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Cell Injury & Adaptation for Pre_AMS 2011(1)

Cell Injury & Adaptation for Pre_AMS 2011(1)

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Sections

  • The Cell and the Environment
  • Causes of Cell Injury
  • General Principles of Cell Injury
  • Cellular Adaptation to Injury
  • Atrophy
  • PhysiologicCauses of Atrophy
  • Pathologic Causes of atrophy
  • Mechanism of Atrophy
  • Brain Atrophy
  • Renal Atrophy
  • Hypertrophy
  • Causes of Hypertrophy
  • Gingival Hypertrophy
  • Hyperplasia
  • Physiologic Hyperplasia
  • Pathologic Hyperplasia
  • Benign Prostatic Hyperplasia
  • Endometrial Hyperplasia
  • Metaplasia
  • Pathologic calcification
  • Pathologic Calcification
  • Intracellular Accumulations
  • Fatty Changes (Steatosis)
  • Liver Fatty Change (Steatosis)
  • Free Radical-Induced Cell Injury
  • Morphology of Necrosis
  • Nuclear Changes
  • Morphological Types of Necrosis
  • Liquefactive Necrosis
  • Necrosis
  • Gangrenous Necrosis
  • Caseous Necrosis
  • Fat Necrosis
  • Fate of Necrotic Tissue
  • Physiologic Apoptosis
  • Apoptosis
  • Bcl-2 Family of Proteins

CELL INJUHY, CELL INJUHY

,
ADAPTATION, AND DEATH ADAPTATION, AND DEATH
Abdulmohsen Alkushi, MD, MSc, FRCPC
Associate ProIessor and Consultant Pathologist
!,944 !,944
W t is the bridge between clinical practice and basic
science.
W Study oI:
underlying causes oI diseases (etiology)
Mechanisms oI diseases (pathogenesis)
Structural and Iunctional changes in cells, tissue, and
organs (morphology, clinical Ieatures, and
complications).
Molecular bases oI diseases.
W eneral and systemic pathology.
%he Cell and the Environment
W Adaptive Responses
Atrophy
Hypertrophy
Hyperplasia
Metaplasia
W Cell niury
Reversible
rreversible
W rreversible Cell
niury:
Necrosis
Apoptosis
Adaptive Responses
rreversible Cell niury
Causes oI Cell niury
W Hypoxia
W Physical Agents
W Chemicals and Drugs
W Microbiologic Agents
W mmunologic Reactions
W enetic DeIects
W Nutritional mbalances
W Aging
eneral Principles oI Cell niury
W %he cellular response to iniurious stimuli depends on:
W the type oI iniury, its duration, and its severity.
W %he consequences oI cell iniury depend on:
W the type, state, and adaptability oI the iniured cell.
W Cellular Iunction is lost Iar beIore cell death occur, and
morphologic changes oI cell iniury lag behind both.
Cellular Adaptation to niury
W Atrophy
W Hypertrophy
W Hyperplasia
W Metaplasia
Atrophy
W DeIinition:
Shrinkage in the size oI the cell by loss oI cell
substance.
When a suIIicient number oI cells are involved,
the entire tissue or organ diminishes in size or
becomes atrophic.
i.e decrease the size oI an organ due to decrease
the size oI its cells
W Atrophy can be physiologic or pathologic.
Physiologic Causes oI Atrophy
W Physiologic atrophy is common during early
development. Some embryonic structures,
such as the notocord or thyroglossal duct,
undergo atrophy during Ietal development.
W %he uterus decreases in size shortly aIter
parturition.
Pathologic Causes oI atrophy
W Decreased workload (disuse atrophy).
W oss oI innervation (denervation atrophy).
W Diminished blood supply (ischemia).
W nadequate nutrition e.g. proIound protein-calorie
malnutrition (marasmus).
W oss oI endocrine stimulation.
W Aging (senile atrophy).
W Pressure atrophy.
Mechanism oI Atrophy
W Atrophy represents a reduction in the structural
components oI the cell. n muscle, the cells
contain Iewer mitochondria and myoIilaments and
a lesser amount oI endoplasmic reticulum.
W %he biochemical mechanisms responsible Ior
atrophy are incompletely understood but are likely
to aIIect the balance between protein synthesis and
degradation.
rain Atrophy
rain Atrophy
Renal Atrophy
Hypertrophy
W Hypertrophy reIers to an increase in the size oI
cells and, with such change, an increase in the size
oI the organ. %hus, the hypertrophied organ has no
new cells, iust larger cells.
W n simple: increase the size oI an organ due to
increase the size oI its cells.
W Hypertrophy can be physiologic or pathologic.
Causes oI Hypertrophy
W Physiologic hypertrophy:
%he massive physiologic growth oI the uterus
during pregnancy.
hypertrophy oI the breasts during lactation.
Skeletal muscular enlargement in athletes.
W Pathologic hypertrophy:
Cardiac enlargement due to hypertension or
Iaulty heart valves
Hypertrophy
Normal
ingival Hypertrophy
Hyperplasia
W Hyperplasia constitutes an increase in the number oI cells
in an organ or tissue, which may then have increased
volume.
W n simple: increase the size oI an organ due to increase the
number oI its cells.
W Hyperplasia and hypertrophy are Irequently both occur
together.
W Hyperplasia can be physiologic or pathologic.
Physiologic Hyperplasia
W Hormonal hyperplasia, examples:
proliIeration oI the glandular epithelium oI the
Iemale breast at puberty and during pregnancy
physiologic hyperplasia that occurs in the
pregnant uterus
W Compensatory hyperplasia, example,
the hyperplasia that occurs when a portion oI
the liver is removed (partial hepatectomy).
Pathologic Hyperplasia
W Endometrial hyperplasia.
W Skin warts.
W Prostatic hyperplasia
enign Prostatic Hyperplasia
Endometrial Hyperplasia
Metaplasia
W Metaplasia is a reversible change in which
one adult cell type (epithelial or
mesenchymal) is replaced by another adult
cell type.
Epithelial Metaplasia
W %he most common epithelial metaplasia is
columnar to squamous epithelium:
as occurs in the respiratory tract in response to chronic
irritation, in smokers.
Stones in the excretory ducts oI the salivary glands,
pancreas, or bile ducts may cause replacement oI the
normal secretory columnar epithelium by stratiIied
squamous epithelium.
A deIiciency oI vitamin A induces squamous
metaplasia in the respiratory epithelium.
Uterine cervical metaplasia during reproductive age.
Epithelial Metaplasia
W Metaplasia Irom squamous to columnar:
as in arrett oesophagus, in which the squamous
esophageal epithelium is replaced by intestinal-like
columnar cells.
W Epithelial metaplasia is a two-edged sword and, in
most circumstances, represents an undesirable
change.
W t may induce, iI persistent, cancer transIormation
in metaplastic epithelium.
Metaplasia
Pathologic calciIication
W Pathologic calciIication means abnormal
deposition oI calcium salts in tissues.
Pathologic CalciIication
W %here are two Iorms oI pathologic
calciIication:
Dystrophic calciIication:
W deposition occurs in nonviable or dying tissues, and
it occurs with normal serum levels oI calcium and in
the absence oI derangements in calcium metabolism.
Metastatic calciIication:
W deposition oI calcium salts in vital tissues, and it
almost always associated with some disturbance in
calcium metabolism, leading to hypercalcemia.
ntracellular Accumulations
W ntracellular accumulation oI abnormal amounts oI
various substances, this may be harmless or may
cause cell iniury.
W substances Iall into three categories:
(1) a normal cellular constituent accumulated in excess,
such as water, lipid, protein, and carbohydrates.
(2) an abnormal substance, either exogenous, such as a
mineral or products oI inIectious agents, or
endogenous, such as a product oI abnormal synthesis or
metabolism.
(3) a pigment such as melanin.
Fatty Changes (Steatosis)
W t means an abnormal accumulations oI
triglycerides within parenchymal cells.
W Most commonly seen in the liver, but it is
also seen in other organs such as heart,
muscle, and kidney.
W Causes oI Iatty changes in the liver include:
Alcohol, diabetes mellitus, obesity, toxins (such
as CCl
4
) , protein malnutrition, and anoxia.
iver Fatty Change (Steatosis)
ntracellular Accumulations
W Exogenous Pigments
%attoos
W dyes phagocytosed
by macrophages
Mechanism oI schemic and
Hypoxic niury
schemic and Hypoxic niury
Reversible niury
W Decreased oxidative phosphorylation
W reduced A%P
increased cytosolic Iree calcium
W reduced activity oI 'sodium pump¨
accumulation oI sodium by cell
isosmotic gain oI water (swelling)
diIIusion oI potassium Irom cell
schemic and Hypoxic niury
Reversible niury
W ncreased anaerobic glycolysis
W glycogen depletion
W lactic acid accumulation
W accumulation oI inorganic phosphates
W reduced intracellular pH
schemic and Hypoxic niury
Reversible niury
W ncreased Cytosolic Calcium
Sources
W Mitochondria, endoplasmic reticulum, external to the cell.
Consequences (activates enzymes)
W A%Pase
decreased A%P
W phospholipase
decreased phospholipids
W endonuclease
nuclear chromatin damage
W protease
disruption oI membrane and cytoskeletal proteins
schemic and Hypoxic niury
Reversible niury
W Detachment oI ribosomes
reduced protein synthesis
W Worsening mitochondrial Iunction
W ncreasing membrane permeability
W Cytoskeleton dispersion
loss oI microvilli
Iormation oI cell surIace blebs
Swelling oI mitochondria, endoplasmic reticulum, and
entire cells.
schemic and Hypoxic niury
rreversible niury
W Mitochondrial changes
severe vacuolization
amorphous calcium-rich densities
W Extensive plasma membrane damage.
W Prominent swelling oI lysosomes.
W Massive inIlux oI calcium (on reperIusion).
W Continued loss oI cell proteins, coenzymes,
ribonucleic acids and other metabolites
W eakage oI enzymes measured in serum
schemic and Hypoxic niury
rreversible niury
W niury to lysosomal membranes
leakage oI degradative enzymes
W activation oI acid hydrolases due to reduced intracellular pH
with degradation oI cell components
W Prominent leakage oI cellular enzymes.
W nIlux oI macromolecules Irom interstitium
W 'Myelin Iigures¨-whorled phospholipid masses
schemic and Hypoxic niury
Mechanisms oI rreversible niury
W Phenomena characterizing irreversibility
inability to reverse mitochondrial dysIunction.
proIound disturbances in membrane Iunction is
a central Iactor.
schemic and Hypoxic niury
W Potential causes oI membrane damage
progressive loss oI membrane phospholipids
W activation oI phospholipase
W reduced synthesis oI phospholipids
cytoskeletal abnormalities
W activation oI proteases
W cell swelling
toxic oxygen radicals.
W Ultimately a massive inIlux oI calcium
Free Radical-nduced Cell niury
W DeIinition OI Free Radicals
Extremely unstable, highly reactive chemical
species with a single unpaired electron in an
outer orbital
W Examples OI Free Radicals
superoxide anion radical (O
2

-
), hydrogen
peroxide (H
2
O
2
), and hydroxyl ions (OH

)
Sources oI Free Radicals
1. Absorption oI radiant energy (e.g.,
ultraviolet light, x-rays).
2. Enzymatic metabolism oI exogenous
chemicals or drugs (e.g., carbon
tetrachloride |CCl
4
|.
3. %he reduction-oxidation reactions that
occur during normal metabolic processes.
Sources oI Free Radicals
4. %ransition metals such as iron and copper donate
or accept Iree electrons during intracellular
reactions and catalyze Iree radical Iormation.
5. Nitric oxide (NO), chemical mediator generated
by endothelial cells, macrophages, neurons, and
other cell types, can act as a Iree radical and can
also be converted to highly reactive nitrite
species.
Reversible and rreversible Cell
niury
W Mechanisms and general pathways oI cell
iniury.
W Morphology oI reversible cell iniury.
W rreversible cell iniury:
Necrosis
Apoptosis
Morphology oI
Cell niury
Morphology oI Reversible Cell
niury
W Cellular swelling (hydropic change,
vacuolar degeneration)
Earliest change
ross: organ pallor, increased weight
Microscopic: small, clear cytoplasmic vacuoles
Reversible Cell niury
Cellular Swelling
rreversible Cell niury
Necrosis
W Necrosis reIers to a spectrum oI morphologic
changes that Iollow cell death in living tissue.
W %he morphologic appearance oI necrosis is the
result oI two concurrent processes:
Enzymatic digestion oI cell.
W Autolysis and Heterolysis.
Denaturation oI proteins.
Morphology oI Necrosis
W Microscopic changes:
Cytoplasmic Ieatures
W Cytoplasmic eosinophilia (more pink staining) and
glassy homogenous cytoplasm.
Nuclear chnages
W karyolysis
W pyknosis
W karyorrhexis
Nuclear Changes
W aryolysis:
Fading oI the basophilia oI the chromatin, due to lyses
oI DNA by DNase activity.
W Pyknosis:
Nuclear shrinkage and increased nuclear basophilia.
%he DNA condenses into a solid, shrunken basophilic
mass.
W aryorrhexis:
%he pyknotic or partially pyknotic nucleus undergoes
Iragmentation.
Necrosis
Necrosis
Nuclear Changes
Morphological %ypes oI Necrosis
1. Coagulative necrosis
t implies preservation oI the basic outline oI the
necrotic cells Ior days. %he aIIected tissues exhibit a
Iirm texture.
the iniury or the subsequent increasing intracellular
acidosis denatures not only structural proteins but
also enzymic proteins and so blocks the proteolysis oI
the cell.
Characteristic oI hypoxic cell death except in the
brain, myocardial and renal inIarct are good examples
Coagulative Necrosis
Coagulative Necrosis
Morphological %ypes oI Necrosis
2. iqueIactive necrosis:
%his is a type oI necrosis characterized by liqueIactive
process resulting in complete digestion oI the dead
cells.
t is characteristic oI Iocal bacterial or Iungal
inIections, because these agents constitute powerIul
stimuli to the accumulation oI inIlammatory cells that
lead to complete digestion oI dead cells.
Hypoxic death oI cells within the central nervous
system oIten evokes liqueIactive necrosis.
rian inIraction and abscess are good examples oI
liqueIactive necrosis.
iqueIactive Necrosis
Necrosis
iqueIactive Necrosis Coagulative Necrosis
Morphological %ypes oI Necrosis
3. angrenous Necrosis:
%his is not a distinctive pattern oI cell death, the term
is still commonly used in surgical clinical practice.
t is usually applied to a limb, generally the lower leg,
that has lost its blood supply and has undergone
coagulation necrosis.
When bacterial inIection is superimposed, coagulative
necrosis is modiIied by the liqueIactive action oI the
bacteria and the attracted leukocytes (09,37030).
angrenous Necrosis
Morphological %ypes oI Necrosis
4. Caseous necrosis:
%his a distinctive Iorm oI coagulative
necrosis, is seen most oIten in Ioci oI
tuberculous inIection
%he term caseous is derived Irom the gross
appearance (white and cheesy) oI the area oI
necrosis.
Unlike coagulative necrosis, the tissue
architecture is completely obliterated
Caseous Necrosis
Morphological %ypes oI Necrosis
5. Fat necrosis:
Focal area oI Iat destruction appears as white,
chalky areas grossly
shadowy outlines oI necrotic Iat cells with
basophilic calcium deposits
Example: aIter acute pancreatitis due to action
oI pancreatic lipases
Fat Necrosis
Fate oI Necrotic %issue
W Ultimately, in the living patient, most necrotic
cells and their debris disappear by a combined
process oI enzymic digestion and Iragmentation,
with phagocytosis oI the particulate debris by
leukocytes.
W I necrotic cells and cellular debris are not
completely destroyed and reabsorbed, they attract
calcium salts and other minerals and become
calciIied. %his is called dystrophic calciIication
rreversible Cell niury
Apoptosis
W DeIintion oI Apoptossis:
iterally means 'Falling away Irom¨
t is programmed and active cell death.
t is a distinctive and important mode oI cell death, ts
development Iollows a cascades oI events start at
initiation phase and ends at execution phase and
involves activations oI several integrated genes, genes
products, and intracellular enzymes called caspases.
W t can be physiologic and pathologic.
Physiologic Examples oI Apoptosis
W %he programmed destruction oI cells during
embryogenesis, including implantation, organogenesis, and
developmental involution.
W Hormone-dependent involution in the adult, such as
endometrial cell breakdown during the menstrual cycle,
ovarian Iollicular atresia in the menopause, the regression
oI the lactating breast aIter weaning, and prostatic atrophy
aIter castration.
W Cell deletion in proliIerating cell populations, such as
intestinal crypt epithelia.
Physiologic Examples oI Apoptosis
W Death oI neutrophils during an acute inIlammatory
response.
W Deletion oI autoreactive % cells in the thymus.
W Death oI immune cells, both and % lymphocytes
aIter cytokine depletion.
W Cell death induced by cytotoxic % cells
Physiologic Apoptosis
W n Iact, Iailure oI certain cells to undergo
physiologic apoptosis may result in
abnormal development, autoimmune
diseases, and uncontrolled tumor
proliIeration.
Pathologic Examples oI Apoptosis
W Cell death in tumors.
W Pathologic atrophy in organs aIter duct obstruction, such as
occurs in the pancreas, parotid gland, and kidney.
W Cell iniury in certain viral diseases, as in viral hepatitis.
W Cell death produced by a variety oI iniurious stimuli that
are capable oI producing necrosis, but when given in low
doses. For example, heat, radiation, cytotoxic anticancer
drugs, and hypoxia can induce apoptosis iI the insult is
mild, but large doses oI the same stimuli result in necrotic
cell death.
Morphology oI Apoptosis
W %he Iollowing morphologic Ieatures, some best
seen with the electron microscope, characterize
cells undergoing apoptosis:
1. Cell shrinkage:
W %he cell is smaller in size; the cytoplasm is dense; and the
organelles, although relatively normal, are more tightly
packed.
2. Chromatin condensation:
W %his is the most characteristic Ieature oI apoptosis. %he
nucleus itselI may break up, producing two or more
Iragments.
Morphology oI Apoptosis
3. Formation oI cytoplasmic blebs and apoptotic
bodies:
W %he apoptotic cell Iirst shows extensive surIace
blebbing, then undergoes Iragmentation into a
number oI membrane-bound apoptotic bodies
composed oI cytoplasm and tightly packed
organelles, with or without a nuclear Iragment.
4. Phagocytosis oI apoptotic cells or bodies:
W by adiacent healthy cells, either parenchymal cells
or macrophages.
Morphology oI rreversible Cell
niury
Apoptosis
H & E section
Electron Microscopy
Mechanism oI Apoptosis
W Apoptosis is the endpoint oI an energy-dependent cascade
oI molecular events, initiated by certain stimuli, and
consisting oI Iour separable but overlapping components:
1. Signaling pathways that initiate apoptosis.
2. Control and integration, in which intracellular positive and
negative regulatory molecules inhibit, stimulate, or Iorestall
apoptosis and thus determine the outcome.
3. A common-execution phase consisting oI the actual death
program and accomplished largely by the caspase Iamily oI
proteases.
4. Removal oI dead cells by phagocytosis
Mechanism oI Apoptosis
Mechanism oI Apoptosis
W enes and gene products that control apoptosis:
cl-2 Iamily oI proteins are oI two types:
W Pro-apoptotic proteins (promote apoptosis) by increasing
mitochondrial membrane permeability and releasing an
apoptotic trigger, cytochrome c, Irom mitochondria into the
cytosol. e.g. ax, and ad.
W Anti-apoptotic proteins (inhibit apoptosis) by preventing
increased mitochondrial membrane permeability e.g. cl-2,
and cl-x.
p53 promote apoptosis in cells that have DNA damage
and Iailed to be repaired
cl-2 Family oI Proteins
W Pro-apoptotic protiens:
ax
ad
W Anti-apoptotic proteins:
cl-2
cl-x
Example oI Apoptosis:
DNA Damage-Mediated Apoptosis
W Exposure oI cells to radiation or chemotherapeutic agents
induces apoptosis by a mechanism that is initiated by DNA
damage and that involves the tumor-suppressor gene p53.
W p53 accumulates when DNA is damaged and arrests the
cell cycle (at the
1
phase) to allow additional time Ior
repair.
W I the repair process Iails, p53 triggers apoptosis via ax.
Dysregulated apoptosis
(" too little or too much" )
W %wo groups oI disorders may result Irom
such dysregulation:
1. Disorders associated with inhibited apoptosis
and increased cell survival. Here, low rate oI
apoptosis may prolong survival oI abnormal
cells, these accumulated cells can give rise to.
a) Cancers
b) Autoimmune disorders.
Dysregulated apoptosis
(" too little or too much" )
2. Disorders associated with increased apoptosis and
excessive cell death. %hese diseases are characterized
by a marked loss oI normal or protective cells and
include:
a) neurodegenerative diseases, such as in the spinal muscular
atrophies
b) ischemic iniury, such as in myocardial inIarction and stroke
c) virus-induced lymphocyte depletion, such as occurs in
acquired immune deIiciency syndrome (ADS).
ntrinsic Molecular Programs oI
Aging
When somatic cells replicate, a small section oI
the telomere is not duplicated, and telomeres
become progressively shortened .
Shortened telomeres are proposed to signal a
growth checkpoint allowing cells to become
senescent.
Conversely in immortal cancer cells, telomerase
is reactivated, and telomeres are not shortened.
ntrinsic Molecular Programs oI
Aging
W Normal human Iibroblasts have
limited numbers oI divisions.
W Cells Irom children undergo more
number oI divisions than cells
Irom older people.
W n contrast, cells Irom patients
with Werner's syndrome, a rare
disease characterized by
premature aging, have markedly
reduced number oI divisions.
W AIter a Iixed number oI divisions,
all cells become arrested in a
terminally nondividing state,
known as cellular senescence.
ntrinsic Molecular Programs oI
Aging
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