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patho > regeneration and healing > Flashcards

regeneration and healing Flashcards

1
Q

injury flow chart

A
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2
Q

regeneration VS healing/repair

A

-REGENERATION:
-REPLACEMENT of damaged or dead cells/tissue by cells of the same type
-May occur by proliferation of differentiated cells that survive injury and can still proliferate (e.g., hepatocytes)
-May occur from tissue stem cells and their progenitors (e.g. skin, GI mucosa)
-Tissues with high proliferative capacity
-Intact basement membrane…and intact immature cells
-Must have intact connective tissue scaffold

-HEALING/REPAIR:
-reparative tissue RESPONSE to a wound, inflammation or necrosis
-also proliferation of vascular endothelial cells, fibroblasts

-Laying down scar formation (collagen deposition) -> when extracellular matrix framework is damaged
-Pure repair with scar formation mostly occurs in tissues which do not have regenerative abilities (permanent tissue)

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3
Q

cell types based on proliferation potential

A

-Labile cells- continuously divide quickly -> epithelial cells, lymphoid, hematopoietic (bone marrow), GI mucosa
-when you have chemo it kills cancer but it also kill these^^

-Stable Cells- MOST tissues, only proliferates when needed (low rate) -> re-enter cell cycle under specific STIMULI (quiescent): parenchymal cells, liver, lung, kidney, smooth muscle cells, osteoblasts, chondroblasts, endothelial cells, smooth muscle, fibroblasts

-Permanent Cells…terminally differentiated, (dont regenerate)
-heal by scar formation mostly
-neurons, cardiac muscle, skeletal muscle

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4
Q

growth factors

A

-Proteins that regulate cell proliferation
-come from Macrophages- may also come from epithelial and stromal cells
-bind to receptors to deliver signals to target cells -> transcription of genes
-Important in locomotion, contractility, differentiation, angiogenesis
-know the red ones
-VEGF, FGF, TGF-beta
-TNF- key influence on other cytokines -> cause systemic manifestations
-interleukins-regulator of other cytokines

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5
Q

growth factor: VEGF

A

-vascular endothelial GF
-important in new blood vessel formation (angiogenesis)!!
-triggered by hypoxia
-increases vascular permeability
-promotes angiogenesis in chronic inflammation, wound healing, and tumors
-angiogenesis= neovascularization
-stimulates blood cells to bring to wound for repair
-anti VEGF drugs- stop a blood supply for cancer cells

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6
Q

growth factor: FGF-2

A

contributes to re-epithelization of skin wounds, induces new blood vessel formation, etc.

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7
Q

growth factor: TGF-beta

A

-scar formation
-is POTENT fibrogenic agent!!
-stimulates fibroblast chemotaxis, enhances production of COLLAGEN, fibronectin, and proteoglycans; inhibits collagen degradation
-anti-inflammatory
-inhibits epithelial cells

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8
Q

healing/repair by connective tissue deposition (scar)

A

-!!FOLLOWS INFLAMMATION - but before it actually ends (spectrum) – see later
-Migration and proliferation of fibroblasts
-Angiogenesis
-Scar formation (collagen, other ECM protein synthesis
-Connective tissue remodeling
-Wound contraction
-Prototype – skin – see later
-Most healing is combination of regeneration and repair; depends on ability of tissue cells to proliferate, integrity of ECM, resolution or chronicity of injury or inflammation

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9
Q

connective tissue deposition

A

-Migration and proliferation of fibroblasts into injury site
-Deposition of ECM proteins produced by these cells
-Orchestrated by cytokines and GFs which include PDGF, FGF-2, and TFG-beta. Major sources are inflammatory cells, especially macrophages

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10
Q

connective tissue: fibroblasts

A

-!!48-96 hrs- macrophages are dominant cell (first 24hrs neutrophils are dominant)
-ex. someone got a cut 2 days ago. what the most dominant cell -> macrophage!

-Controlling fibroblasts: Macrophages
-Migration by chemokines (TNF, PDGF, TGF-B, FGF),
-Proliferation by growth factors (PDGF, EGF, TGF-B, FGF, IL-1, TNF)
-Fibrinogenesis: TGF-B

-Fibroblast actions:
-Create matrix of type III collagen and fibronectin (tensile strength ≈ 10%)
-Replaced eventually (3 months) by type I collagen (tensile strength ≈ 70 - 80%)

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11
Q

extracellular matrix!

A

-mechanical support for cells (anchorage and migration)
-Scaffold for tissue renewal (must not be destroyed)- stores GF and must be at least partially intact for regeneration
-made up of collagen, elastin, fibrillin, cell adhesion molecules, proteoglycans, hyaluronic acid
-Controls cell growth – regulates cell proliferation via signaling by receptors of integrin family

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12
Q

two forms of ECM

A

-(1) interstitial matrix

-(2) basement membrane – closely associated with cell surfaces, made up of mostly type 4 collagen (nonfibrillar), laminin, heparan sulfate, and proteoglycans
-if you dont breach basement membrane -> cancer is treatable
-once breached -> metastasize

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13
Q

collagen

A

-just know collagen is very complex and has a triple helix
-if not made well -> disease
-Laid down by fibroblasts
-Requires Vitamin C (Scurvy)

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14
Q

collagens types

A

-!Type I - high strength (tendons, bone, scars (MATURE)
-Type II - cartilage
-!Type III - pliable organs like wall of blood vessels, GI tract -> !!1st collagen deposited in wound healing!!
-!Type IV - found in all basement membranes in basal lamina

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15
Q

stages of inflammation, proliferation, maturation

A
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16
Q

collagen accumulation remodeling

A

-appearance and regression of cells occur at same time -> neutrophils, macrophages, endothelial cells, fibroblasts (in order)
-healing happens after inflammation but before it ends
-there is an overlap with inflammation and granulation tissue
-granulation tissue is important for healing bc it has things like blood vessels
-macrophage, angiogenesis, fibroblasts -> make up granulation tissue -> this should be present if wound is on its way to healing!!!!!!!

17
Q

healing/repair

A

-Migration, proliferation of fibroblasts and deposition of loose connective tissue
-new vessels (angiogenesis) and leukocytes (mostly macrophages)
-Type III collagen (immature) synthesis
-Cellular-cellular interactions via (growth) factors
-deposition of collagen by fibroblasts
-tissue remodeling
-wound contraction
-Sit in ECM: glycoproteins and proteoglycans

18
Q

glycoproteins, proteoglycans, and GAGS

A

-just know glycoproteins are in the ECM
-Glycoproteins- for cross linking of collagen fibers to make stronger; responsible for overall structure of scar

19
Q

granulation tissue: angiogenesis

A

-granulation tissue is made up of macrophages, fibroblasts (lay down collagen), and new vessels (angiogenesis)
-Endothelial cells (cells that line the blood vessels) grow extensions (pseudopodia) toward wound site
-cells divide, and new cells create a new lumen
-Main control: !VEGF (vascular endothelial growth factor) -> stimulates endothelial cells to proliferate

20
Q

angiogenesis

A

-VEGF – most important growth factor, especially in chronic inflammation, wound healing, and tumors
-VEGF-A - most important in angiogenesis; stimulates survival, proliferation and motility of endothelial cells, initiating sprouting of new capillaries, promotes vasodilation and contributes to vessel lumen formation
-FGF-2 stimulates proliferation of endothelial cells
-Newly formed vessels FRAGILE, stabilization requires recruitment of PERICYTES and smooth muscle cells and deposition of ECM proteins; angiopoeitins 1 and 2, PDGF, and TGF-beta participate in stabilization and these processes

21
Q

angiogenesis: new blood vessel development from EXISTING VESSELS

A

-!!!!!VEGF promotes vasodilation by stimulating production of NO; also increases vessel permeability
-VEGF buds new blood vessels
-FGF-2 stimulates proliferation of endothelial cells and promotes migration of macrophages and fibroblasts to damaged area
-Pericytes from abluminal surface separate, breakdown basement membrane, form vessel sprout
-Endothelial cells migrate towards angiogenic stimulus (area of tissue injury)
-Endothelial cells proliferate and mature
-Periendothelial cells (pericytes and vascular smooth muscle cells) recruited to form mature vessel

22
Q

timeline of wound

A

-24hrs- neutrophils
-48 hrs- macrophages
-6 days- maturation- collagen, myofibroblasts

23
Q

3 phases of cutaneous wound healing

A

Phase 1- Inflammation- 2-5 days
Phase 2- Proliferation- 2 days-3 weeks
Phase 3- Maturation- scar

24
Q

phase 1 - inflammation

A

-Immediate -> 2-5 days
-Bleeding stops- constriction of vessels, formation of clot!
-Triggers for acute inflammation:
-Cell damage, bacteria, and clotting cascade!
-Acute inflammation- vasodilation, phagocytosis
-Cells- neutrophils then macrophages

25
Q

phase 2- proliferation

A

-2 days to 3 weeks
-angiogenesis
-Granulation tissue-
-1- fibroblasts: to lay down collagen
-2- angiogenesis : to supply the repair/regeneration process
-generates scarring

26
Q

phase 3- maturation

A

-Type III collagen is replace by type I !!!!
-Acquires final tensile strength
-Remodeling: scar tissue becomes avascular and acellular!!!

-Wound contraction- wound edges pull together to close the defect
-Myofibroblasts- fibroblasts with muscle filaments -> move and come together
-Display feature of fibroblasts and smooth muscle cells

27
Q

healing by combinations of regeneration and repair: first and secondary intention

A

-Best example - skin wound
-Healing by first intention or primary union (epithelial regeneration):
-injury only involves epithelial layer
-Clean skin wounds (e.g., surgical excision) – death of limited number of epithelial and connective tissue cells
-Inflammation, proliferation of cells, maturation of connective tissue
-Wounds with opposed edges; involves only epithelial layer

-Healing by second intention
-Edges of skin cannot be brought together, unopposed edges
-tissue loss greater
-epidermal cells need longer time to cover surface
-cant restore original architecture
-more intense inflammatory reaction
-abundant granulation tissue, extensive collagen deposition forming substantial scar
-involves much greater destruction ECM -> more likely to produce greater amount of FIBROSIS
-Degree of FIBROSIS directly proportional to the amount of destruction or disruption of ECM.

28
Q

epithelial growth factor (EGF)

A

-acts on keratinocytes to migrate, divide
-acts on fibroblasts to produce granulation tissue
-similar to TGF-alpha

29
Q

remodeling of connective tissue

A

-!!Granulation tissue replacement by scar involves changes in ECM composition
-!!Balance between synthesis and degradation of ECM proteins
-!!Degradation accomplished by matrix metalloproteinases (MMPs)
-MMPs produced by fibroblasts, macrophages, neutrophils, synovial cells, and some epithelial cells
-MMP synthesis and secretion regulated by growth factors, cytokines, and other agents

-MMPs include:
-interstitial collagenases (cleave fibrillary collagen)
-gelatinases (degrade amorphous collagen and fibronectin)
-stromelysins (degrade variety of ECM components including proteoglycans, laminins, fibronectin, and amorphous collagen)

-!!Activity shut down by tissue inhibitors of metalloproteinases (TIMPs)

-if synthesis and degradation are not matching -> too much scar tissue

30
Q

wound contraction

A

-Occurs in large surface wounds (secondary intention)
-Formation at edge of wound of network of !myofibroblasts! - have characteristics of smooth muscle cells, contract in wound tissue
-Myofibroblasts made from tissue fibroblasts via PDGF, TGF-beta, and FGF-2 released by macrophages at wound site

31
Q

tensile strength of wound

A

-End of first week, wound strength-about 10% of unwounded skin; after a few months plateaus at about 70 to 80% (approximately 3 months)
-it will never go back to normal

32
Q

deterrent to wound healing

A

-Local infection….degrade granulation tissue; persistent tissue injury and inflammation

-Hypoxia….deters collagen fibril crosslinking e.g, arteriosclerosis, inadequate circulation

-Trauma

-Foreign bodies

-Diabetes….glycosylation (bonding of glucose to RBC and protein) impairs neutrophil and macrophage phagocytosis

-Malnutrition….decrease in proliferation phase, Vit C needed for hydroxylation

-Immunodeficiency

-Medications..corticosteroids blunt inflammatory process; NSAIDS inhibit platelet function

-Hormones – glucocorticoids (anti-inflammatory and inhibit collagen synthesis)

-Mechanics – early motion of wound can separate edges
-sneezing can reopen a wound

-Size, location, type of wound – e.g. face (more vascular) heals faster than foot

33
Q

wound retarding factors (local VS systemic)!

A

-LOCAL:
-DECREASED BLOOD SUPPLY!!!
-without blood there is no -> inflammatory cells, GF, fibroblasts
-Denervation
-Local Infection
-Foreign Body
-Hematoma- mechanical
-Mechanical stress
-Necrotic tissue

-SYSTEMIC:
-DECREASED BLOOD SUPPLY!!!
-Age
-Anemia
-Malignancy
-Malnutrition
-Obesity
-Infection
-Organ failure
-Immunosuppression
-Diabetes

34
Q

Complications

A

-Deficient scar formation – wound dehiscence and ulceration
-Excessive scar formation – keloid (scar tissue !extends beyond boundary of original wound!)
(Hypertrophic scar – excessive amounts of collagen resulting in raised scar)
-Contractures – especially in palms, soles, anterior thorax commonly after serious burns; exageration of contraction

35
Q

ulceration

A

-lower extremity, poor circulation in diabetes, PVD

36
Q

keloid vs hypertrophic scar

A

-KELOID
-disorganized
-collagen formation
-extends beyond borders of original wound
-frequently recur after resection

-HYPERTROPHIC SCAR
-parallel collagen formation
-confined to border of original wound
-infrequently recur after resection

37
Q

healing- review

A

-Injury activates coagulation pathway and blood clot forms on wound surface
-VEGF increases vessel permeability and edema
-Neutrophils appear within 24 hours, clean out debris and bacteria
-Neutrophils replaced by macrophages by 48 - 96 hours which clear debris, fibrin, foreign material and promote angiogenesis, ECM deposition
-Fibroblast migration to injury site mediated by cytokines, TNF, PDGF, TGF-beta, and FGF
-Fibroblast proliferation triggered by growth factors – macrophages main source
-24 to 48 hours - epithelial cells move from wound edge along cut margins of dermis, deposit basement membrane components; produce thin, continuous epithelial layer
-Increase in collagen fibrils to bridge incision
-Fibroblasts, vascular endothelial cells proliferate to form !granulation tissue! by 5 to 7 days, fills wound, neovascularization maximal
-Wbc infiltrate, edema, increased vascularity disappear by second week
-!!!!!!! TGF-beta is most important fibrogenic agent: causes fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased ECM degradation by MMPs
-Increased collagen accumulation and regression of vascular channels –original granulation tissue scaffold converted to pale, avascular scar made up of fibroblasts, dense collagen, elastic tissue, other ECM components
-By end of first/second month – scar is composed of acellular connective tissue without inflammation, covered by intact epithelium

38
Q

An experiment is being conducted on the effects of certain drugs on wound healing. After the administration of drug A, a cut is made in the thigh of a laboratory rat and one week later, a biopsy is taken of the area. At high magnification, the tissue has capillaries, fibroblasts, and a variable amount of inflammatory cells (mostly mononuclear such as macrophages, but with occasional neutrophils still present). What type of tissue does this best represent?

A

A. scar tissue
B. granulation tissue****
C. purulent tissue
D. permanent tissue (heart, skeletal tissue)
-not scar tissue yet -> not enough collagen

39
Q

A 70 year old woman presents with acute chest pain and shortness of breath. She undergoes a cardiac catherization which shows an occlusion of the left anterior descending coronary artery. Lab studies and EKG are consistent with an acute myocardial infarction. Which of the following is the most likely pathological finding in the affected heart muscle 6 weeks later?

A

A. Capillary-rich granulation tissue (5-7 days)
B. Granulomatous inflammation
C. Neutrophils and necrotic debris (day 1)
D. Collagen-rich scar tissue**
E. Vascular congestion and edema (when you first get the injury)

patho (11 decks)

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