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
IL1-beta
recruits luekocytes to come in and clean up dead cells (activated by inflammasomes)
Gout
urate crystals that stimulate IL1-Beta
Vascular Changes in Acte Inflammation
increase blood flow and permeability to bring cells and materials for response to injury or threat
Rubor
Redness - due to increased blood flow that causes congested capillary beds
Erythema
redness
Calor
warmth, due to increased blood flow
Tumor
increase permeability causing exudate of fluid into tissues and swelling
what dilates in vascular changes in acute inflam?
arterioles - so they flood the capillaries with blood.
Histamine - acute inflam
acts on smooth muscle cells of arterioles to cause vasodilation
Permeability in Acute inflammation
1) endothelial cells contract due to mediators 2) endothelial injury 3) transcytosis
This is done in the post-capillary venules
endothelial cell contraction mediators in acute inflammation
Early: histamine, bradykinin
Later: IL1, TNF
Transcytosis
material transported through cells in vesicles
Exudate vs transudate- common cause
Ex: due to vascular permeability
Trans: increased hydrostatic or decreased osmotic pressure
Exudate vs transudate- protein content
Ex: increased
trans: decreased
Exudate vs transudate- cell content
Ex: increased inflammation, RBC
Trans: few cells
Exudate vs transudate- Specific gravity
Ex: high
Trans: low
Exudate
results form increased vascular permeability due to inflammation. Causes cells and proteins in extracellular environment
Transudate
due altered intravascular pressure; filters just the fluid. (increased capillary pressure, decreased blood protein)
Leukocyte Recruitment
1)migration/rolling 2) adhesion 3) transmigration 4) chemotaxis
Margination
vasodilation slows blood flow in post-capillary venule, causing larger/slower moving luekocytes into periphery.
Stasis
thicker and slower blood due to leakage into interstitial space; gives things more opportunity to contact.
Rolling
stimulated endothelial cells express Selectins which have affinity for sugars on leukocyte surface
What stimulates P-selectin?
Histamine
what stimulates E selectin
IL-1
Adhesion (acute inflammation)
chemokines signal specific area of luekocytes to act.
Integrins are activated on leukocyte surface and Cellular adhesion molecules are on endothelial cells
Integrins
cell surface structures on leukocytes that are activated in adhesion – CD11 and CD18
What triggers cell adhesion molecules in adhesion step of acute inflammation?
IL-1 and TNF
Leukocyte adhesion deficiency
AR, defective integrin CD18; delayed sep of umbilical cord, increased circulating neutrophils; recurrent bacterial infection
Transmigration
Leukocytes squeeze between endothelial cells in post-capilary venules and cells secrete collagenase
Diapedesis
when leukocytes squeees between endothelial cells
Collagenase
breaks up basement membrane in transmigration
Chemotaxis
leukocytes move toward inflammation following chemical gradient.
Chemotatic agents
endogenous and exogenous - bacterial products, cytokines, C5b, Arachidonic acid metabolites.
Activation of leukocytes in acute inflammation
Phagocytosis, killing/degrade engulfed material, secrete material to kill; produce inflammatory mediators
Phagocytosis in Activation - acute inflammation
1) recognition of particle to leukocyte (receptors for microbes, necrotic cells, opsonins) 2) engulfment and formation of vacule 3) killing of vauolated material
Destruction of Phagocytosed material - acute inflam
Done by HOCl strong radical, NO, and lysosomal enzymes (elastase, lysozymes)
NADPH oxidase
converts O2 into O2-
SOD
converts O2- into H2O2
What converts H2O2 into HOCl
myeloperoxidase
Secretion of compounds for degradation - acute inflammation
enzymes or antimicrobial proteins; Neutrophil extracellular traps
Neutrophil extracellular traps
nuclear chromatin is imbedded with antimicrobial material and extruded to trap microbes.
Outcomes of Acute Inflammation
Resolution; chronic Inflammation; scarring
Resolution of acute inflammation
injured tissue can regenerate due to minimal tissue injury
when does acute inflammation turn into chronic
offending agent is not removed; often results in scarring or resolution.
Stimuli of Chronic inflammation
Persistent infection; immune mediated disease; prolonged exposure to toxins
Immune mediated diseases that cause chronic inflammation
autoimmune, allergic disease
Endogenous substances that cause chronic inflammation
atherosclerosis, cancer
Steps in Chronic Inflammation?
1) mononuclear cell infiltrate 2)tissue destruction 3) repair: neovascularization and fibrosis
Mononuclear cell infiltrate in chronic inflammation
lymphocytes and monocytes circulate and give rise to macrophages that infiltrate into tissues to ingest microbes and debris, initiate tissue repair and secrete inflammatory mediators.
Classical Activation - what activates these
M1-
endotoxins, IFNgamma (T-cell cytokine), foreign material
Classical Activation -what do these macrophages produce?
ROS, NO, lysozymal enzymes, proinflammatory cytokines
Classical Activation - function of macrophages
killing microbes, chronic inflammation
Alternative activation - activation of macrophages
IL-4, IL-13 (t cells, eosinophils, mast cells)
Alternative activation - what does these macrophages produce?
growth factors for new vessels and fibroblast activation
Alternative activation - function of macrophages
tissue repair and fibrosis
Players in chronic inflammation
Lymphocytes, eosinophils, mast cells
Lymphocytes in Chronic Inflammation
CD4+ T cells secrete cytokines to promote inflammation.
Th1 CD4+ secretes…
IFN-gamma to activate classical macrophage pathway
Th2 CD4+ secretes…
IL-4, IL-5, IL-13 to activate alternative
Th17 CH4+ secretes
IL-17 to recruit neutrophils and monocytes
Eosinophils in chronic inflammation
T cell secrete eoxtaxin.
Most notable in parasite infection and allergic reactions with IgE.
Mast cells in chronic inflammation
quickly release inflammatory mediates (histamine and AA); coated with IgE to trigger mediated release; known for anaphylactic reactions
Granulmatous Inflammation
Enlarged marcophages form a nodule that is composed of epitheloid histiocyte that is surrounded by lymphocytes; forms capsule to prevent spread
What disease are characteristic of granulomatous inflammation?
TB, leprosy, fungi, crohn’s disease, sarcoidosis
Systemic effects of inflammation
Fever, Acute phase proteins in blood,
Fever
due to increased COX activity in perivascular cells of hypothalamus to increase PGE2 to raise temp.
Endogenous pyrogens
IL-1, TNF
Acute phase proteins in blood - systemic effects of inflammation
AL-6 cuases hepatocytes to increase protein secretion that can be used to monitor inflammation process
What are the acute phase blood proteins?
C-Reactive proteins, Serum Amyloid A; Fibrinogens
Serum Amyloid A
adheres to cell walls and act as opsonins
Fibrinogen
binds to blood cells and causes them to form stacks that sediment – erythrocyte sedimentation rate
what triggers leukocyte release from bone marrow
TNF and IL-1 - leukocytosis
Left shift in leukocytosis
increase in number of immature WBCs
Colony Stimulating Factors in chronic inflammation
In continue inflammation, increase bone marrow production of leukocytes
Neutrophilia is due to…
bacterial infection
Lymphocytosis is due to..
viral infections
eosinophilia is due to..
asthma, parasite infection
Leukopenia is due to..
decreased luekocytes, specific infections (typhoid)
Hydrostatic Pressure
increase pressure on arterial end to push fluid outside of capillaries. Increased due to high blood pressure that can lead to fluid build up.
Osmotic Pressure
is the pull of the fluid back into veins due to high protein content in vasculature. Drop in osmotic: due to liver disease with lack of albumin; block in lymphatics, vessel wall damage
what causes extravasation of fluid into tissues?
Increased capillary hydrostatic pressure, decreases plasma osmotic pressure, increase vascular permeability; exceeds capacity for lymphatic drainage.
Edema
fluid buildup in tissue;
Effusion
Fluid build up in spaces
Transudate results from..
increased Hydrostatic pressure, reduced oncotic pressure
Exudate results from..
increased vascular permeability: inflammation and direct damage to endothelial cells
Specific Gravity of transudate vs exudate?
Tran is low = less than 1; exudate is higher = greater than 1
Total protein conc. in transudate vs. exudate
Trans: 3.0 g/dL
Protein fluid/serum ratio in transudate/exudate
0.5 for exudate
Glucose Fluid/Serum ratio in transudate and exudate
> 0.5 in transudate;
why is glucose higher in transudate than exudate?
you have bacteria and other things to metabolize glucose in the fluid outside of the vessel
WBC count in transudate vs. exudate?
Trans: non for few
Exudate: many
Hyperemia
Arteriolar dilation; physiological reasoning to bring more oxygenated or nutritional blood to area.
Hyperemia occurs during
exercise and inflammation
Congestion
Outflow obstruction in venous end; backs up into capilaries and arterioles. deoxygenated blood gets suck and causes ischemia in adjacent tissues.
What causes congestion?
local obstruction, congestive heart failure
appearance of hyperemia vs congestion?
hyperemia: red
Congestion: dark/purple color
what causes pulmonary edema and plural effusion?
Left heart failure (fluid buildup in lungs)
what does decreased blood flow out of heart from left ventricular failure lead to?
decreased blood flow to kidney.
Decreased renal blood flow..
compensates by holding onto Na and H20, which increases volume of dilute blood. This causes fluid to leak out and causes peripheral edema.
Right heart failure leads to..
back up in venous system –> liver congestion, splenic congestion, GI varices.
Ascites
fluid in the abdomen, when cirrosal surface starts moving fluid into abdominal cavity due to right heart failure.
Hemorrhage
blood outside of vasculature due to vessel damage, low level/function of platelets; low level/function of coagulation factors
how are small breaks in blood vessels repaired?
small clots form on the surface to cover damage, but does not block flow and vessels.
Petechiae
hemorrahge 1-2 mm in size; very small due to ineffective platelet and clotting factors
Pupura
> 3 mm hemorrhage
Ecchymoses
1-2 cm hemorrhage; usually resembles a bruise
Hematoma
large blood collection within tissue
Thrombosis (three factors)
Endothelial lining, abnormal blood flow; hypercoagulability
Thrombosis is most common in what age group?
elderly because of accumulation of epithelial damage - hypercholesteremia, diabetes, athersclerosis
Factor V leiden
mutation that makes them prothrombotic; usually occurs as young adults
Formation of a thrombis
layering of platelets and fibrin mesh. Usually it stops after a few layers that do not obstruct flow; but if out of control, thrombosis does not stop accordingly.
Lines of Zahn
lines of platelets and RBC in throbis
Post-morten thrombis
not layered and thick, because blood is not flowing.
Abnormal blood flow in thrombosis causes.
Stasis (atrial fibrilation, bed rest) turbulance (atherosclerosis, vessel narrowing)
Hypercoagulability in thrombosis - causes
inherited (factor V leiden); acquired (disseminated cancer)
Thromboembolus
Most due to immobility. But also due to estrogen, pregnancy, previous or current cancer, coagulation abnormalities, limb trauma or orthopedic procedures, obesity.
Laminar flow
large things flowing in center and small particles move towards edge.
what does stasis do to laminar flow?
decreases it, and platlets and WBC move towards endothelium and stick and bind –> fluid build up, congestion, edema.
how does estrogen promote emboli
pushes liver to make more coagulants and less anticoagulants.
Pulmonary Embolus stymptoms
chest pain, poor flow to area of lung, decreased oxygenation, lung infarction
Recanalization
process of long term thrombus. that sometimes breaks down to left fluid leak through.
Embolus in venous system
Thromboemboli, fat/bone marrow, amniotic fluid, tumor
Embolus in Arteriole system
Thromboemboli, arteroemboli
why do emboli form in venous over arteriole?
flow is too fast in arteriole, mostly forms due to atherosclerosis
DIC
Disseminated Intravascular Coagulation
Thrombosis and hemorrhage can occur simultaneously
DIC - pathology
an underlying condition that promotes widespread damage leads to systemic activation of coagulation which leads to widespread fibrin deposition and thrombosis. But as you use all your platelets and coagulants, you start bleeding in new areas.
DIC symptoms
Respiratory insufficiency, MSC, convulsions, acute renal failure, petechiae/purpura, GI and oral hemorrhage, Shock
Causes of DIC
hemolytic anemia, thrombocytopenia, low fibrinogen, elevated D-dimer, and other fibrin degradation produces
Infarction
tissue death (necrosis) caused by vessel occlusion. most often coagulative and liqueficative in brain.
White Infarction
due to arterial insuffidicney, single blood supply, no reperfusion, often in dense tissue like heart, kidney, spleen.
Red Infarction
block of blood flow temporarily, or in tissue with multiple sources of blood flow. Due to venous insuffidiency, dual bloodflow, yes to repurfusion, loose tissue in lung, liver, intestine.
Shock
circulating blood volume or BP is not adequae to perfuse body tissues –> muliorgan damage.
Cardiogenic shock
myocardial pump failure; caues myocardial damage, extrinsic compression, outflow obstruction
Hypovolemic shock
low blood volume due to severe dehydration, hemorrhage, bruns
Pathophysiology of shock
low cardiac output, low BP leads to vasoconstriction, increased DR, renal conservation of fluid –> coolness, pallor, tachycardia, low urine output
SIRS
system inflammatory response syndrome
SubsetL septic Shock: due to microbial infection.
SIRS pathophysiology
Elevated inflammatory mediators leads to fever, DIC, , acute respiratory distress
Arterial vasodilation, vascular leakage, venous blood pooling
arterial vasodilation leads to
hypotension, warm, flushed skin
Vascular leakage leads to..
hypotension, edema
Venous blood pooling leads to..
reduced cardiac output, increased HR
Is septic shock responsive to IV fluids
NO!
what inflammatory mediators are Vasoactive Amines?
Histamine and Serotonin
Synthesis of Vasoactive Amines
Storage in cells, ready for quick release
Effects of Histamine - basic
Arterial dilation, endothelial contraction
What cell types is histamine release from?
Mast cells, basophils, platelets
how is histamine released?
Mast cells release them based on physical features, immune binding to IgE, complement (C3a and C5a), releasing proteins, neuropeptides, cytokines
what complement factors cause histamine release?
C3a and C5a
What cytokines cause histamine release?
IL-1 and IL-8
How is histamine inactivated?
histaminase
Is histamine plasma or cell derived?
Cell
Serotonin basic effects
Vasoconstriction to aid in clotting
Source of serotonin
platelet granules
Is serotonin plasma or cell derived?
Cell
What inflammatory mediators are Arachidonic Acid Metabolites?
Prostaglandin, Thromboxane, leukotriene, lipoxin
synthesis of arachidonic Acid metabolites?
From cell membrane phospholipids; from cyclooxyrgenase and lioxygenase
Cycoloxygenase Pathway produces…
produces prostalandins and thromboxanes
Lipoxygnase pathway produces…
Leukotrienes and lipoxins
Basic effects of Arachidonic Acid?
inflammation and homeostasis
Arachidonic acids are released from
leukocytes, mast cells, enothelium, platelets
How do arachidonic acid metaboites let inactivated?
spontaneous decay and enzymes
prostaglandin is produced by what pathway?
cyclogyogenase from Arachidonic acid metabolites in many sites throughout the body
What are the basic effects of prostaglandin?
Pain, Fever, vasodilation, increased vascular permeability, inhibit clotting
how are prostaglandins inactivated?
NSAIDs, croticosteroids, COx2 selective
what does corticosteroids inhibit?
phospholipase A2 in prostaglandin syntehsis
Thronboxane synthesis pathway
cycooxygenase pathway: prostaglandin H2 to thromboxane
Thromboxane basic effects
vasoconstriction, promotes platelet aggregation
how is thromboxane inhibited?
COX inhibitors, naproxen, synthase inhibitors
Leukotriene sythesis
lioxygenase pathway
Leukotriene basic effects
bronchospasm, chemotactic for neutrophils, increase vascular permeability
LTB4
Leukotriene that is chemotactic for neutrophils
LTC4, LTD4, LTE4
leukotrienes to increase vascular permeability
Lipoxin sythesis
lipoxygenase pathway generated as leukocytes enter tissue
Lipoxin basic effects
inhibit neutrophils adhesion and chemotaxis; antagonize leukotrienes
which arachidonic acid inflammatory mediator is anti-inflammatory?
lipoxin
Platelet Activating Factor Sythesis
Phospholipase A2 leaves lipids from cell membranes
Platelet Activating Factor Storage
continuously produced at low quantity, regulated by enzymes
Platelet activating factor effects
platelet activation, aggregation, vasodilation, vascular permeability, bronchoconstriction, stimulation of platelets to produce mediators
Tumor Necrosis Factor
A cytokine
what are major cytokines?
TNF, IL-1, Chemokines (CXC, CC)
synthesis of cytokines
stimulated by microbes, immune complex, T-mediators
TNF Effects
endothelial activation, leukocyte binding and recruitment, Systemic effects: fever, acute phase protein synthesis
IL-1 effects
endothelial activation, leukocyte binding and recruitment Systemic effects: fever, acute phase protein synthesis
IL-1
Cytokine, very similar to TNF
TNF and IL-1 is produced from
macrophages, mast cells, endothelial cells
Are cytokines pro or anti-inflammatory?
all are pro inflammatory except IL-10
Chemokines
CXC and CC
Chemokine Effect
Chemotaxis, activation of leukocytes
Chemokines are produced from…
macrophages, mast cell, endothelial cells
CXC
chemokine, chemotactic for neutrophils
CC
chemokine, chemotactic for a variety of cells
Eotaxin
Chemokine, chemotactic for Eosinophils
Chronic Cytokines
INF-gamma, IL-12
INF-gamma
Cytokine, classical macrophage activation
IL-12
cytokine, growth/function of T-cells
Reactive oxygen radicals types
superoxide radical, hydroxyl radical, hypochlorous radical
How are reactive oxygen radicals synthesized?
NAPDH oxidase pathway using NADPH oxidase, SAD, myeloperoxidase
Effects of Oxygen Radicals
Damage microbes and host tissues
what cells produced oxygen radicals
activated neutrophils
what inhibit/deactivated oxygen radicals
endogenous antioxidants (superoxide dimutase)
Nitric Oxide
Reactive oxygen sepecies produced from Nitric oxide synthase and L-arginine
NO - effect
kill microbes, vasodilation, antagonizes platelet activation, reduces leukocyte recruitment
NO is produced by…
Type II macrophages and endothelial cells produced by IL-1, INFgamma, and bacterial endotoxins.
Lysosomal Enzyme inflammatory Mediators
Azuorphil specific gelatinous Secretary granules
Azurophil speicic gelatinase secretory granules effect
kill microbe and ingest digested material with acid proteases and neutral proteases
Acid proteases
produced by lysosomal enzymes that are active within phagolysosomes at low pH
Neutral proteases
produced by lysosomal enzymes that are active outside of cell in neutral pH (collagenase)
Substance P category
Neuropeptide inflammatory mediator
Where is Substance P released from?
nerves and inflammatory cells (macrophages, eosinophils, lymphocytes, dendritic cells)
Substance P effects
initiation inflammation, vascular tone, permeability. Active in lung and GI, binds to neurokinin-1 receptor to generage proinflammatory effect in immune and epithelial cells
Complement synthesis
inactive molecules in circulation that are activated and produce proeolysis. C3 converts converts C3 to C3a to C3b. C3b activates C5 converts to initiate MAC. Classical, alternative, lectin
Complement effects
inflammation, immunity, increased vascular permeability and release of histamine, leukocyte activation, opsonin
what complement proteins cause leukocyte activation?
C5a, C4a, and C3a
What complement has opsonin properties?
C3b
What cells produce complement?
Hepatocytes, tissue macrophages, monocytes, epithelial cells
What inhibits complement pathway
C1-inhibitor and Decay-Accelerating factor and Factor H
C1-inhibitor
blocks activation of C1
Decay-Accelerating factor and Factor H
limit C3 and C5 convertase formation
Factor XII
a coagulation/kinin
Hageman factor
Factor XII
Coagulation/kinin inflammatory mediators
Factor XII (hageman) Factor Xa, Thrombin
Hageman factor effect
activated kinin sytem, clotting factor, leads to bradykinin and increased vascular permeability, dilation and pain.
Positive feedback in Hageman factor
Kallikrein is chemotactic and activates Factor XII
Factor Xa effects
increased vascular permeability
Thrombin effect
activates protease activated receptor on Endothelial cells, cleaves fibrinogen to increase finrinopeptides that increase vascular permeability and are chemotactic, cleaves factor 5 into 5a
Thrombin
Factor IIa
Fibrinolytic Sytem
inflammatory mediators that result in vascular permeability, dilation, and C3a formation
Anti-Inflammatory Mediators
Destruction of circulating pro-inflammatory, lipoxins, complement regulatory, IL-10 to down regulate activated macrophages, TGF-Beta, intracellular compounds that antagonize pro-inflammatory cell states.
IL-10
secreted by macrophages to down regulate activated macrophages - anti-inflammatory
