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144 Cards in this Set
- Front
- Back
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free radical induced cellular injury - DNA fragmentation |
free radicals react with thiamine in nuclear and mRNA to produce single strand breaks |
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free radical induced cellular injury - protein cross-linking |
-free radicals promote sulfhydryl-mediated protein cross-linking -this results in increased degradation or loss of activity |
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CHEMICAL MEDIATORS OF INFLAMMATION
preformed mediators |
-found in secretory granules
-histamine (from mast cells/basophils/plt) -serotonin (from platelets) -lysosomal enzymes (from neut/macro) |
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CHEMICAL MEDIATORS OF INFLAMMATION
newly synthesised |
-prostaglandins (leucocytes, platelets) -leukotrienes (leucocytes) -platelet activating factors (leucoytes) -nitric oxide (macrophages) -cytokines (lymphocytes / macrophages) -activated oxygen species (leucocytes) |
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list 5 mechanisms of increased vascular permeability in inflammation |
-gaps due to endothelial contraction (vasoactive mediators, common) -direct injury (fast, short lived, e.g. tox/burn) -leucocyte-dependent injury (long lived) -increased transcytosis (VEGF) -angiogenesis (persists until intercellular junctions form) |
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what is a complement system? |
system made of plasma-derived proteins that are present as inactive forms are activated to become proteins that cleave other complement proteins amplifying the cascade - these ultimately help antibodies/phagocytes clear pathogens |
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how many complement systems are there? |
9 |
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overview of complement pathways |
CLASSICAL - antibody:antigen binding
ALTERNATIVE - microbe surface molecules
LECTIN BINDING - lectin binds microbe |
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what is Decay Accelerating Factor? |
-protein that is encoded by CD55 gene -regulates complement system on cell surface -recognises C4b and C3b fragments that are created during C4 and C3 activation -can interfere with cascades to block formation of the membrane attack complex |
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ACUTE INFLAMMATION
serous inflammation |
outpouring of thin fluid derived from plasma or secretions of mesothelial cells lining the pleural and pericardial cavities
e.g. effusion/blister |
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ACUTE INFLAMMATION
fibrinous inflammation |
severe injuries or cancer cause increased vascular permeability allowing fibrinogen to pass the vascular barrier -> fibrin formation and deposition in the extracellular space
e.g. fibrinous pericarditis |
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ACUTE INFLAMMATION
suppurative inflammation |
neutrophils, necrotic cells and oedema produces pus - localised suppuration
e.g. pyogenic bacteria - staphylococcus e.g. acute appendicitis |
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ACUTE INFLAMMATION
ulcers |
local defect of surface of organ/tissue produced by sloughing/shedding of inflammatory necrotic tissue |
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OUTCOMES OF ACUTE INFLAMMATION
resolution of acute inflammation |
clearance of injurious stimulus clearance of mediators & inflammatory cells replacement of injured cells normal function |
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OUTCOMES OF ACUTE INFLAMMATION
fibrosis |
can come from - vascular changes - pus formation/abscess -> healing - resolution of chronic inflammation
causes loss of function |
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features of chronic inflammation (3) |
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overview of chronic inflammation |
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causes of chronic inflammation (4) |
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define granulomatous inflammation |
pattern of chronic inflammation characterised by focal accumulations of activated macrophages which often develop and epithelioid appearance |
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infectious examples of granulomatous inflammation |
-TB (caseating) -leprosy -syphillis -cat scratch disease -schistomiasis egg emboli |
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non-infectious examples of granulomatous inflammation |
-silica -sarcoidosis (non caseating/necrotising) |
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what is a granuloma |
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TB in granulomatous disease |
-IFN gamma, activated from T-cells causes macrophage activation -> transformation to epithelioid and giant cells (granuloma)
-the granuloma is called a tubercle and typically exhibits caseous necrosis with central amorphous debris and loss of cellular detail |
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leucocytes in the acute phase response |
-initially due to accelerated release of cells from bone marrow caused by IL1 and TNF -causes increase in immature neutrophils i.e. a left shift -prolonged infection causes proliferation of precursors in the bone marrow, caused by increased production of colony stimulating factors (CSFs) |
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acute phase response and acute phase proteins |
-increased production of C-REACTIVE PROTEIN and FIBRINOGEN -CRP is synthesised by the liver |
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acute phase response and fever |
-exogenous pyrogens (endotoxins) stimulate leucocytes to release cytokines such as IL1 and TNF i.e. endogenous pyrogens -these release cyclooxygenases that convert a.a. into prostaglandinds -in hypothalamus, PGs stimulate production of NTs such as cAMP, which function to set temperature set-point at higher level |
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chemotaxis in acute inflammation |
-chemotaxis is movement down a chemical gradient
-EXOGENOUS; bacterial products
-ENDOGENOUS; cyclosporine, arachydonic acid derivatives, cytokines (IL8)
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what does activation of the alternative, classical and lectin pathway lead to? |
cleavage of C3 into C3B and C3A |
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C3A activation |
-C5a and C3a inflammation
-recruitment and activation of leucocytes
-destruction of microbes by leucocytes |
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effects of C3b activation |
deposition of C3b on microbe causes:
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macrophage activation in chronic inflammation |
macrophages are activated by cytokines from immune-activated T-CELLS e.g. IFN-gamma (a cytokine) or by non-immune activation e.g. endotoxin, fibronectin, chemical mediators |
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activated macrophage products that cause tissue injury (6) |
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activated macrophage products that cause fibrosis (4) |
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sequence of events in acute inflammation (6) |
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dystrophic calcium deposition |
'abnormal tissue, normal calcium'
-found in areas of necrosis -ageing or damaged heart valves -TB -intra/extra-cellular crystals (apatite) with continued deposition in layers called a psammoma body |
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process of irreversible cell death |
-influx of calcium -lipid breakdown -> cell mb destruction
MORPHOLOGY; incr swelling, nuclear changes
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pyknosis |
condensation of chromatin in dying cell nucleus |
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karyohexis |
fragmentation of nucleus |
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karyolysis |
dissolution of cell nucleus into cytoplasm |
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fat necrosis |
-not a specific form of necrosis -focal fat destruction -seen in pancreatitis where lipase breaks down adipose and can combine with calcium to form soap i.e. saponification |
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caseous necrosis |
-seen in tuberculosis -type of coagulative necrosis that differs from the usual in that tissue architecture is completely destroyed -amorphous granular debris encloses in an inflammatory border (granuloma) giving a cheese-like appearance |
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liquefactive necrosis |
-dead cells are digested into thick liquid mass i.e. pus/exudate in infection
e.g. bacterial/fungal infection, hypoxic CNS injury
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coagulative necrosis |
-caused by hypoxic cell injury -acidosis denatures proteins & lysosomal enzymes -> blocks proteolysis of damaged cells -basic cell outline preserved for 1/52 -cell eventually phagocytosed by inward movement of WCC in inflammatory reaction -heals by scar formation e.g. gangrene (wet also has liquefacive necrosis) |
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what is an ischaemic reperfusion injury |
restoration of flow can return function of reversibly injured cells but also damage or kills cells that are still alive |
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mechanism of ischaemic reperfusion injury |
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cellular effects of NECROSIS (size, plasma membrane, cellular contents, adjacent inflammation, nucleus) |
SIZE; increased swelling PLASMA MB; disrupted CELL CONTENTS: ezymatic digestion may leak from cell ADJACENT INFLAMMATION: frequent NUCLEUS: pyknosis/karhyohexis/karyolysis
irreversibly pathological |
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cellular effects of APOPTOSIS (size, plasma membrane, cellular contents, adjacent inflammation, nucleus) |
SIZE: shrinkage PLASMA MB: disrupted CELL CONTENTS: intact with altered structure ADJACENT INFLAMMATION: no NUCLEUS: fragments
often physiological, may be pathological after cellular injury or DNA damage |
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define cellular injury |
-any process or event that disrupts a cell's homeostasis -results from functional and biochemical abnormalities in one or more of several essential cellular components
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process of cellular injury overview |
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hyperplasia |
-increased number/proliferation of cells -common preneoplastic response to stimulus -physiological response to specific stimulus and cells remain subject to normal regulatory control mechanisms
e.g. BPH/cushings/endometrial/breast/intimal |
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hypertrophy |
-increase in cell size -can cause increase in volume of organ or tissue due to enlargement of component cells -caused by mechanical signals e.g. stretch -caused by trophic signals e.g. growth factors
PHYSIOLOGICAL: skeletal muscle PATHOLOGICAL: LVH in hypertension |
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atrophy, with phys/path examples |
-decrease in cell size -can cause entire organ to decrease in size
PHYSIOLOGICAL - thymus atrophy during early human development
PATHOLOGICAL - skeletal muscle atrophy/diffuse atrophy
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metaplasia |
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definitions of hypoxia and ischaemia |
BOTH ARE STATES OF OXYGEN DEPRIVATION
hypoxia - decreased O2 supply
ischaemia - lack of blood flow; i.e. decreased O2 supply and substrate
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mechanisms of cellular injury |
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reversible cell injury cascade |
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morphology of reversible cell injury |
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cellular response to increased demand/trophic stimulation |
hyperplasia/hypertrophy |
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cellular response to decreased nutrients/trophic stimulation |
atrophy |
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cellular response to chronic chemical or physical irritation |
metaplasia |
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cellular response to decrease in oxygen supply, chemical injury or infection |
acute/self limited; acute reversible injury
progressive & severe; irreversible injury -> cell death
mild chronic injury; organelle alterations |
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cellular response to genetic or acquired metabolic changes |
intracellular accumulations and calcification |
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cellular response to prolonged life span with cumulative sub lethal injury |
cellular ageing |
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metastatic calcium deposition |
'normal tissue, abnormal calcium caused by hypercalcaemia'
accumulates in kydneys, lung, gastric mucosa, systemic arteries, pulmonary veins as these environments lose acid to become alkali - predisposing to calcium deposition
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metastatic calcium deposition causes |
-increased parathyroid hormone
-destruction of bone tissue
-renal failure
-vitamin D-related causes e.g. vit D intoxication and sarcoidosis causing hypercalcaemia |
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what are free radicals |
chemical species with single unpaired electron in outer orbit
they are chemically unstable and react with other molecules, causing chemical damage
initiate autocatalytic reactions; molecules that react with free radicals are converted into free radicals |
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intracellular sources of free radicals |
-redox reactions generate free radicals -nitric oxide (NO) can act as a free radical -ionising radiation (UV/XR) can hydrolyse water into hydroxyl (OH) and hydrogen (H) free radicals -metabolism of exogenous chemicals such as CCl4 can generate free radicals -free radical generation is a 'physiological' antimicrobial reaction |
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mechanisms of neutralisation of free radicals (6) |
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free-radical cellular injury - lipid peroxidation of membranes |
double bonds in the polyunsaturated membrane lipids are vulnerable to attack by oxygen free radicals |
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role of histamine in acute inflammation |
-histamine is a vasoactive amine that causes vasodilation and increased permeability
-platelet activating factor (PAF) is a phospholipid-derived mediator produced by mast cells which leads to platelet aggregation, vasodilation, bronchospasm and leucocyte activation |
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where is histamine found |
MAST CELLS - released by physical trauma, IgE immune reaction, complement C5A/C3A, cytokines (TNF/IL-1)
BASOPHILS
PLATELET GRANULES - collagen, thrombin, ADP, Ag/Ab, platelet activating factor
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what is a kinin |
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what are interleukin-1 and TNFα? |
-Interleukin-1 is a family of 11 cytokines -TNFα is a cytokine -they are activated by macrophages -chemotactic -involved in acute phase reactions and endothelial activation -they are endogenous pyrogens |
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endothelial effects of cytokines |
-increased leucocyte adherence, prostacyclin (PGI2) synthesis, procoagulant |
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effects of cytokines on fibroblasts |
-fibroblast proliferaation -increased collagen synthesis -increased PGE synthesis |
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how do leucocytes affect cytokines |
affect cytokine secretion and priming |
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features of acute phase response |
-pyrexia -somnolence -anorexia -neutrophilia -CRP rise -SIRS |
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CHEMICAL MEDIATORS OF INFLAMMATION
factor XII (Hageman Factor) activation |
-hageman factor is plasma protein produced by liver -part of coagulation cascade -activates factor XI and prekallikrein in vitro -active hageman factor = XIIa -initiates activation of kinin, complement and clotting/fibrinolysis systems
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bradykinin and role in inflammation |
-formed by cleavage of kininogen cleaved by kallikrein to BRADYKININ
EFFECTS -smooth muscle contraction -arteriolar dilation -increased venular permeability -pain |
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cytokine and inflammation overview |
-cytokines are proteins produced by activated lymphocytes and macrophages that modulate function of other cell types
-major cytokines involved in inflammation are TNF and IL1
-stimulated by bacterial products, immunoglobulins and toxins |
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CELL CYCLE - prophase |
chromatin condensation |
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CELL CYCLE - metaphase |
chromomomes align along metaphase plate |
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CELL CYCLE - anaphase |
chromosomes break at centromeres and sister chromiatids move to opposite poles of cell |
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CELL CYCLE - telophase |
daughter nuclei form and nuclear envelopes form around each nucleus |
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CELL CYCLE - cytokinesis |
cytoplasm of single eukaryotic cell is divided to form two daughter cells |
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CELL CYCLE - G2 (gap 2) interphase |
G2 checkpoint control mechanism ensures everything is ready to enter mitosis phase and divide |
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CELL CYCLE REGULATION
cyclin-dependent protein kinase |
CDKs are enzymes that phosphorylate to signal that a cell is ready to enter the next stage of the cell cycle
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CELL CYCLE REGULATION
cyclins |
-undergo constant cycle of synthesis/degradation during cell division
-bind to cyclin-dependent protein kinases to form cyclin-CDK complex
-this signals cell to continue cell cycle |
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CELL CYCLE REGULATION
G1 cyclins |
-bind to cyclin-dependent kinase proteins during G1
-signal exit from G1 and entry to the S phase |
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CELL CYCLE REGULATION
mitotic cyclins |
-accumulate during G2
-bind to CDKs to form mitosis promoting factor
-signals G2 cell to enter mitosis |
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collagen VI |
site; ubiquitous in microfibrils
disorder: Bethlem myopathy |
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collagen VII |
site: anchoring fibrils at dermal-epidermal junctions
disorder: dystrophic epidermolysis bullosa |
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collagen IX |
site; cartilage & intervertebral discs
disorder; multiple epiphyseal dysplasias |
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collagen XVII |
site; transmembrane collagen in epidermal cells
disorder; generalised atrophic benign epidermolysis bullosa |
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collagen XV |
site; endostatin-forming collagens
disorder; knobloch syndrome |
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collagen XVIII |
site; endothelial cells |
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CELL CYCLE
mitosis |
-cell division -cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells -the metaphase checkpoint in the middle of mitosis ensures the cell is ready to divide -eukaryotic cell separates chromosomes in its cell nucleus into two identical sets in two nuclei -mitosis and cytokinesis define mitotic phase |
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CHEMICAL MEDIATORS OF INFLAMMATION
complement activation |
-complement is found in plasma, made by liver
-ANAPHYLATOXINS - C3a &C5b
-BINDS TO MICROBIAL CELL SURFACE - C3b
-MEMBRANE ATTACK COMPLEX - C5B6-9 |
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CELL CYCLE
synthesis - interphase |
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CELL CYCLE
G1 (GAP 1) - interphase |
-cells increase in size (growth phase) -G1 checkpoint controls mechanism -first stage of interphase -biosynthetic activities of cell markedly increase -amino acids used to form proteins and enzymes -required for S phase -duration variable -under control of p53 gene |
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INTRACELLULAR COMMUNICATIONS
5 types |
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INTRACELLULAR COMMUNICATIONS
fatty change
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steatosis
abnormal accumulation of triglycerides within parenchymal cells
causes; toxins, malnutrition, DM, BMI+, anoxia
e.g. liver, heart, SkM, kidneys |
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INTRACELLULAR COMMUNICATIONS
cholesterol and cholesterol esters |
phagocytic cells overloaded with lipid in pathological processes
e.g. atherosclerosis |
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INTRACELLULAR COMMUNICATIONS
proteins |
excess influx to cells or cells produce excess of protein
e.g. nephrotic syndrome, alcoholic hyaline |
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INTRACELLULAR COMMUNICATIONS
glycogen |
abnormality in metabolism of glucose/glycogen
e.g. DM (renal/cardiac/islet cells) e.g. glycogen storage diseases |
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INTRACELLULAR COMMUNICATIONS
pigments |
COAL DUST; carbon -> anthracosis
LIPOFUSCIN; lipid/pro from free radical peroxidation of subcellular mb lipids. Marker of free radical injury = brown atrophy
MELANIN; freckles
HAEMOSIDERIN; local systemic iron excess |
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CELL CYCLE
G0 Gap 0/quiescence |
-G0 is a resting phase where the cell has left cycle and stopped dividing -a.k.a. post mitotic or senescent cells -cells can remain G0 for long periods of time and even indefinitely -cellular senescence can occur in response to DNA damage or degradation that would make a cell's progeny unviable -some cells enter G0 semi-permanently (liver/kidney) -some cells do not enter G0 (epithelial cells) |
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4 mechanisms of intracellular accumulations |
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stimuli causing inflammation (6) |
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PRIMARY WOUND HEALING
week 4 |
scar comprises cellular tissue devoid of inflammatory infiltrate, covered by epidermis
tensile strength increases but can take months to obtain maximal strength |
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PRIMARY WOUND HEALING
week 2 |
continued accumulation of collagen and proliferation of fibroblasts
leucocyte infiltration/oedema/increased vascularity disappears
regression of blood vessels |
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PRIMARY WOUND HEALING
day 5-7 |
incisional space filled with granulation tissue
maximal neovascularisation
collagen fibrils more abundant and begin to bridge the incision
epidermis recovers its normal thickness |
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PRIMARY WOUND HEALING
day 3-5 |
neutrophils replaced by macrophages
granulation tissue invades incisional space
collagen fibrils deposit at margin - fibres are vertically oriented and do not bridge incision
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PRIMARY WOUND HEALING
24-48h |
epithelial cells from edges migrate and move along margins
epithelial cells deposit membrane components
epithelial cells fuse in midline beneath surface scab to form thin epithelial layer |
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PRIMARY WOUND HEALING
first 24h |
neutrophils present at margins moving toward the fibrin clot
epidermis at cut edges thickens due to basal cell mitosis |
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PRIMARY WOUND HEALING
immediately following incision |
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wound healing by second intention overview |
occurs with extensive cell or tissue loss e.g. skin and regeneration of parenchymal cells cannot restore original cell architecture
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wound healing by secondary intention process |
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7 steps of wound healing |
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GROWTH FACTORS & CYTOKINES IN WOUND HEALING
monocyte chemotaxis |
platelet derived growth factor
tumour growth factor beta |
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GROWTH FACTORS & CYTOKINES IN WOUND HEALING
fibroblast migration |
platelet derived growth factor
tumour growth factor beta
tumour necrosis factor
IL-1 |
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GROWTH FACTORS & CYTOKINES IN WOUND HEALING
fibroblast proliferation
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platelet derived growth factor
tumour necrosis factor |
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GROWTH FACTORS & CYTOKINES IN WOUND HEALING
angiogenesis |
vascular endothelial growth factor |
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GROWTH FACTORS & CYTOKINES IN WOUND HEALING
collagen synthesis |
platelet derived growth factor
tumour growth factor beta |
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GROWTH FACTORS & CYTOKINES IN WOUND HEALING
collagenase secretion |
platelet derived growth factor
tumour necrosis factor
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SCARS
1. migration and proliferation |
migration & proliferation of fibroblasts to the site of injury
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SCARS
2. deposition of ECM |
fibroblasts progressively deposit increasing amounts of extracellular matrix
net collagen accumulation is also dependent on decreased degradation |
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SCARS
3. tissue remodelling |
tissue remodelling
balance between ECM synthesis and degradation results in remodelling of the connective tissue framework |
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angiogenesis from endothelial precursor cells |
angioblast-like cells called endothelial precursor cells are stored in bone marrow and can be recruited to initiate angiogenesis |
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angiogenesis from pre-existing vessels |
-vasodilation in response to NO & VEGF-induced decreased permeability -proteolytic degradation of basement mb of parent vessel -migration of endothelial cells toward angiogenic stumulus -proliferation of endothelial cells -maturation of endothelial cells including inhibition of growth and remodelling into capillary tubules -recruitment of peritendothelial cells to support endotheloial tubes and form mature vessel |
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healing vs regeneration |
REGENERATION is growth of cells/tissues to reduce lost structures, requires intact connective tissue scaffold
HEALING can have variable proportions, regeneration & scar formation. Healing w/ scar formation occurs if ECM framework damaged |
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CHRONIC INFLAMMATION
growth factors |
-activation of macrophages and lymphoctes due to persistent stimulus
-growth factors PDGF, FGF, TGFß
-causes proliferation of fibroblasts, endothelial cells and fibrogenic cells -increased collagen synthesis -> FIBROSIS |
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CHRONIC INFLAMMATION
cytokines
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-activation of macrophages and lymphoctes due to persistent stimulus
-cytokines TNF, IL-1, IL-4, IL-13
-increased collagen synthesis -> FIBROSIS |
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CHRONIC INFLAMMATION
decreased metalloproteinase activity
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-activation of macrophages and lymphocytes due to persistent stimulus
-decreased collagen degradation ->FIBROSIS
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COMPLICATIONS OF CUTANEOUS WOUND HEALING
deficient scar formation |
wound dehiscence due to mechanical stress e.g. midline laparotomy dehiscence
ulceration due to poor circulation or sensation e.g. diabetic or vascular ulcer |
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COMPLICATIONS OF CUTANEOUS WOUND HEALING
excessive formation of repair components |
hypertrophic excess collagen formation
keloids go beyond original wound boundaries
exuberant granuloma - resectable w/o recurr.
desmoids - granuloma that cannot be resected |
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COMPLICATIONS OF CUTANEOUS WOUND HEALING
contractures |
exaggeration of normal wound contraction leading to joint immobility
especially soles, anterior chest wall, ACF
common after burns |
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factors delaying wound healing mnemonic
DID NOT HEAL |
Drugs / Infection/Ischaemia / Diabetes
Nutrition / Oxygen / Toxins
Hypothermia/Hyperthermia EtOH Acidosis Local anaesthetic |
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collagen I |
ubiquitous in hard/soft tissues
disorder; osteogenesis imperfecta, EDS |
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collagen II |
found in cartilage, vitreous humour and intervertebral discs
disorder; achondrogenesis type II, spondyloepithelial dysplasias |
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collagen III |
found in hollow organs, soft tissues
disorder; vascular EDS |
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collagen V |
found in soft tissues & blood vessels
disorder; classical EDS |
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collagen IX |
found in cartilage & vitreous humour
disorder; strickler syndrome |
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basement membrane collagen IV and deficiency |
IV present in BM
deficient in alport syndrome |
