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Terms in this set (87)
Overview of Tissue healing process:
Explain Tissue healing:
-restoration of the integrity of injured tissue
-Lost / destroyed tissue is replaced by living tissue
-may occur by the process of tissue regeneration and/or by CT scarring
2 General ways in which Tissue healing occurs:
1. Regeneration - Replacement of lost tissue by same tissue type
2. Connective tissue scarring - Replacement of lost tissue by Granulation tissue (Fibrosis)
(Both can occur as well)
Process by which Tissue healing occurs by replacement of lost tissue by same tissue type is called _______________
2 types of Regeneration:
-Complete regeneration (e.g. In Labile cells + stable cells- epidermis, GI tract, hematopoietic system)
-Compensatory growth (In stable cells- liver, kidney)
2 Types of Connective tissue scarring:
-Scar formation (due to a big wound)
-Fibrosis (due to chronic inflammation)
--> Both involve Fibrous CT (granulation tissue) deposition.
The type of tissue repair that occurs in only Stable cells is called ________________
The type of tissue repair that occurs in both Labile cells and stable cells is called ________________
"Renewal" or Regeneration
______________ is a tissue healing process that act to deposit connective tissue that holds the remaining tissues together but does not restore normal function.
Explain Tissue healing by Fibrosis:
-After an organ/tissue has undergone severe chronic inflammation, inflammatory cells (lymphocytes, macrophages) generate cytokines that trigger off generation of CT.
-This new granulation tissue acts like a GLUE to hold the remaining tissue together
--> physiologically affects the FUNCTION of tissue/organ.
Chronic inflammation induce Which mechanism of tissue healing?
Explain compensatory growth:
-Type of Regeneration
-occurs in stable cells
-Once there has been extensive damage + necrosis in the tissue/organ --> Remaining tissue in that organ will undergo hyperplasia or hypertrophy to increase in size and restore back to normal SIZE.
(e.g. kidney does not regenerate new nephrons, but can enlarge by compensatory hypertrophy of nephrons)
3 major classes of cells:
(based on cell cycle replicative capacity)
*Labile cells - continuously replicate throughout life
*Stable cells - Quiescent with a very low rate of replicative rate, but growth factors can induce them into higher replication rate
*permanent cells - terminally differentiated, exhibit little/no replication (once they die, they're gone for good)
Hepatocytes are (Labile/Stable/Permanent) cells.
Give examples of Labile cells, Stable cells, and Permanent cells:
Labile - skin, ducts, mucosas (all epitheliums)
Stable - solid tissue parenchyma (liver, kidney, pancreas), endothelium, smooth muscle, fibroblasts
Permanent - Neurons, cardiac myocytes, striated skeletal muscle
Mutant proto-oncogene alleles are typically (recessive/dominant)
Mutant Tumor suppressor gene alleles are typically (recessive/ dominant)
_______________ type of cells can experience increase in cell replication rate in presence of growth factors, hormones
During _______ phase of cell cycle, ALL intracellular constituents except DNA are duplicated.
What happens if the DNA damage occurs during G1 phase?
G1/S checkpoint will not allow entry of DNA into S phase, instead DNA is sent back to G1 phase and try to get repaired.
--> If it cannot be repaired successfully, permanently incapable of any further replication & often undergoes apoptosis
Name 3 major Cell cycle checkpoints :
1. G1 checkpoint (Start or restriction checkpoint)
2. G2/M checkpoint
3. Spindle checkpoint (metaphase-to-anaphase)
Name 4 major Cell cycle Regulatory genes:
-Growth promoting proto-oncogenes (dominant oncogenes)
-Growth inhibiting tumor suppressor genes (recessive oncogenes)
-Genes involved in DNA repair
-Genes that regulate cell programmed cell death or cell senescence
(others: Cyclins, CDK, CDK inhibitors, etc)
Oncogenes vs proto-oncogenes
Proto-oncogenes: makes NORMAL proteins that help cells grow. Has dominant allele, so active mutation of one of 2 alleles will convert it to oncogene.
Oncogene: "Cancer-forming genes" that make ABNORMAL proteins in neoplasia or cancer (mutated proto-oncogene)
Proto-oncogenes ___________ growth of cells by regulating cell cycle.
Tumor suppressor genes ___________ growth of cells by regulating cell cycle.
Function of Tumor suppressor genes:
-NORMAL genes that downregulate cell cycle --> slows down & inhibits cell cycles
-have nothing to do w/ tumor as long as it stays unmutated.
(named so b/c it was discovered in cancer cells)
______________ genes generate proteins that foster cell cycle progression
______________ genes generate proteins that slow/ inhibit cell cycle progression
Tumor suppressor genes
General mechanism of how normal cells enter G1 of cell cycle:
1. Binding of growth factor to G0 cell receptor
2. Activation of growth factor receptor
3. Signal transduction to nucleus
4. Activation of nuclear regulatory factors
5. Progression of genes into G1 of cell cycle.
ALL processes related to Cell cycle are regulated by interaction between ________________
Cyclins & CDK (Cyclin-dependent kinases)
The degree of stimulation in G1 phase depends on the balance between _______________ and ________________
Inhibitors + kinases (activators) that are bound to CDK, Cyclin-dependent kinases
Function of RB (Retinoblastoma) gene:
--> LIMITS/restricts how quickly cells will progress from G1 to S phase.
Prevent excessive cell growth by inhibiting cell cycle progression From G1 --> S phase until a cell is ready to divide
(Once ready, it allows entry to S phase)
_______________ gene prevents progression of cell from G1 to S phase until a cell is ready to divide.
RB (Retinoblastoma) gene
Function of Cyclin-dependent kinases (CDK) in cell cycle:
-Becomes activated by binding to Cyclin --> phosphorylating activity of "Kinase" activated --> signals the cell that it's ready to pass into next stage of cell cycle --> directs to specific target proteins to regulate cell cycle (e.g. G1/S cyclins send CDK to S phase targets)
-When not attached by Cyclin, CDK's are normally Inactive, bound by CDK inhibitors.
Kinase vs Phosphatase
Kinase attaches a phosphate group to a protein
Phosphatase removes a phosphate group from a protein
Which amino acids of a protein are phosphorylated by kinases?
--> All have -OH side chains
___________ gene is called the "governor of cell cycle "
Retinoblastoma (RB) gene
_______________, once phosphorylated, function in generating many phosphorylated proteins needed as enzymes to drive the cell cycle
Name all types of Cyclin proteins:
A, D, E
_____________ is a recessive tumor suppressor gene first identified in Familial retinoblatoma
_____________ is a protein generated by Retinoblastoma gene.
_______________ protein modulates an on/off switch for transition from G1 into S phase of the cell cycle
Explain the MECHANISM of how Rb protein allows cells entry from G1 to S phase:
In G0/G1, Rb is tightly bound to E2F, which is a crucial S phase cell cycle protein TF.
Rb protein gets Phosphorylated by CDKs (activated by growth factors)--> leads to dissociation of E2F from Rb
Free E2F acts as transcription factor and activates nuclear promoters of S phase genes thereby "releasing the brake" --> allows cells to enter S phase.
In G0/G1, Rb protein is tightly bound by _______________, but _______________ triggers release of this protein off of Rb protein, which then enter the ________________ .
-E2F transcription factor
-Hyperphosphorylation by CDKs
Nucleus to activate transcription S-phase related genes
What is the consequence of not having enough growth factors but instead having a lot of Growth inhibitors in a cell?
Growth inhibitors activate CDK inhibitors --> Inactivate CDKs --> cannot hyperphosphorylate the Rb protein --> No dissociation of E2F protein occurs --> Therefore, cell cycle is arrested at G1 phase, cannot proceed to S phase.
Rb gene is an example of (Growth inhibiting tumor suppressor gene / Growth promoting proto-oncogenes)
Growth INHIBITING tumor suppressor genes
What are some examples of Growth promoting proto-oncogenes?
What are some examples of Growth inhibiting suppressor-oncogenes?
Growth factors, hormones
3 Required settings in order for Tissue healing to occur by REGENERATION:
1. Tissue has to be comprised of labile or stable cells
2. There must be some preservation of original tissue (that then can undergo proliferation)
3. There must be Preservation of tissue scaffolding (ECM)
Mechanism of how Regeneration of Stratified squamous epithelium occurs:
1. Once skin is lost, growth factors released to trigger rapid replication by mitosis
2. Basal cells replicate
3. Basal cells eventually undergo Contact inhibition & cease replication
4. These cells undergo differentiation into stratified squamous epithelium
What is Contact inhibition?
Regulatory mechanism in functions to keep cells growing into a layer of ONE CELL LAYER thick. --> Cell cycle is arrested when the cells have formed a confluent monolayer & contact each other
--> this control mechanism is lost in malignant cells, leading to uncontrolled proliferation & tumor formation
Destruction/ inflammation of Alveoli of the lung, as a result of mild Pneumonia, is a (reversible/irreversible) process that can be returned to normal by ________________ mechanism.
-Tissue regeneration (proliferation / replication of alveolar & bronchiolar epithelial cells in the lung --> back to normal)
Mild consolidating lobar pneumonia heals by ______________ process.
Abscessing Bronchopneumonia heals by ______________ process.
(Function/structure returned back to normal)
Scar formation (CT scarring)
(destroyed lung tissue replaced by granulation tissue)
Cells in the Lung are (stable/ labile) cells.
(Remember Lungs are NOT like kidney, liver. Lungs are lined with respiratory epithelium, mostly simple cuboidal/ squamous)
_______________ mechanism of Tissue healing is able to restore the tissue completely back to normal structurally and functionally as if nothing happened
Regeneration in Labile and Stable cells.
Regeneration by which type of cells can completely restore back to normal, functionally and structurally?
+ Labile cells
What happens when the Liver is cut in half?
Tissue regeneration occurs by Compensatory growth.
--> remaining cells undergo hypertrophy + Hyperplasia to increase in size and restore the SIZE.
(removed tissue itself is not restored)
What happens when one of two kidneys is removed?
Compensatory hypertrophy of the Nephron + kidney
--> kidney does not regenerate new nephrons, but ENLARGE by compensatory hypertrophy of nephrons
________________ is required for effective Tissue healing by Regeneration.
(e.g. basement membrane, ECM)
Required settings in order for Tissue healing to occur by Connective tissue scarring:
Tissue must be comprised of Permanent cells
1. There must be EXTENSIVE tissue necrosis
2. Tissue scaffolding must be destroyed
Must occur as a result of Chronic inflammation
Tissue healing by Connective tissue scarring occurs by deposition of ______________
Define Granulation tissue:
Fibrous connective tissue comprised of NEWLY formed blood vessels (angiogenesis), proliferating fibroblasts (fibroplasia) and LATER synthesis of Type I Collagen
--> Forms a SCAR.
3 Major components of Early Granulation tissue:
1. Angiogenesis (new blood vessels)
2. Fibroplasia (proliferating fibroblasts)
3. Inflammation & Necrotic tissue
What types of vessels are developed in Angiogenesis in granulation tissue?
Explain the mechanism of Formation of Granulation tissue:
1. Debridement of dead tissue by acute and chronic inflammatory cells
2. Proliferation of Fibroblasts (Fibroplasia)
3. Formation of new, very leaky blood vessels (angiogenesis)
4. In LATER stages, Type I collagen is released extracellularly by fibroblasts --> scar formation
_______________ must occur in order for Granulation tissue to form, otherwise tissue healing cannot occur.
Debridement of dead tissue
Mechanism of Angiogensis:
1. Endothelial cells from "parent vessels" undergo replication, proliferate --> sprouting of capillaries --> migrate into area of granulation tissue
Wrapped around the newly forming blood vessels are the Pericytes that form the basement membrane.
very leaky b/c tight junctions haven't formed.
Compare Early vs. Later Granulation tissue:
Early - Angiogenesis, fibroplasia, Inflammation, necrotic tissue
Later - Angiogenesis, fibroplasia, COLLAGEN deposition
Mechanism of Collagen synthesis & Release:
1. Fibroblasts synthesize Type I protocollagen peptides
2. Extracellular secretion of protocollagen helical peptides --> Form collagen fibrils
3. Apoptosis & Resorption of granulation tissue (no longer needed)
4. Cross-linking of collagen fibrils, forming a mature collagen scar.
Compare Maturing vs, Mature granulation tissue:
-No more blood vessels
-Fibroblasts differentiated into Myofibroblasts
-NO CELLS LEFT.
-Mature, acellular, covalently cross-linked collagens
Function of Myofibroblast:
Muscle-like fibroblasts that cause contractions, pushing the collagens tightly together
--> All occurring in a maturing granulation tissue.
Healing by FIRST vs. SECOND intention
by Connective tissue scarring:
-minimal tissue damage
-Apposing portions of injured tissue can easily be brought in close opposition
-small amount of collagen scar deposition
-Extensive tissue damage
-Apposing portions of injured tissue cannot be brought in close opposition to another
-Large amount of collagen scar deposition
Examples of Healing by First vs. Second intention:
First - well sutured surgical incision (little/no scar retraction)
Second -Infarctions, abscesses, 3rd degree burns, lacerations
Wound "Contraction" is much more apparent in scar formation by (First/Second) intention, and this appearance is due to _______________
Contraction by the Myofibroblasts
(Fibroblasts differentiate into myofibroblasts, instead of to collagen at a later stage of healing)
What type of Injury is required for Scar formation to occur?
-Extensive tissue necrosis
-Destroyed tissue scaffolding
Mechanism of how Chronic inflammation results in Fibrosis:
Chronic inflammation cause Macrophages to differentiate into a SECOND type of macrophage
--> This M2 generates growth factors & cytokines that recruit Fibroblasts to make fibrous CT resulting in accumulation of collagen --> FIBROSIS
(tissue doesn't need to be destroyed, these can occur readily in normal cells)
Consequence of Liver undergoing mild vs. Chronic inflammation
Mild inflammation :
- proliferation of hepatocytes --> Regeneration back to normal (function completely restored)
-Deposition of connective tissue, proliferation of hepatocytes w/in disrupted matrix --> Extensive Fibrosis --> Non-functional liver.
Name all possible Abnormalities in tissue repair by CT scarring:
-Dehiscence of wound
-Excessive formation of granulation tissue (proud flesh)
-Excessive collagen deposition (Hypertrophic scar, keloid)
-Scar contracture, adhesions
Dehiscence of wound:
-Abnormality of CT scarring
-Cause: Insufficient crosslinking of collagen fibrils --> not enough tensile strength --> Scar ruptures
-edges of a wound no longer meet
-a.k.a. "wound separation"
The phenomena of having excessive formation of granulation tissue and having the scar be pushed out of surface is called __________________
______________ is formed on the skin due to Excessive collagen deposition
Hypertrophic scar is due to excessive deposition of ______________ during tissue healing.
Proud flesh is due to excessive formation of _________________ during healing.
Describe Adhesion :
-Abnormalities in Tissue repair
-If scar formation occurs in GI tract, it can cause Adhesions where various organs stick to each other --> prevents normal function
Compensatory growth can mainly occur in 2 organs:
Liver Cirrhosis is associated with Which type of healing process?
Chronic Steatohepatitis is associated with Which type of healing process?
Name 2 liver conditions that lead to Liver Fibrosis:
(T/F) Only permanent cells undergo Fibrosis if under chronic inflammation.
ANY type of cells can undergo FIBROSIS as long as chronic inflammation is occurring.
Tissue damage occurring in _____________ cells will ALWAYS heal by connective tissue scarring
Superficial skin wounds heal by ________________
Deep excisional wounds heal by ________________.
Myocardium infarction heals by ________________
Chronic pancreatitis heals by ________________.
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Tissue/Organ injury and death
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