Cell injury and Degeneration

Disease at the cellular level

• Why do animals become sick or diseased?

• Sick cells result in sick animals

cellular dysfunction → organ dysfunction →

animal dysfunction
 Disease at the cellular level
• “Cellular Pathology”
– Rudolf Virchow (mid-19th century) – the father of
pathology
– “disease can not be understood unless it is realized
that the ultimate abnormality must lie in the cell”
– “pathology is physiology with obstacles”
– Created the terms:
• Thrombosis • Hypertrophy
• Leukemia • Amyloid
• Atrophy • Myelin
• Teratoma
 Cellular Responses to Stress
• The normal cell is confined to a fairly narrow range of function
and structure by:

– Genetic programs of metabolism, differentiation, and

specialization
– Constraints of neighboring cells
– Availability of metabolic substrates

• Normal cells handle normal physiologic demands and maintain

homeostasis (steady state)
 Cellular Responses to Stress
• More severe physiologic stresses and some pathologic
stimuli cause physiologic and morphologic cellular
adaptations

– Achieve new but altered steady states

– Preserve the viability of the cell
– Modulate function as cell responds to stimuli
 Cellular Responses to Stress
• If the limits of the adaptive response to a stimulus are
exceeded, or if a cell is exposed to an injurious agent or
stress → cellular injury results

• Cell injury is reversible to a certain point…

• If the stimulus persists or is severe enough from the

beginning, the cell reaches “the point of no return” and
suffers irreversible cell injury and cell death.
 Normal cells and adaptations
• Cells have specialized functions
– Specialized structures based on their functions

• All cells have certain “standard” organelles

– Synthesis of lipids, proteins, CHOs
– Energy production
– Transport of ions and other molecules
 Cellular adaptations
• Cells exist in a narrow physiochemical range of
conditions

• HOMEOSTASIS – tight control of pH, electrolyte

concentration, etc.

• Departure from homeostasis leads to cell “damage”

• Cells respond to homeostatic challenges by

“adaptation”

• Cell death results if a new level of homeostasis can not

be achieved
Stages in the cellular response to stress and injurious stimuli
 Examples of cellular adaptations
• Increase in muscle mass with exercise

• Increase in cytochrome p450 mixed function

oxidation expression in hepatocytes

• Cells respond (adapt) by either increasing or

decreasing content of organelles
Cellular Responses to Injury
 Cellular Adaptation
• Atrophy: reduction in mass of a tissue or organ

• Hypertrophy: increase in the size of cells, resulting

in enlargement of organs

• Hyperplasia: increased number of cells in an organ

or tissue

• Metaplasia: transformation or replacement of one

adult cell type with another (more on this in
neoplasia lectures)
 Cellular atrophy
•Atrophy – reduction in the mass
of a tissue or organ
•Loss of cells
•Reduction in the size of cells
within an organ

•Adaptive response to altered

demands
•Decreased workload
•Decreased nutrition
•Loss of hormonal stimulation
•Decreased blood supply
•Loss of innervation
 Cellular atrophy
• Reversible cellular change
• Reduced functional capacity
• Continue to control internal environment and produce
sufficient energy for metabolic state

• Example: adrenal cortical atrophy

– Corticosteroid tx inhibits ACTH
– Low ACTH → atrophy of adrenal cortex
– Sudden withdrawal of CS tx → “Addisonian crisis”
– Gradual withdrawal allows cells to return to normal function
 Cellular atrophy
• Prolonged cellular atrophy may lead to death of
some of the cells
– Loss of muscle cells with prolonged denervation

• Atrophy at the organ level may become

irreversible at this point (muscle) or may be
reversible by hyperplasia (liver)
 Cellular hypertrophy
• Hypertrophy –
Normal myocyte
increase in organ/cell Adaptation:
size response to
increased load
– At the organ level, Adapted myocyte
(hypertrophy)
hypertrophy increases
organ size without
cellular proliferation

• Hyperplasia –
increase in number of
cells in an organ
 Cellular hypertrophy
• Cell enlargement in hypertrophy is
different from cell swelling
• Signals are many:
– Increased protein content of cells
– Increased organelle number
• Myofibrils (muscle)
• Mitochondria
• ER
• Anabolic process > catabolic processes
 Cellular hypertrophy
•Liver – “Induction”
hypertrophy of SER
–Response to certain drug
administration
•phenobarbitol, alcohol
–Mixed function oxidases
•Metabolise compounds
•Increase water solubility to
allow excretion
 Cellular hypertrophy
• May not always be advantageous to animal
– Point of diminishing returns
– Heart
• Hypertrophy does not change underlying problem ( for
example valvular stenosis)
– Inability to provide adequate energy/contraction despite
hypertrophy
• Conformational changes associated with hypertrophy
– Decreased ejection volume
• May eventually and up with the organ failure despite
hypertrophy
 Cellular hypertrophy
• Liver – “Induction”
– Effect may be helpful or not helpful
• Tolerance to certain drugs/toxins
• More rapid removal of certain drugs/toxins
• May increase susceptibility to some toxins
– Metabolites may be more toxic than precursors
 Cell injury
• Definition: any change that results in loss of the ability
to maintain the normal or adapted homeostatic state

• At some point, a stimulus exceeds the cells ability to

adapt, and cell injury occurs

• Cell becomes unable to balance the processes that

regulate internal environment
– Morphologic changes that we recognize as cell injury or
degeneration
 Cell injury
• Extent of injury varies
– Severity of stimulus
– Type of cell involved
– Metabolic state at the time of injury

• Reversible or irreversible
– Reversible cell injury: denegeration
– Distinction between reversible cell injury (degeneration) and
cell adaptation may be unclear in some cases
 Morphology of injury
• Histologic slides represent a single time point
– May not be able to determine if a cell is getting
worse or getting better
– May not be able to determine whether the injury
would have been reversible or not, at any given time
point
• Morphologic changes lag behind functional
changes
Schematic of cell injury
 Hallmarks of cell degeneration:
Cellular accumulations
• Cell swelling**
• Fatty change**
• Glycogen accumulation**
• Lipofuscin and ceroid **
– oxidized product from membrane lipids
– yellow to brown
• Hyaline changes**
– Hyaline (adj) vs hyalin (n)
– Dense, homogenous, glossy, translucent
– Many causes (protein leakage most common)
 Hallmarks of cell degeneration:
Cellular accumulations
• Amyloid**
– A complex protein that accumulates within cells
– Homogenous, pink material
• Mucinous changes
– Gelatinous, semi-solid, slimy, clear, stringy
– Serous atrophy of fat
• Calcification**
– Abnormal accumulation of calcium salts in soft tissue
• Gout**
– Birds and reptiles
– Assoc. with renal disease due to ↓ excretion of urates
 Hallmarks of cell degeneration:
Cellular accumulations
• Cholesterol crystals
– Areas of previous hemorrhage or inflammation

• Inclusions
– Viral dz
– Intranuclear or intracytoplasmic
 Cell swelling
• Cell swelling
– Early, almost universal sign of injury
– Cells enlarged (loss of volume
control)
– Compress adjacent structures
• Loss of sinusoids in liver
– Altered staining characteristic
• Pale, cloudy appearance (cloudy
swelling, hydropic degeneration)
• Cytoplasmic vacuoles (vacuolar
degeneration)
– Distended organelles (ER)
– Lipid droplets
 Cell swelling
• Cell swelling
– Results from loss of control of ions/water with net
uptake of water
– Loss of energy control/production
– Not incompatible with life of the cell (depending on
severity) and is often mild and rapidly reversible
– Cell swelling also occurs in lethal injury
 Cell swelling
• Cell swelling
– Gross appearance
• Organ is often pale
• Enlarged, swollen
– Rounded margins
– Heavy
– Wet
• Bulges on cut surface
 Cell swelling
• Effect
– Varies by organ

– Brain: severe effects due to pressure necrosis

– Liver: decreased blood flow, decreased function
– Pharynx: airway obstruction
 Fatty change
• Fatty change
– Nothing to do with adipose tissue
– Accumulation of neutral fats (TG) in a cell
– Common change in injured cells
• Especially cells that metabolize lots of lipids
– Hepatocytes
– Myocardial cells
– Renal tubular epithelial cells
– Diabetes mellitus
– Sick cells tend to accumulate TG

– Gross appearance
• Yellow discoloration (kidney/liver)
• Enlarged (liver)
 Fatty change

Microscopic appearance:
Small to large, clear, non-membrane
bound, intracytoplasmic vacuoles,
nuclei pushed to cell periphery
 Fatty change
• Pathogenesis:
– Overload
• Increased mobilization of fats (anorexia)
• Diabetes mellitus
– Injury to cells
• Toxins, anoxia
– Deficiencies
• Methionine, choline

• Lipidosis
– Normal in young animals (milk diet)
– Normal following fatty meals
 Glycogen accumulation
• Glycogen is normally
found in cells, but
accumulates through
several pathogenic
mechanisms
– Severe prolonged
hyperglycemia
– Presence of high levels
Note: nuclei in center of
of glucocorticoids cells, rather than pushed to
– Lysosomal storage the periphery
diseases
 Glycogen accumulation
• Gross –
– Swollen organ
– Rounded margins (liver)
– Increased pallor

• MICRO –
– Enlarged cells
– Increased pallor
– No nuclear displacement
 Glycogen accumulation
• Pathogenesis
– Prolonged, severe hyperglycemia
• Diabetes mellitus
– Increased corticosteroids
• Cushing’s Syndrome
• Iatragenic
– Enzyme deficiencies
• Glycogen storage diseases
• Defects in a step of glycogen breakdown (glycogen
accumulated in the cell)
 Lipofuscin
• Pigment that collects
in cells
• Gross – brown
discoloration of
affected organs
• Micro – membrane
bound
(autophagosomes)
brown pigment.
– Myelin figures
 Hyaline change
• Catch-all phrase for solid, glossy,
semi-transparent material

• Hyaline droplets - cytoplasm

contains rounded, eosinophilic
droplets, vacuoles, or aggregates
• Hyaline casts – protein casts
within renal tubules
– Unabsorbed protein – morphologic
expression of proteinuria
• Connective tissue hyaline –
compacted collagen, scar tissue
 Amyloid
• Homogenous, amorphic,
eosinophilic
matrix/substance
deposited along basement
membranes and between
cells
• Gross
– Enlarged, pale, waxy,
translucent organ
 Calcification
• Abnormal deposition
of calcium salts
(usually calcium
phosphate or calcium
carbonate) in soft
tissues
• Gross:
– Chalky, white tissue
– Hard, gritty on cut
surface
 Calcification
• Micro:
– Dark blue staining
material
– Along BM
– Stippled throughout cell
– Large clumps
 Calcification
• Widespread excessive calcification is called
“calcinosis”
– Calcinosis circumscripta
– Calcinosis cutis
• When in cavities or lumina, the term
“calculi/calculus” is used
• Effect depends upon location
– Mechanical interference
 Gout
• Accumulation of urate
crystals
– “tophus/tophi”
– Gross:
• White, firm, crystal
deposites
– Micro:
• Granulomas with
radiating crystalline
material
 Gout
• Pathogenesis
– Disturbance of purine metabolism
– Vitamin A deficiency
– Kidney failure
• 2 forms – Avian
– Visceral – Reptiles
– Articular – Occasionally mammals
 Subcelluar morphology of injury
• Nuclear change
– Chromatin clumping
– Condensation (pyknosis)
– Dramatic nuclear change is usually indicative of necrosis
• Ultrastructural changes
– Plasma membrane
• Loss of surface features (microvilli, cilia)
• Desmosome breakdown
• “bleb formation”
– Mitochondria
• Swelling (may eventually rupture)
• Loss of dense granules
• Calcium deposits
 Subcelluar morphology of injury
• Ultrastructural changes
– ER
• Dilatation (contributes to vacuolar microscopic
appearance)
• Dissociation of ribosomes
– Phospholipids from damaged organelle membranes
accumulate to form “myelin figures”
– Lysosomes
• Dilation and rupture
• Usually a late event/terminal event in cell injury
 Subcelluar morphology of injury

Lysosomes packed with concentrically laminated, peroxidized,

autophagocytized cell membranes.
 Lethal injury and necrosis
• Irreversibly injured cells can exhibit all of the previous
changes
• Once death occurs, degradation begins
– Increased eosinophilia (altered proteins, loss of ribosomes,
decreased cytoplasmic RNA)
– Moth eaten cytoplasm
– Loss of cellular detail
– Nuclear changes
• Pyknosis
• Karyorhexis
• Karyolysis

Discussed further in necrosis lectures…

 B

Normal liver
Necrotic hepatocytes exhibiting
nuclear pyknosis (A)
and karyorrhexis (B)
 Pathogenesis of cell injury
• Numerous causes of cell damage (6 discussed following…)
• Oxygen deprivation
– Hypoxia
• Decreased blood oxygen supply
– Pulmonary/non-pulmonary
• Decreased blood flow
– Hypovolemia
– Vasoconstriction
– Cardiogenic
– Shock
– Ischemia
• Infarction
• Complete or almost complete loss of blood flow
 Pathogenesis of cell injury
• Physical agents
– Trauma
– Radiation
– Burns
• Chemical agents
– Huge variety
– Concentration, dose, length of exposure
– Variety of actions
• Injure cell membranes
• Interfere with metabolism
 Pathogenesis of cell injury
• Infectious agents
– Viruses, bacteria, protozoa, fungi
– Elaborate toxins
– Host inflammatory responses
• Nutritional imbalances
– Deficiencies
Fats, proteins, CHOs, vitamins
– Excesses
• Genetic defects
 Mechanisms of cell injury
• Cellular response depends upon:
– Type of injury
– Duration of injury
– Cell state at the time of injury
– Adaptability of the injured cell
• Exact point of injury may be difficult to
determine
 Mechanisms of cell injury (targets)
• 4 intracellular systems are particularly
vulnerable:
– Cell membrane
– Aerobic respiration (mitochondria)
– Protein synthesis (rough ER, ribosomes)
– Preservation of genetic integrity (nucleus)
• Injury at any of these leads to wide ranging
consequences and secondary effects
 Cell injury: Mechanisms
• Interfere with substrates or enzymes
– Most vulnerable systems are energy production
• Glycolysis
• Citric acid cycle (fleuroacetate)
• Oxidative phosphorylation (cyanide)
• Produce enzymes or molecules that degrade cell
components
– Most vulnerable component is membrane
• Phospholipases (Clostridium perfringens)
• Free radicals
 Cell injury: Common Pathway
• Injuries are variations on theme that lead to
injury and death, a “Common pathway”
– ATP depletion
• Oxidative phosphorylation of ADP to ATP
– Reduction of oxygen by electron transport chain in mitochondria
• Glycolytic pathway
– ATP from glucose in the absence of oxygent
» Lactate produced as a by-product
• Tissues vary greatly in their ability to utilize pathways
– Brain: almost no glycolysis
» Rapid anoxic injury and death (~4 min)
– Muscle: abundant glycolysis
• Frequent pathway in ischemic and toxic injuries
 Cell injury: Common Pathway
• Oxygen & Oxygen derived free radicals
– Partially reduced reactive oxygen species
• Damage proteins, lipids, nucleic acids
– Kept under control by scavenging systems
• “Dead end” molecules that absorb free radical energy
without passing it on
– Free radicals are “auto-catalytic”, especially in
membranes
 Cell injury: Common Pathway
• Intra-cellular Calcium/loss of Calcium homeostasis
– Normal cytosolic Ca maintained at low concentrations
• Mg/Ca ATP pumps
– Increased Calcium
• Increased membrane permeability
• Increased phospholipase activity
• Increased protease activity
• Increased ATPase activity
• Increased endonuclease activity
• Self destruction
– Activation of apoptotic pathways
 Cell injury: Common Pathway
• Defects in membrane permeability
– Plasma membrane
– Mitochondrial membrane
– Direct damage
• Perforin, complement (MAC), inflammation
– Indirect damage
• Calcium levels
• ATP depletion
 Cell injury: Common Pathway
• Irreversible mitochondrial damage
– Direct or indirect targets of virtually all cell injuries
– Damaged by toxins to hypoxia
• Increased Ca, Oxygen stress, degradation of
phospholipids
– Damage expressed as high conductance channel
formation (mitochondrial permeability transition)
• Prevents maintenance of the proton motive
force/membrane potential that runs the electron transport
chain
 Cell Injury: Mechanisms
• Ischemic/Hypoxic Injury
– Very common type of injury
– Hypoxia: decrease in oxygen to affected tissues
• Respiratory efficiency
• Cardiac function
• Tissue demand
• Blood flow remains
– Substrates for anaerobic metabolism delivered
– Glycolytic pathway can be used
» Maintenance of cell function (for awhile anyway)
» pH, lactate/lactic acid
 Cell Injury: Hypoxia/Ischemia
• Ischemia: loss of blood flow to affected tissues
– Hypovolemia
– Infarction
– Vasoconstriction
– Shock
– Loss of oxygen + loss of substrates
• Aerobic + anaerobic metabolism hit
– Rapid depletion of ATP
– Rapid loss of cell function
– Reversible to a point
• Eventually passes a “Point of no return”
– Cell can no longer resume energy production, even when given the necessary
substrates
– Variable cell to cell, tissue to tissue
 Cell Injury: Hypoxia/Ischemia
• Reperfusion injury: paradoxical increase in
death of cells after blood flow is restored
– GDV
– Stroke
– Myocardial infarction
 Cell Injury: Hypoxia/Ischemia
• Oxidative phosphorylation in the mitochondria
ATP depletion widespread cellular effects
– Na/K ATPase (sodium pump)
• Na accumulates in cell
• Water follows Na
• Cell swelling
– ADP, Phosphates, lactate
• Further cell swelling
 Cell Injury: Hypoxia/Ischemia
• Energy metabolism altered
– Glycolysis
• ATP + ADP glycolysis
– glycogen stores
– lactic acid
– ↑organic phosphates
– pH
 Cell Injury: Hypoxia/Ischemia
• Structural disruption of protein synthesis
– Detachment of ribosomes from RER
– Dissociation of polysomes into monosomes
• Functional consequences
– Heart muscle ceases to contract w/in 60 sec
– Neurons cease to fire or fire erratically
• Loss of consciousness
 Cell Injury: Hypoxia/Ischemia
• Continuing ATP depletion
– Cytoskeleton dispersal
• Loss of micro-villi
• Formation of “blebs”
– Swelling of mitochondria
– ER dilation
– More cell swelling
 Membrane damage
• Contributing factors
– Mito dysfunction
• ATP → Ca activation of mito phospholipases
accumulation of free fatty acids → change in membrane
permeability(mito permeability transition)
– Short circuits oxidative phosphorylation ↓ ATP
– Loss of membrane phosphlipids
• Activation of phospholipases
– ↓ membrane phospholipids
– Ca
 Membrane damage
• Contributing factors
– Reactive Oxygen species
• Free Radicals
• Return of blood flow →↑↑ free radicals
• Deactivate/denature enzymes
• Deactivate/denature membrane components
– Self propagating
– Lipid breakdown products
• Unesterified fatty acids, acyl carnitine, etc
– Detergent effect on membranes
– permeability of membranes
 Membrane damage
• Contributing factors
– Loss of intracellular amino acids
• Protective effect against free radical damage
• Loss of membrane integrity
– Ca into mitochondria
 Bottom Line:
• Hypoxia/ischemia affect oxidative
phosphorylation and cause decreased ATP.
Membrane damage is a critical step in the
movement of a cell from reversible to
irreversible damage. Ca is an important
mediator of biochemical and morphologic
alterations leading to cell death.
 Reperfusion Injury
• Restoration of blood
– Allow cells to recover (obvious)
– Cause death of cells that were otherwise not
irreversibly injured
• Variable numbers of cells may proceed to die
after blood flow is restored
– Significant event in heart attacks, strokes, GDV, and
other ischemic events
 Reperfusion Injury
• Mechanisms
– Free radical formation
• Incomplete reduction of oxygen by damaged
mitochondria
• Oxidases derived from leukocytes, endothelial cells, and
parenchymal cells
• Recruitment of inflammatory cells (neutrophils) by
damaged cells
– Neutrophils release free radicals, enzymes, etc.
– “Innocent bystander” damage
 Free Radicals
• Chemical species with an unpaired electron in
their outer orbit
• Reactive with adjacent molecules
– Proteins, lipids, carbs, nucleic acids
– Especially damaging to membranes
• Free radical induced membrane damage is autocatalytic
– Molecules with which free radicals react are themselves
converted to free radicals
– Reaction is self propagating
 Free Radicals
• Formation
– Absorption of radiant energy
• UV light, X-rays
– Metabolism of chemicals
• CCL4
– Byproduct of normal metabolism
• Normal respiration molecular oxygen is reduced sequentially to form water.
– Intermediates produced
» Superoxide anion radical O2-.
» Hydrogen peroxide H2O2
» Hydroxyl ions OH.
– Transition metals (Fe, Cu)
• Fenton reaction – greatly enhances oxidative cell damage
– Nitric Oxide (NO)
• Converted to peroxynitrite (ONOO-), NO2, NO3-
 Free Radicals
• Injurious effects
– Lipid peroxidation of membranes
• Initiated when double bonds of unsaturated fatty acids are
attacked – particularly by OH.
• Yields peroxides, which are reactive and yield more
peroxides (propagation)
• Reaction continues until a termination event occurs
– Free radical captured by a scavenger
» Vitamin E
– Oxidative modification of proteins
• Oxidation of amino acid side chains
• Protein-protein cross-links
• Oxidation of protein backbone protein fragmentation
• Enhanced degradation/turnover of critical proteins
 Free Radicals
• Injurious effects
– DNA lesions
• React with thymine to form cross-links
• Single stranded breaks
• Implicated in cell aging
• Implicated in malignant transformation of cells
 Free Radicals
• Protection: enzymatic and non-enzymatic
systems to inactivate free radicals
• Non-enzymatic
– Anti-oxidants
• Block formation or scavenge
• Vitamin E, vitamin A, ascorbic acid, glutathione
– Metal transport/storage proteins
• Bind to Fe, Cu to prevent them from participating in the
Fenton reaction
• Transferrin, ferritin, lactoferrin, ceruloplasmin
 Free Radicals
• Enzymatic
– Catalase (peroxisomes)
• H2O2 (2H2O2 O2 +2H2O)
– Superoxide dismutases (many cell types)
• H2O2 (2O2-. + 2H H2O2 + O2)
• Manganese superoxide dismutase (mito)
• Copper-Zinc superoxide dismutase (cytosol)
– Glutathione peroxidase
• (H2O2 + 2 GSH GSSG) –GSSG=glutathione homodimer
• 2OH. + 2 GSH GSSG + 2H2O
Free Radicals
 Free Radicals
• The final effects induced by free radicals is
dependant on the balance between free radical
formation and the cells defense systems that
scavenge or terminate free radicals.
 Chemical Injury
• Directly toxic compounds
– Capable of interacting with critical molecular
components or cellular organelles
• Mercuric chloride
– Binds to sulfhydril groups of cell membranes and proteins
– Inhibits ATPase dependent transport
» Increased membrane permeability
– Toxicity greatest in cells that absorb, excrete, or concentrate
(kidneys, intestine)
• Cyanide
– Mitochondrial cytochrome oxidase
– Blocks oxidative phosphorylation
• Chemotherapeutic agents
 Chemical Injury
• Indirectly toxic compounds
– Vast majority of toxins
– Converted to reactive toxic metabolites by mixed
function oxidases (P-450)
• SER of liver, lung, other organs
• Metabolites directly interact with cell membranes/proteins
– Less common
• Metabolites are/form free radicals
– Lipid peroxidation
– Membrane damage
– Most common
 Chemical Injury
• Carbon tetrachloride (CCl4)
– CCl4 CCl3. + Cl-
– Oxidation of fatty acids
• Autocatalytic reaction
• Acetaminophen (Tylenol)
– Sulfonation/glucuronidation in liver
– Small amount converted to highly reactive metabolite
• Normally detoxified (scavenged) by GSH (glutathion scavenger)
• GSH system can be overwhelmed
– Large amounts (overdose)
– Massive cell necrosis
 Bottom Line
• Chemical injury can be due to direct
interactions of injurious chemical with cells, but
is usually due to interaction of free radical
metabolites with membranes and proteins
 Irreversible cell injury
• Transition state between living and dead cell

• Exact “point of no return” is not possible to

identify

• Exact point of death is not possible to identify

Reversible vs. irreversible injury

u ry
e inj
ibl
ers
v
Re
 Reversible vs. irreversible injury

Stages in the evolution of cell Timing of biochemical

injury and death and morphologic
changes in cell injury
 Irreversible cell injury
• Morphologic hallmarks of
irreversible cell injury and death
– Severe mitochondrial swelling
– Large flocculent densities in mito
matrix
– Increased loss of proteins, enzymes,
co-enzymes
– Greatly increased membrane
permeability
• Leakage of enzymes (ALT, ALP, CPK,
etc.)
• Initiation of inflammation
 Irreversible cell injury
• Massive influx of Ca
into cell
• Made worse during
reperfusion
• Ca functions as 2nd
messenger
– Activates/deact various
enzymes
 Irreversible cell injury
• Lysosomal membrane permeability
– Leakage of lysosomal enzymes
– Activation of acid hydrolases (remember pH?)
• RNAse, DNAse, proteases, phosphatases, glucosidases,
cathepsins
– Digestion of cytosolic/membrane constituents
 Irreversible cell injury
• Mitochondrial
dysfunction and
membrane damage “1 –
2 punch”
• Membrane damage is the
central factor in
irreversible cell injury
On to necrosis…