Tissue Healing and Repair Flashcards

1
Q

What is repair? and what are the two types

A
  • restoration of tissue architecture and fucntion after injury
    • regeneration: proliferation of residual (uninjured) cells and maturation of tissue stem cells
      • skin, liver, or intestinal mucosa
      • basement memebrane intact=no scar
    • healing with scar formation: occurs when complete restitution is not possible (supporting structures severely damaged and /or injured tissues are incapable of dividing)
      • collagen deposition provides structural support (fibrosis)
      • resposnse to chronic damage
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2
Q

WHat is a labile tissue and give some examples

A

continous renewal of cells

hematopoietic cells in marrow, surface epithelia, mucosal epithelia (ducts, gi, bladder, resp)

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3
Q

what are stable tissues?

A
  • parenchyma of most solid organs is made up of stable tissues
  • in stable tissue regeneration occurs but is limited. only regenerate when they are “called upon”
    • pancreas. adrenal, lung, thyroid, kidney liver has even more regenerative capacities( functional not form)
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4
Q

How do non-dividing cells respond to injury?

A
  • repair by connective tissue
    • neurons, cardiac myofibers (but neurons dont have connective tissue)
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5
Q

What cells are able to participate in cell proliferation and regeneration?

A
  • remnants of injured tissue
  • vascular endothelial cells
  • fibrosblasts
  • tissue stem cells
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6
Q

What signals do cells that are regenerating respond to and what do the signals cause?

A
  • cells respond to signals from growth factors and extracellular matrix (ECM)
  • the growth factors come from macrohages, stroma, epithelia
  • they stimulate cell division, increase cell size and promote cell survivial
  • growth factors bind to cell receptors (most often on cell surface) and influence gene expression
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7
Q

how does tissue regeneration occur in eithelia and skin?

A

rapid replacement occurs from residual cells and tissue stem cells

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8
Q

describe tissue regeneration in parenchymal organs

A
  • there is more limited proliferation of residual cells in the following organs: pancreas, adrenal, thyroid and lung
  • the liver has more regenerative capacity (function not form)
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9
Q

What happens if residual cells cannot proliferate?

A

scarring occurs

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10
Q

What are the two major mechanisms of liver regeneration?

A
  • heaptocyte proliferation after partial hepatectomy
    • even with only 10% of liver remaining regrowth can occur
    • driven by cytokines IL-6, heaptocyte growth factr (HGF)
  • Liver regeneration from progenitor cells: when the proliferative capacity of the liver cells is impaired progenitor cells contribute!
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11
Q

what are stem cells and what are the different types?

A
  • cells that are able to “self renew” and asymmetrically replicate
  • in labile and stable tissues they are the source of new cells that replace dead cells
  • Embryonic and adult stem cells
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12
Q

what is asymmetric replication

A

stem cells divide this way

with cell division, a daughter cell differentiates, but the other daughter cell remains a stem cell

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13
Q

Describe the difference between embryonic and adult stem cells

A
  1. Embryonic stem cells
    1. pluripotent stem cells able to differentiate into all tissues
  2. Adult stem cells
    1. lineage specific (skin and GI epithelium) stem cells or multipotent progenitor cells (bone marrow)
      1. multipotent=broad differentiation capabilities. able to generate fat, cartilage, bone, endothelium and muscle
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14
Q

What is the extracellular matrix and describe its 2 basic forms

A
  • a network surrounding cells
  1. interstitial matrix: 3D amorphous gel synthesized by fibroblasts
  2. basement memebrane: highly organized interstitial matrix present around epithelial cells, endothelial cells and smooth muscle cells. synthesized by mesenchyme and epithelium
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15
Q

What is the role of the ECM

A
  • mechanical support
  • regulate cell proliferation (through integrins)
  • provide scaffold essential for healing without scar
  • storage of growth factors: fibroblast growht factor, hepatocyte growth factor
  • creates a “microenvironment”
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16
Q

What are the components of the ECM

A
  1. Fibrous structural proteins
    1. collagen: structural proteins providing strength
    2. elastin: form elastic fibers with fibrilin, allowing for recoil
  2. Proteoglycans and hyaluronan: highly hydrated gels
    1. provide compressability for joint
    2. contain growth factors
  3. Adhesive glycoproteins and receptors
    1. FIbronectin: major component of interstial ECM
    2. Laminin: major component of basment membrane
    3. Adhesion molecules: cell adhesion molecules (CAMs)
      1. immunoglobulins, cadherins, selectins, integrins
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17
Q

What are the steps in scar formation?

A
  1. inflammation
    1. macrophages:
      1. M1 macrophage: clear microbes and necrotic tissue and promote inflammation
      2. M2: produce growth factors that stimulate cell proliferation
  2. Cell proliferation and angiogenesis:
    1. epithelial cells, endothelial and other vascular cells, fibroblasts
    2. grnaulation tissue=fibroblasts connective tissue, new blood vessels and scatteres chronic inflammatory cells (helps with the healing process)
  3. Remodeling: reorganization of collagen to produce a scar
18
Q

What is angiogenesis

A
  • occurs from pre-existing vessels
    • vasodilation: NO and VEGF
    • VEGF helps w migration of endothelial cells towards the injured area
    • PDGF and TGF-B recruit pericytes and smooth muscle cells
    • Notch signaling-regulates sprouting and branching of new vessels
19
Q

How do fibroblasts migrate to the site of injury and proliferate?

A
  • endothlium and inflammatory cells secrete growth factors
    • TGF-B (transforming growth factor)
    • PGDF (platelet derived growth factor
    • FGF (FIbroblast growth factor)
  • leads to deposition of extracellular matrix where collagen at first is loose and eventually become dense and inactive forming a scar
20
Q

What is the source and function of Vascular endothelial growth factor (VEGF)

A

Source: Mesenchymal cells

Function: Induces angiogenesis in injury and in tumors (stimulates endothelial cells)

21
Q

WHat is the source and function of Fibroblast growth facotr (FGF)

A

Source: macrophages, mast cells, endothelial cells, fibroblasts (and more)

Function: induces angiogenesis; promotes migration of fibroblasts, epithelial cells and macrophages

22
Q

What is the source and function of platelet derived growth factors (PDGF)

A

Source: platelets, macrophages, endothelial cells, smooth muscle cells, epithelium

Function: induces fibroblast smooth muscle, endothelial cell proliferation and migration; stimulates production of ECM

23
Q

What are the sources and functions of transforming growth factor-B (TGF-B)

A

Source: platelets, endothelium, epithelium, lymphocytes, macrophages, smooth muscle cells, fibroblasta

Function: suppresses endothelial proliferation/migration and acute inflammation; stimulates production of ECM proteins

24
Q

WHat is the hallmark of repair process

A

Granulation tissue: fibroblasts (collagen) and endothelial cells proliferate (new vessels)

25
Q

explain the maturation of fibrous tissue

A
  • over time the scar remodels
  • there are decreased vessels
  • some degradation of collagen, and other extracellular matrix proteins accomplished by matrix metalloproteinases (MMP) containing zinc
    • secreted by several cell types: firboblasts, macrophages, neutrophils etc.
    • regulation of MMPs by growth factors and cytokines
26
Q

what is the difference between granulation tissue and mature scar

A
  • granulation tissue
    • many blood vessels
    • loose connective tissue and edema
  • mature scar
    • ature collagen and less vessels
27
Q

summarize healing with a scar

A
  • injury
    • macrophages emigrate to area of damage and area becomes semi liquid
  • vascular granulation tissue
    • capillary bud grows into damaged area to form network
    • macrophages secrete fibogenic and angiogenic factors
  • fibrovasculature granulation tissue
    • fibroblasts proliferate to begin to deposit collagen
  • collagenous scar
    • dense collagen and inactive fibroblasts with reduced vascularity
28
Q

What is healing by first intention? (primary union)

A
  • a wound that is closed by approximmation of wound margins, placement of graft, or surgical incision closed with stiches or staples
  • acute wounds within 24 hours of injury before granulation tissue forms
  • ex: uninfected surgical incision approximated by sutures!
29
Q

What is healing by second intention?

A
  • wound is left open (no surgical closer) and allowed to close by epithelialization, granulation tissue and wound contraction
  • commonly used in management of infected wounds
  • approximation of wound edges occurs via epitheliazation
  • occurs when more extensive damage leaves a tissue defect: large wounds, abscess, ulceration
  • more intense inflammatory response due to large fibrin clot and more necrotic material to be removed
  • larger amount ot granulation tissue formed to fill defect
  • substantial scar formation with thinned epidermis
30
Q

List 4 examples of defects in healing

A
  • venous leg ulcers, arterial ulcers, pressure sores, diabteic ulcers
31
Q

what is a keloid?

A
  • a defect in healing, raised skar due to excess collagen
  • the mechanism is not completely understood but there is increased activity of TGF-B and IL-1 (firogenic cytokines) are proposed mechs
  • heritable (AA increased risk)
32
Q

What is exuberant granulation?

A
  • defect in wound healing where the granulaiton protrudess above surrounding skin and prevents re-epithelization
33
Q

What is the significance of formation of contractures during wound helaing?

A

normally wounds contract with healing but excessive contraction may result in deformity of ound/surrounding tissues for example after serious burns

34
Q

WHat is Ehlers-Danlos syndrome (EDS)?

A
  • genetic defect in collagen synthesis or structure
    • there are 30 types of collagen and 6 variations of EDS) but Classic is defect in colagen type IV
    • tissue containing the type of collagen affected lack tensile strength
      • skin: hyper-extensible, fragile, easilt traumatized
      • joints and ligamentL hypermobile
      • rupture of internal organs (colon) and larger arteries
      • poor wound healing
        *
35
Q

What is marfan syndrome?

A
  • a mutation affecting fibrillin
    • fibrillin is a major comonent of microfibrils in the ECM that is widely distributed in body and is abundant in aorta, lens and ligament
    • symptoms:
      • degeneration of aorta: aneurysm and dilation
      • dislocation of lens
      • abnormalities of aortic and mitral valves
      • long legs, arms fingers
      • hyper-extensible joints
36
Q

List 2 events associated with inflamamtion and the growth factors/mediators involved

A
  1. formation of scab and clot
  2. acute inflammatory reaction; swelling, redness, and pain (24 hours)

fibrin, fibronectin, histamine selectins integrins PECAM1

**then the wound is sutured closed**

37
Q

List steps of wound healing associated with granulation tissue and the associated growth factors/mediators

A
  1. epithelial cells at margins undergo mitosis and migrate towards center (24 to 48 hours)
  2. a thin layer of epithelail cells covers the wound (48 hrs)
  3. granulation tissue invades the wound (migration and proliferation of fibroblasts) (day 3)
  4. New vessel growth into granulation tissue at peak (angiogenesis) ( day 5)
  5. Epidermis is now full thickness (day 5)

**when you remove the sutures the wound strength drops down back to 10% from 70%**

TGFa, EGF, FGF

VEGF, FGF

**then sutures are removed**

38
Q

LIst the steps of wound healing involved in ECM deposition and remodeling

A
  1. collagen fibers grow into granulation tissue (collagen synthesis) ( second weel)
  2. scar consists of cellular connective tissue w/o inflammatory cells ( one month)
  3. connective tissue remodeling (subsequent weeks)

PDGF, FGF, TGFB

Matrix metalloproteins

39
Q

What factors can influence healing?

A
  • nutrition: vit C deficicnecy
  • Metabolic status
    • ie diabetes
  • circulatory status: poor perfusion prevents necessary cells from acess
  • steroids: inhibit TGFB and decrease fibrosis
  • infection: prolongs inflammation=tissue injury
  • mechanical factors: increased loacl pressure=dehiscence (rupture)
  • foregin bodies: prolong inflammation
40
Q

list two examples where you may have too much healing, and that is a problem

A

keloid

exuberant granulation

41
Q

What is cirrhosis? What is the appearance? What are causes?

A

Scarring of the liver - type of repair

In infections of the liver like chronic hepatitis, hepatocytes often regenerate to form fibrosis and nodules.

Alcoholism, primary biliary cirrhosis, and obesity.