Unit 2 Exam Material Flashcards
Regeneration of Injured cells in essence is…
cell proliferation, drive by growth factors and dependent on integrity of ECM
Cell types proliferating during tissue repair
Remnants of injured tissue; vascular endothelial cells; fibroblasts
Fibroblasts in tissue repair
source of fibrous tissues that form scar to fell defects that cannot be corrected via regeneration
Three groups of tissues
1) Labile 2) Stable 3) Permanent
Labile Tissues
Continuous cell turnover due to stem cells and proliferation of mature cells
Labile Tissue examples
Bone marrow, surface epithelium on skin, GI, ducts, urothelium
Stable Tissues
Quiescent with minimal replication; capable of proliferation in response to injury of loss of tissue mass; limited regenerative capacity
Stable Tissue Examples
parenchyma of solid organs - liver, kidney; Endothelial cells, fibroblasts, smooth muscle cells.
Permanent Tissues
terminally differentiated and non-proliferative; insufficient regeneration, dominated by scar formation.
Permanent Tissue examples
Nuerons and cardiac muscle
Stem cells are characterized by two properties…
Self renewal; asymmetric replication
Two types of stem cells
embryonic and adult
Embryonic Stem Cells
most undifferentiated; gives rise to ectoderm, endoderm, mesoderm
Adult Stem cells
tissue stem cells; less undifferentiated. Found among differentiated cells within organ/tissue; more limited in self-renewal capacity and lineage potential. Important in tissue homeostasis!
What do growth factors do?
stimulate survival and proliferation, promote migration, differentiation, other responses
Where are growth factors produced?
macrophages; lymphocytes; parenchymal/stromal cells
mechanism of growth factor activation
recruited to site of injury by macrophages or lymphocytes or inactive and activated at sight of injury
autocrine
signaling occurs directly on same cell that produces factor
paracrine
signaling between adjacent cells
Endocrine
signaling over great distances
Three main types of growth factor Receptors
Tyrosine Kinase; G protein; receptors without intrinsic enzymatic activity
ECM function
mechanical support, control cell proliferation; scaffolding for tissue renewal; establish tissue microenvironments
Components of ECM
1) fibrous structural proteins 2) water-hydrated gels 3) adhesive glycoproteins
Function of Fibrous structural proteins in ECM
collages, elastins - tensile strength and recoil
Water hydrated gel in ECM - function
proteoglycans and hyaluronon - resilience and lubrication
Adhesive glycoproteins in ECM - function
connect matrix elements to one another and to cells
Interstitial Matrix
Between cells in connective tissue that is synthesized by mesenchymal cells.
Components of Interstitial matrix
fibrillar and non-fibrillar collagen; fibronectin; elastin; proteoglycans; hyaluronate
Basement Membrane
beneath epithelial, endothelial and smooth muscle that is synthesized by overlying epithelium and underlying mesenchyme
Components of basement membrane
type IV collagen; laminin; proteoglycan
what happens if ECM is damaged?
tissue repair can only be accomplished by scar formation
Repair of labile tissues
injured cell are rapidly replaced by residual cells and differentiation of stem cells - basement membrane must be intact
Stable tissue repair
Regeneration can occur, but is usually more limited (exception of the liver)
Liver Regeneration/Repair capabilities
40-60% of liver can be removed in living donor transplant; can also regnerate after insults (hepatitis) if enough framework is intact
Liver Regneration biochemistry
TNF triggers Kuppfer cell to release IL-6, which triggers the priming of hepatocytes. In transition from G0 to G1, EGF, TGFalpha, and HGF trigger cell proliferagion
When do scars form?
if tissue injury is severe or chronic that results in damage to parenchymal cells and epithelia, as well as connective tissue; OR when non-dividing cells are injured
What is scar formation?
replacement of non-regenerated cells with connective tissue OR by a combo of regeneration and scar formation
Steps in Scar Formation
Angiogenesis; migration and proliferation of fibroblasts and deposition of CT; maturation and reorganization of fibrous tissue to produce scar
Granulation Tissue
Connective tissue in scar formation
Steps in Angiogenesis in scar formation
1) Vasodliation 2) separation of pericytes and breakdown of basement membrane 3) migration of endothelial cells toward area of injury 4) proliferation of endothelial cells just behind migratory cells 5) remodeling into capillary tubes 6) recruitment of periendothelial cells to form mature vessel 7) suppression of proliferation and migration and deposition of basement membrane
What triggers vasodilation in angiogenesis
VEGF in induces NO and increased permeability
Periendothelial Cells include
Pericytes and smooth muscle
Deposition of connective tissue
migration and proliferation of fibroblasts; deposition of ECM proteins
What induces deposition of CT in scar formation
cytokines and GFs inlcuding PDGF, FGF, TFG-beta from inflammatory cells (activated M2 macrophages)
TGF-Beta
most important cytokine for deposition of CT in scar formation
Remodeling of CT is dependent on…
balance between synthesis and degradation of ECM proteins
Degradation of collagen and ECM is accomplished by…
Matrix Metalloproteinases
where are MMPs produced?
lots of cell types (fibroblasts, macrophages, neutrophils)
What are the types of MMPs
interstitial collagenases, gelatinases, stromelysins
what factors influence tissue repair?
Nutritional deficiencies, metabolic diseases, vascular impairment; whether the inciting insult has been terminated or persists or whether a new insult is introduced (infection)
Nutritional Factors that influence tissue repair..
Protein deficiency, Vit C deficiency both impair collagen synthesis
Metabolic Factors that influence tissue repair..
Diabetes and glucocorticoids delay tissue repair
how do glucocorticoids affect tissue repair
inhibit TFG-beta production and dimish fibrosis
Vascular factors that influence tissue repair..
thrombosis, ateriosclerosis and atherosclerosis, venous drainage impairment all lead to ischemia
Hypertrophic scar
scar close to the boundaries of injury; increased collagen syntehsis; parallel collagen arrangement; regresses; infrequently recurs after resection
Keloid
lots and lots of disorganzed collagen, way outside of boundary of injury; Does not regress, recur following resection
pathologic scar
accumulation of excessive amounts of collagen
contracture
injury that occurs across a joint line
Repair sequence
1) vascular reaction - dilation and increased permeability 2) acute or chronic inflammatory phase 3) repair phase with collagen deposition, angiogenesis, and regeneration if possible
First intention healing
First: epithelial regeneration is principle mechanism
second intention healing
second: complex involving regeneration and scarring
Differences in first and second intention healing..
2: larger clot or scab rich in fibrin forms at surface of wound; inflammation crease more necrotic debris and exudate; larger defects require greater volume of granulation tissue to fill gaps to lead to greater mass of scar tissue
Wound Contraction
involved in secondary healing, attributed to myofibroblasts
composition of granulation tisue
fibroblast, new capillaries, loose eCM, inflammatory cells
sutured wound strength
70% normal strength
wound strength with suture removal
10%
Wound strength three months after suture removal
70-80%
Cell adaptations to stress
reversible changes in number, size, phenotype, metabolic activity or function in response to physiologic or pathologic changes
types of cell adaptations
hypertrophy, hyperplasia, atrophy, metaplasia
Hypertrophy
increase in size of cells to result in increase in size of organ due to functional demand or GF or hormone stimulation
Hyperplasia
increased number of cells; both physiologic or pathologic
Physiologic hyperplasia
hormonal: female breast or compensatory: liver regneration
Pathologic hyperplasia
due to excessive hormonal or GF stimulation (endometrial hyperplasia)
Atrophy
decrease/shrinkage in size and functional capacity of cell
Physiologic Atrophy
due to loss of hormone stimulation, decreased workload, aging
Pathologic atrophy
due to denervation or diminished blood supply
Mechanism of atrophy
decreased protein synthesis and increased protein degradation
Metaplasia
reversible change in which one differentiated cell type is replaced by another differentiated cell type
Metaplasia mechanism
cell type sensitive to stress is reaplaced by another cell type better able to withstand stress
Barret Esophagus
example of metaplasia - long standing acid reflux changes from squamous epithelium to intestinal type epithelium
Reversible Cell injury
recoverable if damaging stimulus is removed; injury has not progressed to severe membrane damage and nuclear dissolution
Irreversible cell injury
Cell death - necrosis, apoptosis
Reversible Injury - morphology
Cellular swelling, accumulation of fats, plasma membrane alterations, mitochondrial changes, dilation of ER and detachment of ribosomes, nuclear alterations
Cellular swelling
failure of energy dependent ion pumps in PM to disrupt ionic and fluid homeostasis
Fatty Changes in reversible cell injury
accumulation of lipid vacuoles within cytoplasm; increased entry and synthesis of FFA and decreased FA oxidation
Plasma membrane alterations with reversible injury
blebbing, blunting, distortion of microvilli, loosening intracellular attachments
myelin figures
seen in reversible injury - phospholipid masses derived from damaged cell membranes
Mito changes with reversible injury
swelling and phospholipid rich amorphous densities
Nuclear alterations with reversible injury
clumping of chormatin
Cell size in Necrosis and Apoptosis
Necrosis: enlarged
Apoptosis: shrinkage
Nucleus in Necrosis and Apoptosis
Karyolysis in Necrosis; fragmentation in apoptosis
Plasma membrane in Necrosis and Apoptosis
Necrosis: disrupted
Apoptosis: intact but with altered structure
Cellular contents in Necrosis and Apoptosis
Necrosis: enzymatic digestion that leaks out of cells
Apoptosis: are intact
Adjacent Inflammation in Necrosis and Apoptosis
Necrosis: frequent
Apoptosis: none
Physiologic or pathologic role in Necrosis and Apoptosis
necrosis: invariably pathologic (irreversible cell injury)
Apoptosis: physiologic - means of eliminating unwanted cells
Irreversible injury cellular morphology
Cytoplasmic Changes: increased eosinophilia and loos of RNA Basophilia Nuclear changes: breakdown of DNA and chromatin
Eosinophilia
increased binding of eosin to to denatured cytoplasmic proteins; increased pink stain
Pyknosis
nuclear shrinkage and increased basophilia (DNA condenses); condensed blue/purple nuclues
Karyorrhexis
pyknotic nulcues fragments
Karyolysis
dissolution of nucleus - breakdown of denatured ; basophilia of chromatin fades
Steps in nuclear changes
Pyknosis, karyorrhexis, karyolysis
Pattens of tissue necrosis
coagulative (gangrenous), liquefacative, caseous, fat, fibrinoid
Coagulative necrosis
Tissue architecture preserved for several days, pale ghost-like cells; most often seen due to infarcts
Liquefactive Necrosis
accumulation of inflammatory and leukocyte enzymes; due to focal bacteria and fungal infections hypoxia in CNS
Caseous Necrosis
necrotic appears as collection of fragmented of lysed cells and amorphous granular debris enclosed within inflammatory border
Fat Necrosis
fat destruction due to activated pancreatic lipases. Fats are hydrolyzed into FFAs that precipitate with calcium to make a chalk gray material
What causes fat necrosis
activation of pancreatic lipases following acute pancreatitis or trauma.
Fibroid Necrosis
antigens and antibodies are deposited on walls of arteries; immune complexes combine with fibrin to form bight pink amorphous appearance
Mechanism of Cell injuries
ATP depletion, mito damage, influx of Calcium, accumulation of reactive oxygen, increased permeability of membranes, accumulation of damaged DNA and misfolded proteins
ATP is generated by
ATP is made from oxidative phos, ADP in mito or glycolysis.
Low ATP leads to…
decreased action of NA pump —> influx of Ca, H20, Ka and efflux of K –> ER swelling; Increased lactic acid and decreased pH to nuclear clumping; detachment of ribosomes and decreased protein synthesis
Which wells are most susceptible to ischemic injury
Neurons (3-5 minutes)
Mitochondrial damage in cell injury
failure of oxidative phosphorylation –> ATP depletion, formation of ROS, formation of high conductance channels and loss of Membrane potential, release of proteins that activate apoptosis.
Dangers of the influx of calcium…
activation of cellular enzymes that lead to membrane damage and nuclear damage, decreased activity of ATPase that leads to increased mitochondrial permeability transition..
Accumulation of ROS is due to..
1) Redox reactions during mitochondrial respiration that lead to H2O2 and OH- radicals
2) phagocytic leukocytes (neutrophils and macrophages)
Consequence of Free Radicals…
increased production –> oxidative stress. (membrane damage, misfolding of proteins, mutations in DNA)
what converts O2- to H2O2?
SOD
Have decomposes H2O2?
glutathione peroxidase converts to H2O
what contributes to membrane damage?
phospholipid loss due to ROS, phospholipid reacylation and phospholipid degradation; lipid breakdown productions; cytoskeletal damage due to protease activation (intracellular Ca)
apoptotic bodies
membrane bound vesicles of cytosol and organelles
activation of apoptosis
Mitochondrial (intrinsic) and Death receptor (extrinsic)
Anti-apoptotic intrinsic pathway
BCL2, BCL-XL, MCL1
Pro apoptotic intrinsic pathway
Bax and Bak
Intrinsic Pathway of Apoptosis
BCL2 senses cell injury that acts on effectors to increase mito permeability to release cytochrome C and pro-apoptotic proteins which start a cascade to lead to endonuclease activation and breakdown.
Extrinsic Pathway of apoptosis
death receptor interacts with ligand to activate adaptor proteins and initiator and executioner caspase 8
Autophagy
process by which cell eats own contents
Intracellular accumulations result from..
inadequate removal, accumulation of abnormal endogenous substance, failure to degrade due to enzyme deficiencies, deposition and accumulation of abnormal exogenous substances.
Lipofuscin
wear and tear pigment that accumulates with age or atrophy. Marker of past free radical injury
Melanin
endogenous brown-black pigment synthesized by melanocytes in epidermis; finder lan lipofuscin
Hemosiderin
Hb bound granular pigments that accumulate when local or systemic excess of iron
Cholesterolosis
deposits of cholesterol in macrophages of gallbladder
Pathologic Calcification
abnormal deposition of calcium salts (with small amounts of iron, mg, and mierals)
Dystrophic calcification
occurs in dead/dying tissues; absence of derangements in Ca metabolism
Metastatic calcifications
occurs in normal tissue; derangement is calcium metabolism
Psammoma body
calcification - sign of increased degeneration and cell turn over.
Acute vs Chronic Inflammation - Onset
Acute: Fast - minutes/hours
Chronic: slow - days
Acute vs Chronic Inflammation - Cellular infiltrate
Acute: neutrophils
Chronic: monocytes/macrophages, lymphocytes
Acute vs Chronic Inflammation - tissue injury
Acute: mild and self limited
chronic: severe and progressive
Acute vs Chronic Inflammation - local and systemic signs
acute: prominent
Chronic: less, may be subtle.
Acute vs Chronic Inflammation - with innate vs. adaptive
acute: largely innate
chronic: involves both innate and adaptive in coordination
stimuli of acute inflammation
Infection; Trauma, Foreign material, immune reaction
what type of infections cause acute inflammation?
bacteria, virus, fungus, parasites; toxins from infectious organisms
The process of acute inflammation
1) receptor activation 2) vascular changes 3) leukocyte recruitment 4) leukocyte activation
Receptor Activation in acute inflammation
PRRs are triggered on PM (extracellular); endosomes (ingested) cytosol (intracellular)
what do TLRs do?
stimulate transcription factors to create mediators for inflammation, interferons for viral infections (in response to microbe infection)
what TFs do TLRs activate?
p28, JNK, NFkB
Inflammasome
mediate cellular response todead and damaged cells (some microbes)
what activates inflammasomes?
uric acid from DNA breakdown; ATP, decreased intracellular K from PM injury, DNA free in cytosol
Where are inflammasomes located?
cytosplasm
where are TLRs located?
PM and endosomes
result of inflammasome activation?
Activates caspase-1 which cleaves IL1Beta into active form