cell injury by prof. soheir saad

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CELL INJUREY
DR.SOHEIR SAAD
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CELL INJURY

• The basis of all diseases is injury to the
  smallest living
• unit of the body, namely the cell.

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• Causes Of Cell Injury
• Hypoxia (deficiency of oxygen) due to
• (i) Ischaemia
• (ii) decrease of oxygen carrying capacity of
• blood due to anaemia, cardiac or
• respiratory failure and CO poisoning.
  
• 2. Physical agent burns, deep cold, radiation,
• mechanical trauma and electric shock.
• 3. Biological agents e.g. viruses, bacterial
• toxins, fungi and parasites.
• 4. Chemical agents
• and drugs e.g. alkalis, acids,insecticides,
  
• alcohol and narcotic drugs air
  pollutants
• et..

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Causes Of Cell Injury

• 5. Endogenous toxins as in case of uremia,
• jaundice and diabetic ketosis.
• 6. Immunologic reactions
• (hypersensitivity).
• 7. Nutritional imbalance such as protein
• calorie malnutrition, starvation,
• obesity, diabetes mellitus an deficiency
• of other substances and vitamins.
• 8. Genetic abnormalities
• as in Down syndrome sickle cell
• anemia.

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Pathogenesis of cell injury

• Hypoxic and ischemic injury to the cells occur
  through-
• (A)- ATP depletion
• (B)- over production of oxygen derived free
  radicals due to imbalance between free radicals
  generation and radical defense system.

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Free Radical Induced Cell Injury

• Free radicals are generated in the cell by
• Mitochondrial oxidation superoxide (O2-),
  Hydrogen peroxide (H2O2), Hydroxyl group (OH)
• Metabolism of iron and copper
• Nitric oxide
• Radiation UV and x-ray

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Free Radical Induced Cell Injury

• How free radicals cause injury
• Lipid peroxidation
• DNA fragmentation
• Cross-linking of proteins

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Free Radical Induced Cell Injury

• How cells prevent injury by free radicals
• Superoxide dismutase
• Glutathione peroxidase
• Antioxidant (vit E, A, C)
• 4.Transport proteins (transferring)

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Other mechanisms caused by all forms of cell
injury include-

• (a) - Defect in membrane selective permeability
• (b)- Increased intracellular ca and loss of ca
  homeostasis that result from damage of both cell
  membrane mitochondrial membrane and ER.
• The increased intracellular Ca cause activation
  of degenerative cellular enzymes as
  protease,ATpase, phospholipase and endonuclease.
  (that cause damage mutation of the nucleus)

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CAUSES OF CELL INJURY
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Cellular Reaction PatternTo Stress Depends On

• 1.Type, duration, and severity of
• stress.
• 2. Type, state and adaptability of
• cell.

I-Irreversible Cell Injury Severe stimuli leads
to necrosis . Apoptosis II-Reversible Cell
Injury Mild stress for short duration leads to
biochemical change or mild form of morphologic
change in the affected cells ( hydropic swelling).
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Overview
Stress
Normal cell
Adapted Cell
- Stress
Stress
Injury
- Stress
Reversibly injured cell
Apoptosis
Irreversibly Injured cell
Dead cell
Necrosis
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IRREVERSIBLE CELL INJURY
NECROSIS

• Definition
• Necrosis is local death of cells while the
  individual is a life followed by morphological
  changes in the surrounding living tissue.
• Causes of cell necrosis See before, but
• the most common causes of cell death are
• viruses, ischaemia, bacterial toxins,
  hypersensitivity, and ionizing radiation.

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Morphologic Change In Necrosis

• The changes dont appear in
• the affected cells by light
• microscopy before 2-6
• hours according to the
• type of the affected
• tissue.

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Changes in the cytoplasm

• Swelling and granularity of the cytoplasm.
• Loss of cellular membrane
• Fusion of cells

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Occur due to hydrolysis of nucleoproteins
Nuclear changes

• I . Pyknosis i.e. the nucleus becomes
• shrunken condensed and deeply stained.
• II . Karyorrhexis rupture of nuclear membrane
  with fragmentation of the nucleus.
• III. Karyolysis the nucleus dissolves and
  disappears.
• Finally the affected tissue changes to
  homogeneous eosinophilic mass with nuclear
  debris.

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Normal Pyknosis
Karyorrhexis Karyolysis

NUCLEAR CHANGES IN NECROSIS
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Changes in cytoplasm staining

• Opacification denaturation of proteins lead to
  aggregation with resultant opacification of the
  cytoplasm.
• Eosinophilia exposure of basic amino groups
  results in increased affinity for acidic dyes
  such as eosin.

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Biochemical changes

• Release of K by dead cells.
• Release of enzymes into the blood.
• (e.g) increased plasma levels of
  creatinekinases, lactic dehydrogenase and
  aspartate aminotransferase.
• Release of protein or protein breakdown products
  into the blood.

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Biochemical changes

• Enzymes used in Dx of tissue damage
• Myocardium CK (MB isoform), AST, LDH
• Hepatocytes ALT
• Striated muscle CK (MM isoform)
• Exocrine pancreas amylase

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HISTOLOGIC FEATURES OF COAGULATIVE NECROSIS
Normal cell
Karyorrhexis
Reversible cell injury with cytoplasmic
organelle swelling, blebbing ribosome detachment
Karyolysis
Irreversible cell injury with rupture of membrane
organelles, nuclear pyknosis
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TYPES OF NECROSIS

• The variable types of necrosis differ as regards
  causes, gross and microscopic pictures.

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Morphologic pattern of Necrotic Cell mass

• Coagulative necrosis special types of necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis
• Gangrenous Necrosis
• Fibrinoid necrosis
• Zinkers Necrosis

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(1)Coagulative necrosis

• It is mainly caused by sudden ischaemia e.g.
  infarction of heart, kidney and spleen.
• Grossly,
• it appears dry pale opaque. It is triangular ?
  subcapsular with the base towards the capsule of
  the affected organ. This is due to the fan like
  distribution of the supplying blood vessels.
• The infarct area is surrounded by narrow zone of
  inflammation and congestion.
• Microscopically,
• the structural outline of the affected
  tissue
• is preserved but the cellular details are
  lost.

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This is an example of coagulative necrosis. This
is the typical pattern with ischemia and
infarction (loss of blood supply and resultant
tissue anoxia). Here, there is a wedge-shaped
pale area of coagulative necrosis (infarction)
in the renal cortex of the kidney.
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B
A
Coaqulative and Liqufactive necrosis (A)Kidney
with coaculative necrosis with loss of nuclei and
clumping of cytoplasm but with preservation of
basic tubular architecture. (B)A Focus of
liquefactive necrosis in the kidney caused by
fungal seeding ,The Focus is filled with white
cells and cellular debris,creating a renal
abscess that obliterates the normal architecture
.
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GROSS AND MICROSCOPIC PICTURE OF NECROSIS
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Coagulative necrosis of the left ventricular
wall
(From ROBBINS BASIC PATHOLOGY,2003)
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(2) Liquifactive necrosis

• The necrosed tissue undergoes rapid
• softening
• e.g.( 1)infarction of the nervous tissue
• (2) suppurative inflammation
• (Abscess)
• Grossly the affected tissue appears as
  homogenous amorphous substance.
• Microscopically it appears as homogenous
  eosinophilic structure.

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Grossly, the cerebral infarction at the upper
left here demonstrates liquefactive necrosis
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B
A
Coaqulative and Liqufactive necrosis (A)Kidney
with coaculative necrosis with loss of nuclei and
clumping of cytoplasm but with preservation of
basic tubular architecture. (B)A Focus of
liquefactive necrosis in the kidney caused by
fungal seeding ,The Focus is filled with white
cells and cellular debris,creating a renal
abscess that obliterates the normal architecture
.
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(3) Caseous necrosis

• It is characteristic of tuberculosis. The
  necrotic tissue undergoes slow partial
  liquefaction forming yellow cheesy material.
• Microscopically,
• it shows amorphous granular eosinophilic
• material lacking the cell outlines.
• Grossly, the caseous material resembles clumpy
  cheese (caseous necrosis)
• The cause of necrosis in TB Is hypersensitivity
  reaction caused by the tuberculoprotein content
  of the cell wall of Mycobacterium..

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Caseous necrosis in LN. Amorphous ,granular
,eosinophilic ,necrotic center is surrounded by
granulomatous inflammation.
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Large Caseating Tubercle
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AREA ,YELLOW-WHITE AND CHESSY
A tuberculous lung with a large area of caseous
necrosis
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(4) Fat necrosis

• It is necrosis of adipose tissue including two
  types
• 1.Traumatic caused by trauma to adipose tissue
  e.g. breast and subcutaneous tissue.
• 2. Enzymatic which occurs in case of acute
  haemorrhagic pancreatitis.
• .

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• Fat necrosis
• Grossly Opaque and chalky
• LM outline of necrotic fat cells filled with
  amorphous basophilic material (calcium soaps).
• i. e. Digestion of peritoneal fat by
  pancreatic enzymes in pancreatic inflammation.

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Foci of fat necrosis with saponification in the
mesentery
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(5) Gangrenous necrosis

• Due to area of coaculative necrosis folllwed by
  putrefaction dry gangrene.
• OR When the liquifactive action of the bacteria
  is more pronounced it is called
• wet gangrene.

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Obtraction of blood supply to bowel is alrmost
followed by Gangrene
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Dry gangrene
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Moist gangrene
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(6) Fibrinoid necrosis

• a) Collagen diseases (Rheumatic fever,
  Rheumatoid, Sclerodermia, Lupus
• erythematosus and Polyarteritis nodosa).
• b) In the wall of blood vessels in malignant
  hypertension

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Fibrionid Necrosis in a medium- sized artery The
muscular media contain sharply demarcated, Homogen
eous,deeply eosinophilic areas of necrosis
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Fibrinoid change in blood vessel
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(7) Zenkers necrosis

• Of the rectus abdominus muscle and
• diaphragm as a complication of
• bacterial infection particularly typhoid fever.
• The striated muscles lose its striation, swell
  and fuse together in homogeneous structureless
  mass.

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Fate and local effects OF NECROSIS

• 1. A small area undergoes repair
• A) The products of the necrotic cells irritate
  the surrounding tissue forming a zone of
  inflammation.
• B) The accumulated neutrophils in the zone of
  inflammation soften the necrotic tissue and make
  its removal by macrophages and blood stream easy
  and help the process of healing.
• C) Repair by regeneration or fibrosis depends
  upon the type of cells affected
  (labile-stable-permanent).

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• 2. If the necrotic area is wide, its products
  cant be removed and a fibrous capsule form
  around it in order to separate it from the living
  tissue. Areas of necrotic softening in the brain
  become surrounded by proliferated neuroglia
  (gliosis).
• 3. Old unabsorbed caseous lesions and fat
  necrosis usually becomes heavily calcified
  (dystrophic calcification)
• 4-when the necrotic tissue is infected with
  putrefactive Organism------Gangrine

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General effects of necrosis

• 1. Release of enzymes from the breakdown tissue
  into the blood forms the basis of clinical tests
  for diagnosis e.g. detection of transamenase in
  myocardial infarction and liver necrosis in
  hepatitis.
• 2. Absorption of dead products into the
  circulation leads to leukocytosis and fever (Not
  diagnostic).

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APOPTOSIS

• Definition
• It is programmed death of cells in living
  tissues.
• It is an active process differing from necrosis
  by the following points
• Occurs in both physiological and pathological
  conditions.
• Starts by nuclear changes in the form of
  chromatin condensation and fragmentation followed
  by cytoplasmic budding and then phagocytosis of
  the extruded apoptotic bodies.
• Plasma membrane are thought to remain intact
  during apoptosis until the last stage so does not
  initiate inflammatory reaction around it.

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MAJOR CRITERIA OF APOPTOSIS

• 1- Morphological changes
• 2- Chromatin condensation
• 3- DNA fargmentation
• 4- Cell death

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MICROSCOPICALLY

• In the tissue stained with H E apoptosis
  affects single or small clusters of cells and
  apoptotic cell appears as round mass of intensely
  eosinophilic cytoplasm with dense nuclear
  chromatin fragments.

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Examples Of Physiologic And Pathologic Cases
Accompanied With Apoptosis

• 1. Programmed cell death during
• embryogenesis.
• 2. Hormone dependent cell involution in
• case of endometrial cell breakdown
• during menstrual cycle.
• 3. Cell death in tumours during
• regression induced by cytotoxic drugs
• or irradiation.
• 4. In some viral disease e.g. viral
• hepatitis in which apoptotic cells are
• known as councilman bodies.

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Necrosis Vs Apoptosis
Necrosis Apoptosis
Stimuli Histologic Appearance Tissue Reaction Hypoxia And Toxins Cellular Swelling ,burst, releasing their intracellular contents and nuclear changes (Pyknosis ,Karyorrhexsis Karyolysis) Inflammation Physiological and pathological factors Single cell death ,Cells shrink ,chromatin condensation and apoptotic bodies Which engulfed by surrounding cells NO Inflammation Phagocytosis of Apoptotic bodies
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REVERSIBLE CELL INJURY

• EXAMPLES
• 1 Cloudy swelling.
• 2 Hydropic (vacuolar) degeneration.
• 3 Fatty change (Steatosis).

DEGENERATION
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CLOUDY SWELLING It is a reversible cell damage
characterized by accumulation of water inside cell
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PATHOGENES OF CLOUDY SWELLING
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HYDROPIC DEGENERATION Definit
ion Hydropic degeneration is a reversible cell
damage characterized by cumulation of water in
the cell and the formation of vacuoles of
variable size which may replace the whole
cytoplasm. Causes Those of cloudy
swelling. Grossly As cloudy swelling. Microscopic
Cytoplasm is vacuolated and blood capillaries
are compressed.
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Viral hepatitis
The hepatocytes adjacent to the portal tract
(right) are very swollen and hydropic (severe
ballooning degeneration)
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FATTY CHANGE (STEATOSIS)

• Definition
• Steatosis is a reversible cell damage
  characterized by accumulation of fat in non-fatty
  tissues.
• This accumulation of fat is due to the inability
  of the non- fatty tissues to metabolize the
  amount of fat presented to them.

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l. Causes of cloudy swelling. 2. Bacterial
toxins in chronic infections as
tuberculosis. 3. Fatty liver in addition to
the previous causes, fatty change of the
liver occurs certain other conditions A.
Excess intake of fats and carbohydrates. B.
Starvation with fat mobilization from fat
stores. C. Specific liver diseases as viral
hepatitis where diseased liver cells can not
metabolize normal amount of fat brought
to it.
CAUSES
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D. Diabetes mellitus with excess
mobilization of fat to the liver from fat
stores. E. Deficiency of lipotropic factor
containing phospholipids in the liver so
that can be utilized by most of the body
cells. Deficiency of lipotropic factors occurs
in Malnutrition Thyrotoxicosis.
Malabsorption. Chronic alcoholism.
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MICROSCOPIC PICTURE OF FATTY CHANGE
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This is a larger liver with more pronounced fatty
change. pale yellow appearance
NORMAL LIVER
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HEPATIC FATTY CHANGE
The lipid accumulates in the hepatocytes as
vacuoles
NORMAL LIVER
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Wake up
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Intended Learning Outcomes (ILOS)

• Students should list all the causes of cell
  injury.
• Students should understand how the concept of
  cell injury is useful in causation of diseases.
  Students should apply this concept to list the
  possible causes of diseases of any tissue or
  organ in the body.
• Students should understand the consequences of
  cell injury and the targeted structures of the
  cell.
• Students should know the morphologic changes in
  cell death (necrosis and apoptosis)
• Students should understand the meaning of
  apoptosis and the major events in this process.
• 6. Students should know the types of adaptive
  responses and be able to give examples of each
  type.

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THANK YOU