid and RBCs
o More Granulation Tissue present in:
􀂃 Larger wounds and greater inflammatory response (to fill wound dead space)
􀂃 The greater distance between healing wound edges (to fill the gap)
􀂃 Secondary intention wounds

54
Q

PHASES OF WOUND HEALING

DAY 5 to 7: Cell Proliferation and Collagen Deposition

A

􀁸 Granulation tissue fills area
􀁸 Neovascularization is maximal
􀁸 48-96 hours: Cell proliferation and Collagen deposition; macrophages replace neutrophils

55
Q

Roles of Macrophage in Wound Healing

A
  1. Debridement, removal of injured tissue and debris: Phagocytosis, collagenase and elastase
  2. Antimicrobial activity: NO and ROS
  3. Chemotaxis and proliferation of fibrobalsts and keratinocytes: PDGF, TGF-B, TNF, IL-1, KGF-7
  4. angiogenesis: VEGF, FGF-2, PDGF
  5. deposition and remodeling of ECM: TGF-B, PDGF, TNF, OPN IL-1, collagenase, MMPs
56
Q

DAY 7 to 1 MONTH: Scar Formation
􀁸 Leukocyte infiltrate, edema, and increased vascularity disappear
􀁸 Increased collag n accumulation
􀁸 Granulation tissue becomes pale, avascular scar
􀁸 Dermal appendages disappear (i.e hair follicles)
􀁸 After 1 month: scar is made up of avascular connective tissue devoid of inflammatory infiltrate, covered by intact dermis
􀁸 Wound contraction (Made possible by myofibroblast, which express a-actin and vimentin)

A

Steps in scar formation:
1. Inflammation
o clears dead cells and microbes
2. Angiogenesis
o provides nutrient and oxygen to support repair process
o new leaky capillaries lead to edema due to: incomplete interendothelial junction and VEGF
3. Granulation tissue
o migration and proliferation of fibroblasts
o deposition of loose CT, blood vessels and WBCs

57
Q

Factors That Influence Wound Healing:
Systemic Factors:
o Nutrition – protein deficiency, Vitamin C deficiency, inhibit collagen synthesis
o Metabolic status – diabetic microangiopathy
o Circulatory status – inadequate blood supply delays wound healing Hormones – glucocorticoids inhibit collagen synthesis

A

Local Factors:
o Infection – most important factor; Results in persistent tissue injury and delayed healing
o Mechanical Factors – early wound movement would delay healing
o Foreign bodies – unnecessary sutures or fragments of steel glass, or even bone, constitute impediments to healing
o Size, location & type of wound – richly vascularized areas heal faster than poorly vascularized

58
Q

Complications of Wound Healing
Deficient formation of granulation or scar formation leads to wound dehiscence (wound pulling apart at suture line) and ulceration

A

When there is excessive formation of repair components:
o Accumulation of collagen results in hypertrophic scar (raised scar)
o Keloid – excessive deposition of collagen; common among African Americans

59
Q

Complications of Wound Healing
􀁸 Exuberant granulation – proud flesh
o Desmoid – aggressive fibromatoses
􀁸 Contracture causes deformity of wound and the surrounding tissues; prone to develop on the palms, soles, anterior aspect of thorax

A

Fibrosis
o Excessive deposition of collagen and other ECM components in a tissue
o Injurious stimulus caused by infections and other types of tissue injury persists in chronic diseases, causing organ dysfunction and often organ failure; the persistence of these injuries leads to chronic inflammation, which is associated with the proliferation and activation of macrophages and lymphocytes, and the production of plethora of inflammatory and fibrogenic GFs and cytokines.
o Myofibroblasts are the main source of collagen in kidney and lung fibrosis
o Stellate cells are the major source of collagen producers in liver cirrhosis

Pathology 1st LE (12 decks)

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