Transcript Cell and Tissue Injury - Department of Pathology

Cell & Tissue Injury
School of Medicine, UCDHSC
Disease & Defense Block
February 5th, 2007
Francisco G. La Rosa, MD
Assistant Professor, Department of Pathology
University of Colorado at Denver Health Science Center, Denver, Colorado
Stages in the cellular response to stress and injurious stimuli
Principle # 1
• Human disease occurs because of
injury to cells / tissue
Principle # 2
• Most human disease results from injury
to epithelium
Principle # 3
• Injury to one tissue usually affects the
adjacent or underlying tissue as well
Principle # 4
• Cell injury produces morphologic changes
Visual changes in
the cell or tissue
morphology is seen
under microscopy
when cells are
stained.
Cell Injury
Damage or alteration of one or more cellular
components
1. Many types of injury are tissue-specific
because of anatomic relationships and
tissue tropism of chemical and
infectious agents.
2. Cell injury perturbs cell physiology;
the cell does not function at full
capacity
Consequences of Injury
1. No long term effects- - the cell damage is
repaired, the effects of the injury are
reversible.
2. The cell “adapts” to the damaging stimulus.
3. The cell dies, undergoing necrosis. The
damage is irreversible.
Cell Injury Produces:
1. Signs - abnormal physical findings Objective
2. Symptoms - complaints experienced
by the patient - Subjective
Basic Types of Tissues
1.
2.
3.
4.
Epithelium
Muscle (skeletal, smooth, cardiac)
Nerve (CNS, PNS)
Connective (bone, cartilage, soft
tissue, adventitia, ligaments, blood
and lymph, etc)
Epithelium:
Arises from each of three germ layers
1. Cells cover external surfaces (skin); line
internal closed cavities, secretory glands
and tubes (GI, respiratory, GU tracts) that
communicate with external surfaces
2. Liver, exocrine pancreas, parotid glands,
thyroid, parathyroid, kidney epithelium
3. Vascular endothelium and mesothelium
Adaptation to injury
1. Hypertrophy - an increase in the size of the cell
secondary to an increase in cell function.
Increase in the number of mitochondria and ER,
etc.
2. Hyperplasia - an increase in the number of cells
of a tissue in response to a stimulus or injury.
3. Metaplasia - replacement of one type of tissue
with another in response to an injury.
4. Atrophy - decrease in the size and functional
capacity of the cell.
Hypertrophy versus Necrosis
Physiologic hypertrophy of the uterus during pregnancy.
A, Gross appearance of a normal uterus (right) and a gravid uterus
(removed for postpartum bleeding) (left). B, Small spindle-shaped uterine
smooth muscle cells from a normal uterus (left) compared with large
plump cells in gravid uterus (right).
Changes in the expression of selected genes and
proteins during myocardial hypertrophy.
Metaplasia
Diagram of columnar to squamous metaplasia.
Metaplasia
Cell Atrophy, Causes
1.
2.
3.
4.
Loss of blood supply or innervations
Loss of endocrine factors (ex. TSH)
Decrease in the workload
Aging, chronic illness
A, Atrophy of the brain in an 82-year-old male with atherosclerotic disease. Note
that loss of brain substance narrows the gyri and widens the sulci.
B, Normal brain of a 36-year-old male.
Outcomes from cell injury depend upon:
1.
2.
3.
4.
Type of injury
Severity of the injury
Duration of the injury
Type of cell being injured- Some cell
types sustain injury better than others;
some tissues (e.g. liver) have a
capacity to regenerate
Reversible Cell Injury
1. Cell swelling – usually accompanies all
types of injury. Results from an increase
in water permeability. Reverses once
membrane function is restored
2. Increase in extracellular metabolite -Because of a biochemical derangement.
i.e.: Increase in extracellular glycogen in
diabetes
Reversible Cell Injury …
3. Fatty change in liver. Vacuoles of fat
accumulate within the liver cell following
many types of injury: alcohol intoxication,
chronic illness, diabetes mellitus, etc.
This may be due to:
• An increase in entry of free fatty acids
• An increase in synthesis of free fatty acids
• A decrease in fatty acid oxidation
Vulnerable Sites of the Cell
1.
2.
3.
4.
Cell membranes
Mitochondria
Endoplasmic reticulum
Nucleus
Cell Membranes
why so easily injured?
1. Membrane is in contact with the external
environment:
- sustains “trauma”
- extracellular oxidants, proteases, etc.
2. Requires a constant supply of ATP for
normal function (ion pumps)
3. Lipid molecules in the membrane are
easily oxidized and support oxidative
chain reaction called lipid peroxidation
Cell Membrane
Injury
Epithelial cell proximal kidney tubule
A. Normal
B. Reversible ischemic changes
C. Irreversible ischemic changes
Mitochondrial dysfunction in cell injury.
Mitochondrial Injury
Endoplasmic Reticulum Injury
Chaperones, such as heat shock proteins (Hsp), protect unfolded or partially
folded protein from degradation and guide proteins into organelles.
Cell Death
• Apoptosis
• Necrosis
Apoptosis
Agarose gel electrophoresis of
DNA extracted from culture cells
A. Control
B. Exposed to heat
C. Massive necrosis
Morphology of Necrosis
Pyknosis
• Shrunken nucleus with dark staining
• Seen in a necrotic (dead) cell
Karyorrhexis
• Fragmentation of pyknotic nucleus
Karyolysis
• Extensive hydrolysis of pyknotic nucleus
with loss of staining
• Represents breakdown of the denatured
chromatin
Karyolysis
Coagulative Necrosis
• Dead cells remain as ghost-like remnants
of their former self
• Classically seen in an MI
Liquefactive Necrosis
• The dead cell undergoes extensive
autolysis, caused by the release of
lysosomal hydrolases (proteinases,
DNases, RNases, lipases, etc.)
• Seen classically in the spleen and
brain following infarction
Liquefactive Necrosis
(A) Coagulative vs. (B) Liquefactive Necrosis
Caseous Necrosis
(caseum - cheesy)
• Resembles cottage cheese
• Soft, friable, whitish-grey
• Present within infected tissues
• Seen in Tuberculosis
(Mycobacterium tuberculosis)
Caseous Necrosis
Caseous Necrosis
Fat Necrosis
•Leakage of lipases from dead cells attack
triglycerides in surrounding fat tissue and
generate free fatty acids and calcium
soaps
•These soaps have a chalky-white
appearance
•Seen in the pancreas following acute
inflammation
Causes of Cell and
Tissue Injury
Causes of Cell and Tissue Injury
1.
2.
3.
4.
5.
6.
Physical agents
Chemicals and drugs
Infectious pathogens
Immunologic reactions
Genetic mutations
Nutritional imbalances
Causes of Cell and Tissue Injury …
7. Hypoxia and Ischemiacell injury resulting from inadequate
levels of oxygen.
Causes:
A. Inadequate blood supply
B. Lung disease
C. Heart failure
D. Shock
Hypoxia and IschemiaWhy So Important?
All cells in the body require a
continuous supply of oxygen in order
to produce ATP via oxidative
phosphorylation in mitochondria.
ATP is absolutely critical for life.
Susceptibility of specific cells
to ischemic injury
• Neurons: 3 to 5 min.
• Cardiac myocytes, hepatocytes, renal
epithelium: 30 min. to 2 hr.
• Cells of soft tissue, skin, skeletal
muscle: many hours
Functional and morphologic consequences of decreased intracellular ATP
during cell injury.
Hypoxic Injury
Reversible Changes
1. Decrease in extracellular ATP levels
2. Decrease in the Na pump: cell swelling
3. Increase in glycolysis, with a decrease
in intracellular pH
4. Decrease in protein synthesis
Hypoxic Injury
Irreversible Changes
1. Activation of lysosomal enzymes:
lysosomal enzymes are active at low
pH, ca. pH 4-5
2. Degradation of DNA and protein
3. Influx of Ca++, which activates many
lipases and proteases
Problem
Ischemia Reperfusion
Oxygen free radicals produce severe
injury to cellular membranes,
proteins, RNA and DNA.
Hypoxic cells are exposed to
damage from oxygen radicals
Hypoxic cells are exposed to
damage from oxygen radicals
1. Hypoxic patients are given high
levels of oxygen. This oxygen is
toxic to the cells lining the alveolar
spaces in the lung because the
high [02] produces oxygen radicals
Hypoxic cells are exposed to
damage from oxygen radicals
2. Hypoxic tissues are often infiltrated
with PMNs, which have enzymes &
myleoperoxidases producing activated
oxygen
Hypoxic cells are exposed to
damage from oxygen radicals
3. Hypoxic tissues are often reperfused
once the blood supply is restored.
Xanthine oxidase, produced from
proteolysis during hypoxia, generates
free radicals when the 02 is brought
back to normal levels.
GOOD / BAD REACTION
SOD
02- + 02- + 2H+
H202 + 02
BAD REACTIONS
1. H202
++
2. FE
H. + 0H.
+ H202
FE
(very reactive)
+++
0H.
+
+ 0H
FENTON REACTION
3. H202 +
02
0H.
HABER-WEISS REACTION
-
-
+ 0H + 02
GOOD REACTIONS
1. 2 H202
02 + 2H20
GLUTATHIONE PEROXIDASE
2. 2 0H. + 2 GSH
H202 + 2 GSH
2 H20 + GSSG
2 H20 + GSSG
BURNS
Burns, Outcomes
Depend upon:
1. Total surface area burned
2. Depth of burn injury- partial vs
full thickness
3. Whether lungs were injured
4. Whether treatment was prompt
Complications
1.
2.
3.
4.
Neurogenic shock, fluid loss
Infection-Pseudomonas, Staph
Hypermetabolic state
Anemia
Exertional Heat Stroke
1. Hot, dry skin
2. Usually lactic acidosis
3. May lead to ATN, DIC, multi organ failure
Classic Heat Stroke
1. Hot, dry skin
2. No lactic acidosis, but respiratory
alkalosis
3. May lead to hypotension, coma, ATN,
DIC very uncommon
Hypothermic Injury
1. May lead to coma, death. Metabolism
in brain is inadequate.
2. Freezing of cells. This causes local
concentrations of salt to markedly
increase.
3. Poor perfusion of tissuesvasoconstriction, increased
viscosity of blood.
The toes were involved in a frostbite injury. This is an example of "dry"
gangrene in which there is mainly coagulative necrosis from the anoxic
injury.
Electrical Injury
• Death from lightening occurs from heat
production, disruption of neural, cardiac
nerve transmission, cell damage from
electroporation of salts across cell
membranes
• Death can occur from household levels of AC
current, esp. if the skin is wet, or from
respiratory arrest from tetany of chest
muscles
Summary
• All human disease occur because of
cell/tissue injury
• Membranes-outer and mitochondrial are
key targets
• Many early steps are reversible
• Cell death follows going beyond a point
of no return -drop in pH, rise in Ca2+