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CELL INJURY, ADAPTATION,
       and DEATH
Normal cell is in a steady state
“Homeostasis”
Change in Homeostasis due to stimuli -

Injury
Injury - Reversible / Irreversible

Adaptation / cell death
CELLULAR ADAPTATION TO STRESS

    Adaptations are reversible changes in the number, size, phenotype,
      metabolic activity or functions of cells in response to changes in their
      environment

•     Physiologic adaptations are responses of cells to normal stimulation by
      hormones or endogenous chemical mediators

•     Pathologic adaptations are responses to stress that allow cells to
      modulate their structure and function and thus escape injury
Hypertrophy
•is an increase in the size of cells & consequently an increase in the

size of an organ.
•the enlargement is due to an increased synthesis of

          structural proteins & organelles
•Occurs when cells are incapable of dividing


  Types:
       a) physiologic
       b) pathologic
  Causes:
       a) increased functional demand
       b) hormonal stimulation
Physiologic Hypertrophy of the Uterus During Pregnancy




   Gravid Uterus                   Normal Uterus
Small spindle-shaped uterine   Large, plump hypertrophied
smooth muscle cells from a     smooth muscle cells from a
normal uterus                  gravid uterus
Heart hypertrophy in
hypertension
Hyperplasia
•is an increase in the number of cells in an organ or tissue
•an adaptive response in cells capable of replication
•a critical response of connective tissue cells in wound healing


    Types:
             a) physiologic hyperplasia
                    1) hormonal
                       ex. Proliferation of glandular epithelium of the female
                           breast at puberty & during pregnancy
                    2) compensatory – hyperplasia that occurs when a portion
of
                a tissue is removed or diseased
               e.g. partial resection of a liver > mitotic activity 12 hours
                    later
      b) pathologic hyperplasia
Caused by excessive hormonal or growth factor
•



               stimulation
Cell injury, adaptation, and death fix
HYPERPLASIA OF THE PROSTATE GLAND
Atrophy
• Shrinkage in the size of the cell by the loss of cell substance
•Results from decreased protein synthesis and increased protein degradation
       in cells
•Is accompanied in many situations by increased autophagy with resulting
       Increases in autophagic vacoules

        Causes:
•
    Decreased workload
•
    Loss of innervation
•
    Diminished blood supply
•
    Inadequate nutrition
•
    Loss of endocrine stimulation
•
    Aging (senile atrophy)
Atrophy of the brain in an   Normal brain of a 25-year-old
82-year-old man              man
ATROPHY IN OSTEOPOROSIS
Metaplasia
•a reversible change in which one adult cell type ( epithelial or

mesenchymal) is replaced by another adult cell type.
•      is cellular adaptation whereby cells sensitive to a
  particular stress are replaced by other cell types better
   able to withstand the adverse environment

Epithelial metaplasia
  Examples
•
  Squamos change that occurs in the respiratory epithelium in
  habitual cigarette smokers ( normal columnar epithelial cells
  of trachea & bronchi are replaced by stratified squamos
  epithelial cells
•
  Vitamin A deficiency
•
  Chronic gastric reflux, the normal stratified squamos
  epithelium of the lower esophagus may undergo metaplasia
  to gastric columnar epithelium
A.Schematic diagram of columnar to squamos epithelial
B. Metaplastic transformation of esophageal epithelium
Mesenchymal metaplasia Ex. Bone formed in soft
     tissue particularly in foci of injury
METAPLASIA-ESOPHAGUS
METAPLASIA-LUNGS
CELLULAR INJURY
Cell Injury- pertains to the sequence of events when cells have no
  adaptive response or the limits of adaptive capability are
  exceeded

Types of Cell Injury
1. Reversible Injury- injury that persists within certain limits, cells
   return to a stable baseline

2. Irreversible Injury- when the stimulus causing the injury persists
   and is severe enough from the beginning that the affected
                 cells die
   a. necrosis
    b. apoptosis
Causes of Cell Injury
1. Hypoxia
   Causes:
           a. Ischemia
           b. Inadequate oxygenation of the blood
           c. Reduction in the oxygen-carrying capacity of the blood

2. Chemical Agents
   a. glucose, salt or oxygen
   b. poisons
   c. environmental toxins
   d. social “stimuli”
   e. therapeutic drugs

3. Physical agents- trauma, extremes of temperature, radiation, electric
   shock, & sudden changes in atmospheric pressure

4. Infectious agents
5. Immunologic reactions
   Example: anaphylactic reaction to a foreign protein or a drug
            reaction to self antigens

6. Genetic defects
   Examples are genetic malformations associated with Down Syndrome,
   sickle cell anemia & inborn errors of metabolism

7. Nutritional Imbalances
MORPHOLOGY OF CELL AND TISSUE INJURY
•   All stresses & noxious influences exert their effects first at the
    molecular or biochemical level

•   Cellular function is lost far before cell death occurs and the
    morphologic changes of cell injury (or death) lag far behind both

•
  Ultrastructural Changes of Reversible Cell injury
• Alteration in plasma membrane reflecting disturbance in ion
  and volume regulation induced by loss of ATP

2. Mitochondrial changes

3. Endoplasmic reticulum changes

4. Nuclear alterations
PLASMA MEMBRANE ALTERATIONS

                   •Cellular swelling

                   •Formation of cytoplasmic
                    blebs

                   •Blunting and distortion of
                     microvilli

                   •Deterioration and loosening
                   of intercellular attachments
Mithochondrial Changes

              Early it appears condensed as a
              result of loss of matrix protein
              following loss of ATP
              Followed by swelling due to
              ionic shifts
              Amorphous densities which
              correlate with the onset of
              irreversibility
              Finally, rupture of membrane
              followed by progressing
              increased calcification
Endoplasmic Reticulum Changes

                                •Dilation
                                •Detachment of
                                 ribosomes and
                                 dissociation of
                                 polysomes with
                                 decreased protein
                                 synthesis
                                •Progressive
                                 fragmentation and
                                 formation of
                                 intracellular
                                 aggregates of myelin
                                 figures
Nuclear Alterations

• Disaggregation of
  granular and
  fibrillar elements
Two Patterns of Morphologic Change Correlating to
Reversible Injury that can be recognized under the light
Microscope: cellular swelling and fatty change

Cellular Swelling
●
   Is the result of failure of energy-dependent ion pumps in the
    plasma membrane leading to an inability to maintain ionic
   & fluid homeostasis
●
   first manifestation of almost all forms of injury to cells
•microscopically small, clear vacoules may be seen within
  the cytoplasm
•sometimes called hydropic change or vacoular
  degeneration
•swelling of cells is reversible
Hydropic degeneration: kidney
Cloudy swelling & hydropic change reflect failure of membrane
 ion pumps, due to lack of ATP, allowing cells to accumulate
 fluid
Fatty Change
* occurs in hypoxic injury & various forms of toxic( alcohol
       & halogenated hydrocarbons like chloroform ) or
     metabolic injury like diabetes mellitus & obesity
    •manifested by the appearance of lipid vacoules in the
     cytoplasm
    •principally encountered in cells participating in and
     involved in fat metabolism e.g. hepatocytes &
     myocardial cells
    •also reversible
Morphologic Alterations in Reversible Cell Injury

Cell swelling
•




Fatty change
•




Plasma membrane blebbing and loss of microvilli
•




Mitochondrial swelling
•




Dilation of the ER
•




Eosinophilia (due to decreased cytoplasmic RNA)
•
NECROSIS
•Refers to a series of changes that accompany cell

     death, largely resulting from the degradative action of
     enzymes on lethally injured cells
•The enzymes responsible for digestion of the cell
         are derived either from the:
          1) Lysosomes of the dying cells themselves or from
          2) lysosomes of leukocytes that are recruited as
             part of the inflammatory reaction to the dead
             cells
Morphologic alterations in Necrosis
✔
 Increased eosinophilia (pink staining from eosin dye)
✔
 Myelin figures ( whorled phospholipid masses)
✔
 Nuclear changes assume one of three patterns all due to
      breakdown of DNA & chromatin:
        1) Karyolysis
        2) Pyknosis characterized by nuclear shrinkage and
           increased basophila
        3) Karyorrhexis – fragmentation and dissolution
✔
 Breakdown of plasma membrane and organellar
      Membranes
✔
 Leakage and enzymatic digestion of cellular contents
Patterns of Tissue Necrosis

Coagulative Necrosis
➢
  A form of tissue necrosis in which the component cells are
dead but the basic tissue architecture is preserved for at
       least several days
➢
  It is characteristics of infarcts ( areas of ischemic
       necrosis) in all solid organs except the brain


                                           A wedge-shaped kidney
                                           Infarct (yellow) with
                                           preserva
                                           tion of the outlines
Liquefactive Necrosis
➢
  Seen in focal bacterial or occassionally fungal infections
      because microbes stimulate the accumulation of
      Inflammatory cells and the enzymes of leukocytes digest
      ( “liquefy”) the tissue
➢
  This necrosis is characteristic of hypoxic death of cells
      witnin the CNS
➢
  Associated with suppurative inflammation (accumulation
       of pus)
➢
  The areas undergoing necrosis are transformed into a
      Semi-solid consistency or state (liquid viscuous mass)
      Example: abcess
Liquefactive necrosis. An infarct in the brain, showing
dissolution of tissue
Caseous Necrosis
➢
   Encountered most often infoci of tuberculous infection
➢
  Characterized by a cheesy yellow-white appearance of
        the area of necrosis
➢
  It is often enclosed within a distinctive inflammatory
        border

                                    A tuberculous lung with a large
                                    area of caseous necrosis
                                    containing yellow-white and
                                    cheesy debris
Fat Necrosis
➢
  Refers to focal areas of fat destruction, typically resulting
     from release of activated pancreatic lipases into the
     substance of the pancreas and the peritoneal cavity
➢
  Occurs in acute pancreatitis




  Fat necrosis in aqcute pancreatitis. The areas of white chalky deposits
  represent foci of fat necrosis with calcium soapformation (saponification)
  at sites of lipid breakdown in the mesentery
Fibrinoid necrosis
➢
  A special form of necrosis usually seen in immune
      reactions involving blood vessels
➢
  This pattern of necrosis is prominent when complexes of
      antigens and antibodies are deposited in the walls of
      Arteries
➢
  Deposits of these immune complexes together with fibrin
      that has leaked out of vessels result in a bright pink and
      amorphous appearance called 'fibrinoid”

                                         Fibrinoid necrosis in an artery
                                         in a patient with Polyarteritis
                                         Nodosa. The wall of the
                                         artery
                                         shows a circumferential bright
                                         pink area of necrosis with
                                         protein deposition and
                                         inflammation
Gangrenous Necrosis
➢
   This is not a distinctive pattern of cell death
➢
  It is usually applied to a limb, generally the lower leg, that
        has lost its blood supply involving multiple tissue layers
➢
  Types:
✔
  Wet gangrene
✗
 Occurs in naturally moist areas like mouth, bowels lungs
✗
 Characterized by numerous bacteria
✔
  Dry gangrene
✗
 begins at the distal part of the limb due to ischemia and
often occurs in the toes and feet of elderly
              patients due to arteriosclerosis
✗
 This is mainly due to arterial occlusion
✗
 There is limited putrefaction and bacteria fail to
              survive
Cell injury, adaptation, and death fix
SUBCELLULAR RESPONSES TO INJURY

•   Autophagy
•Refers to lysosomal digestion of the cell's own

components
•It is thought to be a survival mechanism in times of nutrient

        deprivation
•Organelles are enclosed in vacoules that fuse with
           lysosomes

    Heterophagy a cell usually a macrophage ingests
     substances from the outside for intracellular destruction
Cell injury, adaptation, and death fix
•   Hypertrophy of Smooth Endoplasmic Reticulum
Cells exposed to toxins that are metabolized in the SER show
  hypertrophy, a compensatory mechanism to maximize
  removal of the toxins
•   Mitochondrial Alterations
  * alterations in size, number, shape & function
  Ex. Mitochondria assume extremely large & abnormal
  shapes (megamitochondria) in hepatocytes in various
  nutritional deficiencies & alcoholic liver disease
       Cellular hypertrophy > # of mitochondria in cells
       Atrophy < # of mitochondria

•    Cytoskeletal Abnormalities
    some drugs & toxins interfere with the assembly & functions
     of Cytoskeleton filaments or result in abnormal
     accumulations of filaments
General Principles Relevant To Most Forms Of Cell Injury
• The cellular response to injurious stimuli depends on the type of
  injury, its duration, and its severity
• The consequences of an injurious stimulus depend on the type ,
  status , adaptability , and genetic makeup of the injured cell
•Cell injury results from functional & biochemical abnormalities in
• one or more of several essential cellular components
         The most important target of injurious stimuli are:
  1) cell membrane integrity, critical to cellular ionic and osmotic
      homeostasis
  2) mitochondrial, the site of adenosine triphosphate (ATP)
       generation
  3) protein synthesis
  4) integrity of the genetic apparatus
  5) cytoskeleton
MECHANISMS OF CELL INJURY

➢
  ATP depletion: failure of energy-dependent functions
  reversible Injury                 necrosis
➢
 Mitochondrial damage: ATP depletion               failure of energy-
   dependent cellular functions              ultimately necrosis;
   under some conditions, leakage of proteins that causes apoptosis
➢
 Influx of calcium: activation of enzymes that damage cellular
  components and may also trigger apoptosis
➢
 Accumulation of reactive oxygen species: covalent modifications of
  cellular proteins, lipids, nucleic acids
➢
 Increased permeability of cellular membranes: may affect plasma
  membrane, lysosomal membranes, mitochondrial membranes;
  typically culminates in necrosis
➢
 Accumulations of damaged DNA and misfolded proteins triggers
   apoptosis
Accumulation of Oxygen-Derived Free radicals (Oxidative
  Stress)

Free radicals are chemical species with single unpaired electron
  in an outer orbital. In such a state the radicals are extremely
  unstable & readily react with inorganic or organic chemicals.

 Free radicals may be generated within cells by
• Reduction-oxidation (redox) reactions
• Nitric oxide (NO)
• Absorption of radiant energy (e.g. ultraviolet light, x-rays)
• Enzymatic metabolism of exogenous chemicals (e.g. carbon
  tetrachloride)
• Inflammation, because free radicals are produced by leukocytes
  that enter tissues
Mechanisms that remove Free radicals
●
 Action of superoxide dismutases (SODS)
●
 Glutathione (GSH) peroxidase
●
 Catalase present in perixisomes
●
 Endogenous or exogenous antioxidants (e.g. vitamins E, A
  and C, and beta-Carotene may either block the formation of
  free radicals or scavenge them once they have formed
●
 Iron and Copper can catalyze the formation of Reactive
  Oxygen Species (ROS)
APOPTOSIS (“FALLING OFF”)
➢
  Is a pathway of cell death that is induced by a tightly
        regulated suicide program in which cells destined to die
        activate enzymes capable of degrading the cells own
        nuclear DNA and nuclear and cytoplasmic proteins
➢
  It differs from necrosis in the following characteristics
          1) Plasma membrane of the apoptotic cell remains
             intact
          2) Has no leakage of cellular contents
          3) Does not elicit an inflammatory reaction in the host
➢
  Sometimes coexist with necrosis
➢
  Apoptosis induced by some pathologic stimuli may
        progress to necrosis
Causes of Apoptosis

Apoptosis in Physiologic Situations
        Death by apoptosis is a normal phenomenon that
serves to eliminate cells that are no longer needed and to
maintain a steady number of various cell populations in tissues

 Programmed destruction of cells during embryogenesis,
  Including implantation, organogenesis, developmental
  involution, and metamorphosis

Involution of hormone- dependent tissues upon hormone



 deprivation such as endometrial cell breakdown during the
 menstrual cycle and regeression of the lactating breast after
 Weaning

Cell loss in proliferating cell populations, such as intestinal



Crypt epithelia
Death of cells that have served their useful purpose, such



as neutrophils in an acute inflammatory response and
Lymphocytes at the end of an immune response

Elimination of potentially harmful self-reactive lymphocytes



Either before or after they have completed their maturation

Cell death induced by cytotoxic T lymphocytes, a defense



mechanism against viruses and tumors that serves to kill
eliminate virus-infected and neoplastic cells
Apoptosis in Pathologic Situations
        Apoptosis eliminates cells that are genetically altered or
Injured beyond repair without eliciting a severe host reaction,
thus keeping the damage as contained as possible

  DNA damage
         Radiation, cytotoxic anticancer drugs, extremes of
  temperature and even hypoxia can damage DNA either
  directly or via production of free radicals


 Accumulation of misfolded proteins
✔
 These may arise because of mutations in the genes
     encoding these proteins or because of extrinsic factors
     such as free radicals
✔
 Excessive accumulation of these proteins in the ER leads
    to a condition called ER stress

    Cell injury in certain infections particularly viral infections

Pathologic atrophy in parenchymal organs after duct



obstruction such as in pancreas, parotid gland and kidney

Morphologic Alterations in Apoptosis
●
 Nuclear chromatin condensation
●
 Formation of apoptotic bodies ( fragments of nuclei and
     cytoplasm)

The fundamental event in apoptosis is the activation of enzyme
called caspases
Two Major Pathways in the Initiation of Apopotosis
1) Mitochondrial ( intrinsic) pathway
       Triggered by loss of survival signals, DNA damage
  and accumulation of misfolded proteins (ER stress)

2) Death receptor (extrinsic) pathway
       Responsible for the elimination of self-reactive
   lymphocytes and damage by cytotoxic T lymphocytes
INTRACELLULAR ACCUMULATIONS

THREE MAIN PATHWAYS OF ABNORMAL INTRACELLULAR
ACCUMULATIONS
●
 A normal substance is produced at abnormal or an increased
  rate, but metabolic rate is inadequate to remove it
  Example. Fatty change in the liver

●
 A normal or abnormal endogenous substance accumulates
  because of genetic or acquired defects in its folding,
  packaging, transport or secretion
  Example. Accumulation of of proteins in anti-trypsin deficiency
●
 An abnormal exogenous substance is deposited and
  Accumulates because the cell has neither the enzymatic
  Machinery to degrade the substance nor the ability to transport
  It to other sites.
  Example. Accumulation of carbon or silica particles
Fatty Change (Steatosis)

Refers to any abnormal accumulation of triglycerides within
✔


   parenchymal cells

Most often seen in the liver but may also occur in the heart,
✔


   Skeletal muscle, kidney and other organs

May be caused by toxins, protein malnutrition, diabetes
✔


   mellitus, obesity and anoxia

Alcohol abuse and diabetes associated with obesity are
✔


    the most common causes of fatty liver
Fatty Liver
Cholesterol and Cholesteryl Esters

✔
    Result of defective catabolism and excessive intake

Present in lipid vacoules of smooth muscle cells and
✔


   macrophages in atherosclerosis (hardening of the aorta)

Give atherosclerotic plaques their characteristic yellow color
✔


    and contibute to the pathogenesis of the lesion

✔
    Xanthomas are hypercholesterolemic tumurous masses
      found in the connective tissue of the skin or tendons
Proteins
✔
  Less common than lipid accumulations
✔
  Occur because excess are presented to the cells or
     because the cells synthesize excessive amounts
✔
  Examples:
     1) Nephrotic syndrome there is heavy protein leakage
        across the glomerular filter due to a much larger
        reabsorption of albumin
     2) accumulation of newly synthesized imunoglobulins
         in RER of some plasma cells forming rounded,
         eosinophilic Russell bodies
     3) Mallory body or “ alcoholic hyalin” is an eosinophilic
        cytoplasmic inclusion in liver cells highly characteristic
        of alcoholic liver disease
     4) Neurofibrillary tangle found in the brain in Alzheimer
        disease
Protein reabsorption droplets in the renal tubular epithelium
Glycogen
✔
 Accumulations of these are associated with abnormalities
     in the metabolism of either glucose or glycogen
✔
 Ex.
     1) In poorly controlled diabetes mellitus, glycogen
        accumulates in renal tubular epithelium, cardiac
        myocytes, and β cells of Islets of langerhans
     2) Glycogen storage diseases or glycogeneses are
        Genetic disorders where glycogen accumulates in
        macrophages of patients with defects in lysosomal
        enzymes
Pigments
➢
  colored substances that are either exogenous or
      endogenous

●
  Exogenous – coming from outside the body
       1) Carbon ( ex. Coal dust)
➔
 Most common air pollutant
➔
 Aggregates of the pigment blacken the
              draining lymph nodes and pulmonary
               parenchyma (Anthracosis)
➔
 Heavy accumulations may induce emphysema
              or a fibroblastic reaction that can result in a
               serious lung disease called coal workers
               pneumoconiosis
●
  Endogenous – synthesized within the body itself
       1) Lipofuscin or “wear-and -tear pigment or lipochrome
✔
 an insoluble brownish-yellow granular intracellular
           material that accumulates in the heart, liver, & brain as
           a function of age or atrophy
✔
 represents complexes of lipid & protein that derive
           from the free radical-catalyzed peroxidation of
           polyunsaturated lipids
✔
 it is not injurious to the cell but is important as a
           marker of past free-radical injury
✔
 the brown pigment when present in large amounts,
           imparts an appearance to the tissue that is called
           brown atrophy
The pale golden brown finely granular pigment seen here in nearly
all hepatocytes is lipochrome (lipofuscin).
2) Melanin
✔
 An endogenous, brown-black pigment synthesized
     exclusively by melanocytes when the enzyme tyrosinase
     catalyzes tyrosine to (DOPA) dihydroxyphenylalanine
     located in the epidermis
✔
 Acts as a screen against harmful ultraviolet radiation
✔
 Basal keratinocytes in the skin can accumulate the
      pigment (e.g. in freckles)
Melanin pigment in melanoma
3) Hemosiderin
✔
  A hemoglobin-derived granular pigment that is
     golden yellow to brown and accumulates in tissues
     when there is a local or systemic excess of iron




✔
 Iron is normally stored within cells in association with the
      protein apoferritin, forming ferritin micelles
✔
 Iron can be identified by the Prussian blue reaction
Local excess of iron & consequently of hemosiderin result
    ✔


     from hemorrhage
     Ex. Bruise




       The original red-blue color of hemoglobin is
       transformed to varying shades of green-blue by the
       local formation of biliverdin (green bile) and bilirubin
       (red bile) from the heme moiety
✔
 The iron of hemoglobin accumulate as golden- yellow
     hemosiderin
Hemosiderosis
✔
 a condition where hemosiderin is deposited in many
      organs and tissues whenever there is systemic overload
      of iron
✔
 It occurs in the following settings
•Increased absorption of dietary iron
•Impaired utilization of iron
•Hemolytic anemias
•Transfusions
    Hereditary Hemochromatosis
✔
 A condition where there is extensive accumulations of iron
      with tissue injury like liver fibrosis, heart failure and
      diabetes mellitus
✔
 Characterized principally by
      1) the deposition of hemosiderin in the following organs (in
          decreasing order of severity):liver, pancreas,
          myocardium, pituitary, adrenal, thyroid, joints & skin
      2) cirrhosis     and 3) pancreatic fibrosis
PATHOLOGIC CALCIFICATION
➢
  implies the abnormal deposition of calcium salts, together
   with small amounts of iron, magnesium, and other minerals

TYPES
A. Dystrophic calcification
✔
 deposition of calcium in dead or dying tissues
✔
 occurs in the absence of calcium metabolic
       derangements ( with normal serum levels of calcium)
✔
 Local deposits of calcium may occur in
         1) necrotic tissue which is not absorbed
●
  old infarcts
●
  tuberculous foci
●
  old collection of pus
●
  dead parasites
●
  acute pancreatic necrosis
2) Tissue undergoing slow degeneration
●
 Hyaline areas in benign tumors
●
 Fibroids
●
 In arteries due to atheromatous degeneration or old age
●
 Old thrombi
●
 Diseased or abnormal heart valves

Pathogenesis
➢
  Initiation ( or nucleation)
➢
  Propagation
          Both may be intracellular or extracellular with calcium
phosphate as the end product
B. Metastatic Calcification
✔
  deposition of calcium salts in normal tissues
✔
 almost always reflects some derangement in calcium
     metabolism ( hypercalcemia)

Four major causes of hypercalcemia
1) Increased secretion of parathyroid hormone, due to either
   parathyroid tumors or production of parathyroid hormone-
   Related protein by other malignant tumors
2) Destruction of bone due to the effects of accelerated
   turnover (e.g. Paget disease),immobilization, or tumors
   (increased bone catabolism associated with multiple
   myeloma, leukemia or diffuse skeletal metastases)
3) Vitamin D-related disorders like vitamin D intoxication and
   sarcoidosis ( in which macrophages activate a vitamin D
   precursor
4) Renal failure, in which phosphate retention leads to
   secondary hyperparathyroidism
CELLULAR AGING
➢
  results from combination of accumulating cellular damage
  (e.g., by free radicals), reduced capacity to divide (replicative
   senescence), and reduced ability to repair damaged DNA

Cellular senescence
➢
  Aging of a person is intimately related to cellular aging

Mechanisms known or suspected to be responsible for cellular
aging
●
  DNA damage
✔
 defective DNA repair mechanisms
    DNA repair may be activated by calorie restriction (known
    to prolong aging in model organisms)
●
  Replicative senescence
✔
 Reduced capacity of cells to divide because of decreasing
     amounts of telomerase and progressive shortening of
     chromosomal ends (telomeres)
     Telomeres
➔
  are short repeated sequences of DNA present at the
           linear ends of chromosomes
➔
  Importance
          * for ensuring the complete replication of chromosome
            ends
         * and for protecting the ends from fusion & degradation

●
  Progressive accumulation of metabolic damage
✔
 Repeated environmental exposure to radiation
✔
 Progressive reduction of antioxidant defense mechanism
     Like Vit. E & glutathione peroxidase
●
  Possible roles of growth factors
Telomerase in Ageing:

Germ
cells




Somatic
cells
WERNER SYNDROME
➢
 A rare disease characterized by premature aging

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Cell injury, adaptation, and death fix

  • 2. Normal cell is in a steady state “Homeostasis” Change in Homeostasis due to stimuli - Injury Injury - Reversible / Irreversible Adaptation / cell death
  • 3. CELLULAR ADAPTATION TO STRESS Adaptations are reversible changes in the number, size, phenotype, metabolic activity or functions of cells in response to changes in their environment • Physiologic adaptations are responses of cells to normal stimulation by hormones or endogenous chemical mediators • Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury
  • 4. Hypertrophy •is an increase in the size of cells & consequently an increase in the size of an organ. •the enlargement is due to an increased synthesis of structural proteins & organelles •Occurs when cells are incapable of dividing Types: a) physiologic b) pathologic Causes: a) increased functional demand b) hormonal stimulation
  • 5. Physiologic Hypertrophy of the Uterus During Pregnancy Gravid Uterus Normal Uterus
  • 6. Small spindle-shaped uterine Large, plump hypertrophied smooth muscle cells from a smooth muscle cells from a normal uterus gravid uterus
  • 8. Hyperplasia •is an increase in the number of cells in an organ or tissue •an adaptive response in cells capable of replication •a critical response of connective tissue cells in wound healing Types: a) physiologic hyperplasia 1) hormonal ex. Proliferation of glandular epithelium of the female breast at puberty & during pregnancy 2) compensatory – hyperplasia that occurs when a portion of a tissue is removed or diseased e.g. partial resection of a liver > mitotic activity 12 hours later b) pathologic hyperplasia Caused by excessive hormonal or growth factor • stimulation
  • 10. HYPERPLASIA OF THE PROSTATE GLAND
  • 11. Atrophy • Shrinkage in the size of the cell by the loss of cell substance •Results from decreased protein synthesis and increased protein degradation in cells •Is accompanied in many situations by increased autophagy with resulting Increases in autophagic vacoules Causes: • Decreased workload • Loss of innervation • Diminished blood supply • Inadequate nutrition • Loss of endocrine stimulation • Aging (senile atrophy)
  • 12. Atrophy of the brain in an Normal brain of a 25-year-old 82-year-old man man
  • 14. Metaplasia •a reversible change in which one adult cell type ( epithelial or mesenchymal) is replaced by another adult cell type. • is cellular adaptation whereby cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment Epithelial metaplasia Examples • Squamos change that occurs in the respiratory epithelium in habitual cigarette smokers ( normal columnar epithelial cells of trachea & bronchi are replaced by stratified squamos epithelial cells • Vitamin A deficiency • Chronic gastric reflux, the normal stratified squamos epithelium of the lower esophagus may undergo metaplasia to gastric columnar epithelium
  • 15. A.Schematic diagram of columnar to squamos epithelial B. Metaplastic transformation of esophageal epithelium Mesenchymal metaplasia Ex. Bone formed in soft tissue particularly in foci of injury
  • 18. CELLULAR INJURY Cell Injury- pertains to the sequence of events when cells have no adaptive response or the limits of adaptive capability are exceeded Types of Cell Injury 1. Reversible Injury- injury that persists within certain limits, cells return to a stable baseline 2. Irreversible Injury- when the stimulus causing the injury persists and is severe enough from the beginning that the affected cells die a. necrosis b. apoptosis
  • 19. Causes of Cell Injury 1. Hypoxia Causes: a. Ischemia b. Inadequate oxygenation of the blood c. Reduction in the oxygen-carrying capacity of the blood 2. Chemical Agents a. glucose, salt or oxygen b. poisons c. environmental toxins d. social “stimuli” e. therapeutic drugs 3. Physical agents- trauma, extremes of temperature, radiation, electric shock, & sudden changes in atmospheric pressure 4. Infectious agents
  • 20. 5. Immunologic reactions Example: anaphylactic reaction to a foreign protein or a drug reaction to self antigens 6. Genetic defects Examples are genetic malformations associated with Down Syndrome, sickle cell anemia & inborn errors of metabolism 7. Nutritional Imbalances
  • 21. MORPHOLOGY OF CELL AND TISSUE INJURY • All stresses & noxious influences exert their effects first at the molecular or biochemical level • Cellular function is lost far before cell death occurs and the morphologic changes of cell injury (or death) lag far behind both • Ultrastructural Changes of Reversible Cell injury • Alteration in plasma membrane reflecting disturbance in ion and volume regulation induced by loss of ATP 2. Mitochondrial changes 3. Endoplasmic reticulum changes 4. Nuclear alterations
  • 22. PLASMA MEMBRANE ALTERATIONS •Cellular swelling •Formation of cytoplasmic blebs •Blunting and distortion of microvilli •Deterioration and loosening of intercellular attachments
  • 23. Mithochondrial Changes Early it appears condensed as a result of loss of matrix protein following loss of ATP Followed by swelling due to ionic shifts Amorphous densities which correlate with the onset of irreversibility Finally, rupture of membrane followed by progressing increased calcification
  • 24. Endoplasmic Reticulum Changes •Dilation •Detachment of ribosomes and dissociation of polysomes with decreased protein synthesis •Progressive fragmentation and formation of intracellular aggregates of myelin figures
  • 25. Nuclear Alterations • Disaggregation of granular and fibrillar elements
  • 26. Two Patterns of Morphologic Change Correlating to Reversible Injury that can be recognized under the light Microscope: cellular swelling and fatty change Cellular Swelling ● Is the result of failure of energy-dependent ion pumps in the plasma membrane leading to an inability to maintain ionic & fluid homeostasis ● first manifestation of almost all forms of injury to cells •microscopically small, clear vacoules may be seen within the cytoplasm •sometimes called hydropic change or vacoular degeneration •swelling of cells is reversible
  • 27. Hydropic degeneration: kidney Cloudy swelling & hydropic change reflect failure of membrane ion pumps, due to lack of ATP, allowing cells to accumulate fluid
  • 28. Fatty Change * occurs in hypoxic injury & various forms of toxic( alcohol & halogenated hydrocarbons like chloroform ) or metabolic injury like diabetes mellitus & obesity •manifested by the appearance of lipid vacoules in the cytoplasm •principally encountered in cells participating in and involved in fat metabolism e.g. hepatocytes & myocardial cells •also reversible
  • 29. Morphologic Alterations in Reversible Cell Injury Cell swelling • Fatty change • Plasma membrane blebbing and loss of microvilli • Mitochondrial swelling • Dilation of the ER • Eosinophilia (due to decreased cytoplasmic RNA) •
  • 30. NECROSIS •Refers to a series of changes that accompany cell death, largely resulting from the degradative action of enzymes on lethally injured cells •The enzymes responsible for digestion of the cell are derived either from the: 1) Lysosomes of the dying cells themselves or from 2) lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells
  • 31. Morphologic alterations in Necrosis ✔ Increased eosinophilia (pink staining from eosin dye) ✔ Myelin figures ( whorled phospholipid masses) ✔ Nuclear changes assume one of three patterns all due to breakdown of DNA & chromatin: 1) Karyolysis 2) Pyknosis characterized by nuclear shrinkage and increased basophila 3) Karyorrhexis – fragmentation and dissolution ✔ Breakdown of plasma membrane and organellar Membranes ✔ Leakage and enzymatic digestion of cellular contents
  • 32. Patterns of Tissue Necrosis Coagulative Necrosis ➢ A form of tissue necrosis in which the component cells are dead but the basic tissue architecture is preserved for at least several days ➢ It is characteristics of infarcts ( areas of ischemic necrosis) in all solid organs except the brain A wedge-shaped kidney Infarct (yellow) with preserva tion of the outlines
  • 33. Liquefactive Necrosis ➢ Seen in focal bacterial or occassionally fungal infections because microbes stimulate the accumulation of Inflammatory cells and the enzymes of leukocytes digest ( “liquefy”) the tissue ➢ This necrosis is characteristic of hypoxic death of cells witnin the CNS ➢ Associated with suppurative inflammation (accumulation of pus) ➢ The areas undergoing necrosis are transformed into a Semi-solid consistency or state (liquid viscuous mass) Example: abcess
  • 34. Liquefactive necrosis. An infarct in the brain, showing dissolution of tissue
  • 35. Caseous Necrosis ➢ Encountered most often infoci of tuberculous infection ➢ Characterized by a cheesy yellow-white appearance of the area of necrosis ➢ It is often enclosed within a distinctive inflammatory border A tuberculous lung with a large area of caseous necrosis containing yellow-white and cheesy debris
  • 36. Fat Necrosis ➢ Refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity ➢ Occurs in acute pancreatitis Fat necrosis in aqcute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soapformation (saponification) at sites of lipid breakdown in the mesentery
  • 37. Fibrinoid necrosis ➢ A special form of necrosis usually seen in immune reactions involving blood vessels ➢ This pattern of necrosis is prominent when complexes of antigens and antibodies are deposited in the walls of Arteries ➢ Deposits of these immune complexes together with fibrin that has leaked out of vessels result in a bright pink and amorphous appearance called 'fibrinoid” Fibrinoid necrosis in an artery in a patient with Polyarteritis Nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation
  • 38. Gangrenous Necrosis ➢ This is not a distinctive pattern of cell death ➢ It is usually applied to a limb, generally the lower leg, that has lost its blood supply involving multiple tissue layers ➢ Types: ✔ Wet gangrene ✗ Occurs in naturally moist areas like mouth, bowels lungs ✗ Characterized by numerous bacteria ✔ Dry gangrene ✗ begins at the distal part of the limb due to ischemia and often occurs in the toes and feet of elderly patients due to arteriosclerosis ✗ This is mainly due to arterial occlusion ✗ There is limited putrefaction and bacteria fail to survive
  • 40. SUBCELLULAR RESPONSES TO INJURY • Autophagy •Refers to lysosomal digestion of the cell's own components •It is thought to be a survival mechanism in times of nutrient deprivation •Organelles are enclosed in vacoules that fuse with lysosomes Heterophagy a cell usually a macrophage ingests substances from the outside for intracellular destruction
  • 42. Hypertrophy of Smooth Endoplasmic Reticulum Cells exposed to toxins that are metabolized in the SER show hypertrophy, a compensatory mechanism to maximize removal of the toxins • Mitochondrial Alterations * alterations in size, number, shape & function Ex. Mitochondria assume extremely large & abnormal shapes (megamitochondria) in hepatocytes in various nutritional deficiencies & alcoholic liver disease Cellular hypertrophy > # of mitochondria in cells Atrophy < # of mitochondria • Cytoskeletal Abnormalities some drugs & toxins interfere with the assembly & functions of Cytoskeleton filaments or result in abnormal accumulations of filaments
  • 43. General Principles Relevant To Most Forms Of Cell Injury • The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity • The consequences of an injurious stimulus depend on the type , status , adaptability , and genetic makeup of the injured cell •Cell injury results from functional & biochemical abnormalities in • one or more of several essential cellular components The most important target of injurious stimuli are: 1) cell membrane integrity, critical to cellular ionic and osmotic homeostasis 2) mitochondrial, the site of adenosine triphosphate (ATP) generation 3) protein synthesis 4) integrity of the genetic apparatus 5) cytoskeleton
  • 44. MECHANISMS OF CELL INJURY ➢ ATP depletion: failure of energy-dependent functions reversible Injury necrosis ➢ Mitochondrial damage: ATP depletion failure of energy- dependent cellular functions ultimately necrosis; under some conditions, leakage of proteins that causes apoptosis ➢ Influx of calcium: activation of enzymes that damage cellular components and may also trigger apoptosis ➢ Accumulation of reactive oxygen species: covalent modifications of cellular proteins, lipids, nucleic acids ➢ Increased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosis ➢ Accumulations of damaged DNA and misfolded proteins triggers apoptosis
  • 45. Accumulation of Oxygen-Derived Free radicals (Oxidative Stress) Free radicals are chemical species with single unpaired electron in an outer orbital. In such a state the radicals are extremely unstable & readily react with inorganic or organic chemicals. Free radicals may be generated within cells by • Reduction-oxidation (redox) reactions • Nitric oxide (NO) • Absorption of radiant energy (e.g. ultraviolet light, x-rays) • Enzymatic metabolism of exogenous chemicals (e.g. carbon tetrachloride) • Inflammation, because free radicals are produced by leukocytes that enter tissues
  • 46. Mechanisms that remove Free radicals ● Action of superoxide dismutases (SODS) ● Glutathione (GSH) peroxidase ● Catalase present in perixisomes ● Endogenous or exogenous antioxidants (e.g. vitamins E, A and C, and beta-Carotene may either block the formation of free radicals or scavenge them once they have formed ● Iron and Copper can catalyze the formation of Reactive Oxygen Species (ROS)
  • 47. APOPTOSIS (“FALLING OFF”) ➢ Is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading the cells own nuclear DNA and nuclear and cytoplasmic proteins ➢ It differs from necrosis in the following characteristics 1) Plasma membrane of the apoptotic cell remains intact 2) Has no leakage of cellular contents 3) Does not elicit an inflammatory reaction in the host ➢ Sometimes coexist with necrosis ➢ Apoptosis induced by some pathologic stimuli may progress to necrosis
  • 48. Causes of Apoptosis Apoptosis in Physiologic Situations Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed and to maintain a steady number of various cell populations in tissues  Programmed destruction of cells during embryogenesis, Including implantation, organogenesis, developmental involution, and metamorphosis Involution of hormone- dependent tissues upon hormone  deprivation such as endometrial cell breakdown during the menstrual cycle and regeression of the lactating breast after Weaning Cell loss in proliferating cell populations, such as intestinal  Crypt epithelia
  • 49. Death of cells that have served their useful purpose, such  as neutrophils in an acute inflammatory response and Lymphocytes at the end of an immune response Elimination of potentially harmful self-reactive lymphocytes  Either before or after they have completed their maturation Cell death induced by cytotoxic T lymphocytes, a defense  mechanism against viruses and tumors that serves to kill eliminate virus-infected and neoplastic cells
  • 50. Apoptosis in Pathologic Situations Apoptosis eliminates cells that are genetically altered or Injured beyond repair without eliciting a severe host reaction, thus keeping the damage as contained as possible  DNA damage Radiation, cytotoxic anticancer drugs, extremes of temperature and even hypoxia can damage DNA either directly or via production of free radicals  Accumulation of misfolded proteins ✔ These may arise because of mutations in the genes encoding these proteins or because of extrinsic factors such as free radicals ✔ Excessive accumulation of these proteins in the ER leads to a condition called ER stress
  • 51. Cell injury in certain infections particularly viral infections Pathologic atrophy in parenchymal organs after duct  obstruction such as in pancreas, parotid gland and kidney Morphologic Alterations in Apoptosis ● Nuclear chromatin condensation ● Formation of apoptotic bodies ( fragments of nuclei and cytoplasm) The fundamental event in apoptosis is the activation of enzyme called caspases
  • 52. Two Major Pathways in the Initiation of Apopotosis 1) Mitochondrial ( intrinsic) pathway Triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress) 2) Death receptor (extrinsic) pathway Responsible for the elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes
  • 53. INTRACELLULAR ACCUMULATIONS THREE MAIN PATHWAYS OF ABNORMAL INTRACELLULAR ACCUMULATIONS ● A normal substance is produced at abnormal or an increased rate, but metabolic rate is inadequate to remove it Example. Fatty change in the liver ● A normal or abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport or secretion Example. Accumulation of of proteins in anti-trypsin deficiency ● An abnormal exogenous substance is deposited and Accumulates because the cell has neither the enzymatic Machinery to degrade the substance nor the ability to transport It to other sites. Example. Accumulation of carbon or silica particles
  • 54. Fatty Change (Steatosis) Refers to any abnormal accumulation of triglycerides within ✔ parenchymal cells Most often seen in the liver but may also occur in the heart, ✔ Skeletal muscle, kidney and other organs May be caused by toxins, protein malnutrition, diabetes ✔ mellitus, obesity and anoxia Alcohol abuse and diabetes associated with obesity are ✔ the most common causes of fatty liver
  • 56. Cholesterol and Cholesteryl Esters ✔ Result of defective catabolism and excessive intake Present in lipid vacoules of smooth muscle cells and ✔ macrophages in atherosclerosis (hardening of the aorta) Give atherosclerotic plaques their characteristic yellow color ✔ and contibute to the pathogenesis of the lesion ✔ Xanthomas are hypercholesterolemic tumurous masses found in the connective tissue of the skin or tendons
  • 57. Proteins ✔ Less common than lipid accumulations ✔ Occur because excess are presented to the cells or because the cells synthesize excessive amounts ✔ Examples: 1) Nephrotic syndrome there is heavy protein leakage across the glomerular filter due to a much larger reabsorption of albumin 2) accumulation of newly synthesized imunoglobulins in RER of some plasma cells forming rounded, eosinophilic Russell bodies 3) Mallory body or “ alcoholic hyalin” is an eosinophilic cytoplasmic inclusion in liver cells highly characteristic of alcoholic liver disease 4) Neurofibrillary tangle found in the brain in Alzheimer disease
  • 58. Protein reabsorption droplets in the renal tubular epithelium
  • 59. Glycogen ✔ Accumulations of these are associated with abnormalities in the metabolism of either glucose or glycogen ✔ Ex. 1) In poorly controlled diabetes mellitus, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of Islets of langerhans 2) Glycogen storage diseases or glycogeneses are Genetic disorders where glycogen accumulates in macrophages of patients with defects in lysosomal enzymes
  • 60. Pigments ➢ colored substances that are either exogenous or endogenous ● Exogenous – coming from outside the body 1) Carbon ( ex. Coal dust) ➔ Most common air pollutant ➔ Aggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (Anthracosis) ➔ Heavy accumulations may induce emphysema or a fibroblastic reaction that can result in a serious lung disease called coal workers pneumoconiosis
  • 61. ● Endogenous – synthesized within the body itself 1) Lipofuscin or “wear-and -tear pigment or lipochrome ✔ an insoluble brownish-yellow granular intracellular material that accumulates in the heart, liver, & brain as a function of age or atrophy ✔ represents complexes of lipid & protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipids ✔ it is not injurious to the cell but is important as a marker of past free-radical injury ✔ the brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy
  • 62. The pale golden brown finely granular pigment seen here in nearly all hepatocytes is lipochrome (lipofuscin).
  • 63. 2) Melanin ✔ An endogenous, brown-black pigment synthesized exclusively by melanocytes when the enzyme tyrosinase catalyzes tyrosine to (DOPA) dihydroxyphenylalanine located in the epidermis ✔ Acts as a screen against harmful ultraviolet radiation ✔ Basal keratinocytes in the skin can accumulate the pigment (e.g. in freckles)
  • 64. Melanin pigment in melanoma
  • 65. 3) Hemosiderin ✔ A hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron ✔ Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles ✔ Iron can be identified by the Prussian blue reaction
  • 66. Local excess of iron & consequently of hemosiderin result ✔ from hemorrhage Ex. Bruise The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and bilirubin (red bile) from the heme moiety ✔ The iron of hemoglobin accumulate as golden- yellow hemosiderin
  • 67. Hemosiderosis ✔ a condition where hemosiderin is deposited in many organs and tissues whenever there is systemic overload of iron ✔ It occurs in the following settings •Increased absorption of dietary iron •Impaired utilization of iron •Hemolytic anemias •Transfusions Hereditary Hemochromatosis ✔ A condition where there is extensive accumulations of iron with tissue injury like liver fibrosis, heart failure and diabetes mellitus ✔ Characterized principally by 1) the deposition of hemosiderin in the following organs (in decreasing order of severity):liver, pancreas, myocardium, pituitary, adrenal, thyroid, joints & skin 2) cirrhosis and 3) pancreatic fibrosis
  • 68. PATHOLOGIC CALCIFICATION ➢ implies the abnormal deposition of calcium salts, together with small amounts of iron, magnesium, and other minerals TYPES A. Dystrophic calcification ✔ deposition of calcium in dead or dying tissues ✔ occurs in the absence of calcium metabolic derangements ( with normal serum levels of calcium) ✔ Local deposits of calcium may occur in 1) necrotic tissue which is not absorbed ● old infarcts ● tuberculous foci ● old collection of pus ● dead parasites ● acute pancreatic necrosis
  • 69. 2) Tissue undergoing slow degeneration ● Hyaline areas in benign tumors ● Fibroids ● In arteries due to atheromatous degeneration or old age ● Old thrombi ● Diseased or abnormal heart valves Pathogenesis ➢ Initiation ( or nucleation) ➢ Propagation Both may be intracellular or extracellular with calcium phosphate as the end product
  • 70. B. Metastatic Calcification ✔ deposition of calcium salts in normal tissues ✔ almost always reflects some derangement in calcium metabolism ( hypercalcemia) Four major causes of hypercalcemia 1) Increased secretion of parathyroid hormone, due to either parathyroid tumors or production of parathyroid hormone- Related protein by other malignant tumors 2) Destruction of bone due to the effects of accelerated turnover (e.g. Paget disease),immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia or diffuse skeletal metastases) 3) Vitamin D-related disorders like vitamin D intoxication and sarcoidosis ( in which macrophages activate a vitamin D precursor 4) Renal failure, in which phosphate retention leads to secondary hyperparathyroidism
  • 71. CELLULAR AGING ➢ results from combination of accumulating cellular damage (e.g., by free radicals), reduced capacity to divide (replicative senescence), and reduced ability to repair damaged DNA Cellular senescence ➢ Aging of a person is intimately related to cellular aging Mechanisms known or suspected to be responsible for cellular aging ● DNA damage ✔ defective DNA repair mechanisms DNA repair may be activated by calorie restriction (known to prolong aging in model organisms)
  • 72. ● Replicative senescence ✔ Reduced capacity of cells to divide because of decreasing amounts of telomerase and progressive shortening of chromosomal ends (telomeres) Telomeres ➔ are short repeated sequences of DNA present at the linear ends of chromosomes ➔ Importance * for ensuring the complete replication of chromosome ends * and for protecting the ends from fusion & degradation ● Progressive accumulation of metabolic damage ✔ Repeated environmental exposure to radiation ✔ Progressive reduction of antioxidant defense mechanism Like Vit. E & glutathione peroxidase ● Possible roles of growth factors
  • 74. WERNER SYNDROME ➢ A rare disease characterized by premature aging