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Reversible andIrreversible cell injury

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Reversible andIrreversible cell injury Powered By Docstoc
					Cell Injury:
                   “Is the
                foundation of
               medical science
                and practice.
                    Without
               pathology, the
                  practice of
               medicine would
                be reduced to
                  myths and
                   folklore”
      Reversible
          and
Irreversible Cell Injury
               Objectives
   Recall Cell Injury and its mechanism
   Reversible and Irreversible cell injury
   Their Mechanisms and morphology
   Necrosis :
                - definition
                - types
   Apoptosis :
                 - definition
                 - causes
                 - examples
    Summary
Cell Injury:


                       CELL DEATH
              Ultimate result of injury, like, ischaemia,
               infection, toxins, immune rxn’s.

              Physiologically seen in embryogenesis,
               lymphoid tissue development,
               hormonally induced involution.

              Therapeutically in cancer radiotherapy
               and chemotherapy.
Cell Injury:


               Cell Injury and Cell Death

     Cell Injury – Reversible
                  – Irreversible

     Cell Death – Necrosis
                 – Apoptosis
Cell Injury:
               Causes of
               Cell Injury
Cell Injury:


         Mechanisms of Cell Injury

    OH, DEATH HAS TEN THOUSAND SEVERAL
    DOORS
    FOR MEN TO TAKE THEIR EXITS....



    -- JOHN WEBSTER, THE DUCHESS OF MALFI (17TH CENTURY)
Mechanisms of Cell Injury
Cell Injury:

      Depletion of ATP

         Na
         +      K+
         Ca2+
Mechanisms of Cell Injury
 Cell Injury:




Mitochondrial
  Damage
Mechanisms of Cell Injury
 Cell Injury:




 Influx of
 Intracellular
 Calcium and Loss
 of Calcium
 Homeostasis
Cell Injury:




               Superoxide dismutase
               (SOD)
Cell Injury:   Cellular and biochemical
                sites of damage in cell
                         injury
Cell Injury:




     Reversible Cell Injury
Cell Injury:


         Reversible Injury
       Reversible Injury
               Cellular swelling
               Fatty change
     Mitochondrial Changes
     Reduced oxidative phosphorylation
     ATP depletion
     Plasma membrane alteration
     Dilation of Endoplasmic reticulum
     Nuclear Alteration
Cell Injury:


         Reversible Injury
    Cellular swelling :
      Incapability of cells to maintain ionic and
  fluid homeostasis.
      As a result of loss of function of plasma
  membrane energy-dependent ion pumps.

     Fatty change:
       Hypoxic injury
       Various forms of toxic or metabolic injury.
Cell Injury:   Reversible Injury
                 Morphology
       Gross: pallor, increased turgor and
        increased weight of the organ.
       Microscopy: small clear vacuoles within the
        cytoplasm (distended and pinched-off
        segments of ER.

       Hydropic change or vacuolar degeneration.
Cell Injury:

  Reversible Changes :
                            Normal Cell
      Plasma membrane
      alteration
      (blebbing).

      Mitochondrial
      damage : swelling,    Reversible
      phospholipid rich     Injury
      small densities.

      Dilatation of the
      endoplasmic
      reticulum with        Irreversible
      detachment of
      polysomes.            Injury

      Nuclear alteration.
Irreversible Cell Injury

    Our lives are filled with joys and strife,
     And what is death but part of life?
     Will come the day that we must die,
    And leave behind those learning why.

           -- "The Pathology Blues"
Cell Injury:    Persistent or excessive injury

                   Irreversible injury.




  Extensive Membrane damage.
  Vacuolization of mitochondria with less ATP production.
  Massive influx of extracellular Ca2+, release of intracellular
  Ca+stores – damage to cell membrane, cytoskeleton, proteins.
  Continued loss of proteins, essential coenzymes and RNAs
  from the hyperpermeable plasma membrane.
  Lysosomal swelling, Injury to its membranes, enzyme leakage,
  digestion of cell.
  Further depletion of intracellular ATP.
Cell Injury:


         Irreversible Cell Injury
          Two consistent characteristics of
           irreversibility:
    1)     Inability to restore mitochondrial function
    2)     Severe cell membrane damage
     • Leak of lysosomal contents leading to
        cytoplasmic and nuclear degradation
     • Massive leak of intracellular substances and
        influx of calcium
Cell Injury:


         Necrosis

       A spectrum of morphological changes that
        follow cell death in living tissue,

       Results from the progressive degradative
        action of enzymes (self or derived from
        leukocytes) on the lethally injured cell.
Cell Injury:


         Necrosis
      Result of:
 1.   Denaturation of intracellular proteins
 2.   Enzymatic digestion of the cell.

      Autolysis: Dissolution of dead cells in a dead
      tissue by the cells own digestive enzymes.

      Morphological changes of necrosis takes
      several hours to develop.
Cell Injury:


         Morphology of Necrotic Cells
     Increased Eosinophilia of cytoplasm
          - loss of RNA (basophilia)
          - denatured cytoplasmic protein

     Glassy homogenous appearance
          - loss of glycogen particles

     Vacuolated cytoplasm (moth-eaten)

     Myelin figure
          – large, whorled phospholipid mass
     Calcification of dead cells (calcium soaps)
Cell Injury:
Cell Injury:
Cell Injury:




Nuclear shrinkage
and increase
basophilia

                                         Fragmentation




                    Loss of basophilia
Cell Injury:




                                            Sequels of Cell Death by
                                                   Necrosis



               Normal cell                                 Karyorrhexis

                             Reversible
                             cell injury
                             with          Irreversible
                             cytoplasmic   cell injury                Karyolysis
                             & organelle   with rupture
                             swelling,     of membrane
                             blebbing &    & organelles,
                             ribosome      & nuclear
                             detachment    pyknosis
Cell Injury:
Cell Injury:


          Types of Necrosis:
         Coagulative necrosis
         Liquefactive necrosis
         Caseous necrosis
         Fat necrosis
Cell Injury:


         Coagulative Necrosis
       Characteristic of Hypoxic death of cells in all tissues
        except the brain.
              – e.g. Myocardial infarction
       Preservation of basic outline of the coagulated cell
       Firm texture of the affected tissue
       Intracellular acidosis
              – protein and enzymes denatured
              – proteolysis inhibited
       Removal of the necrotic cells by fragmentation and
        phagocytosis of the cellular debris by scavenger
        leucocytes and their proteolytic lysosomal enzymes.
Cell Injury:


         Renal Infarction - Coagulative



   A wedge-shaped
    pale area of
    coagulative
    necrosis
    (infarction) in the
    renal cortex of the
    kidney.
Cell Injury:


         Splenic Infarction - Coagulative necrosis
Cell Injury:




  Ischemic necrosis of the myocardium
  A, Normal myocardium.
  B, Myocardium with coagulation necrosis
Cell Injury:


         Renal Infarction - Coagulative necrosis

           Coagulative                 Normal
           necrosis                    renal
                                       parenchyma
Cell Injury:


         Normal & Ischemic - kidney tubule


                                             Microvilli
Cell Injury:

               Liquefactive Necrosis
      Focal bacterial (or fungal) infections
             – accumulation of inflammatory
               cells
     Transformation of the tissue into a liquid
     viscous mass by the powerful action of
     hydrolytic enzymes of bacteria and
     leucocytes.
     Hypoxic death of cells within CNS.
Cell Injury:


         Stroke- Liquefactive necrosis
Cell Injury:




         Lung abscess:
         Liquefactive
         necrosis
Cell Injury:




Coagulative and liquefactive necrosis
        A, Kidney infarct exhibiting coagulative necrosis
        B, A focus of liquefactive necrosis in the kidney
Cell Injury:




The liver shows a small abscess here filled with many neutrophils.
This abscess is an example of localized liquefactive necrosis
Cell Injury:


         Gangrenous Necrosis
       Not a distinctive pattern of necrosis
       Surgical clinical term
       Limb (lower leg)
       Loss of blood supply  coagulative
        necrosis
       Superimposed by bacterial infection
       Coagulative pattern  Dry gangrene
       Liquefactive pattern  Wet gangrene
Cell Injury:


         Gangrene - Diabetic foot
Cell Injury:


         Gangrene - Amputated Diabetic foot
Cell Injury:


         Gangrene Intestine - Thrombosis.
Cell Injury:


         Caseous necrosis
        Cheesy, grey white, soft, friable debris.

        Eosinophilic, amorphous, granular debris
        surrounded by inflammatory cells
        (granulomatous reaction).

        Complete destruction of tissue
        architecture.
Cell Injury:




       A tuberculous lung with a large area of caseous
       necrosis
Cell Injury:




         Caseous necrosis
         in a hilar
         lymphnode
Cell Injury:




      Extensive
      Caseous necrosis
      in a Tuberculosis
      lung.
Cell Injury:




    Tuberculous granuloma showing an area of central
    necrosis, epithelioid cells, multiple Langhans-type
    giant cells, and lymphocytes.
Cell Injury:


         Caseous necrosis - Tuberculosis
Cell Injury:


         Fat Necrosis
       Not a specific pattern
       Focal areas of fat digestion
       Usually via release of activated pancreatic
        lipases into the pancreas and peritoneal
        cavity.
       FFA combine with Ca to produce grossly
        visible chalky white “soaps” (fat
        saponification).
Cell Injury:




               Foci of fat necrosis with saponification in the
               mesentery
Cell Injury:


         Fat Necrosis - Peritoneum.
Cell Injury:


          Sequels of Necrosis:
              Autolysis / Apoptosis
              Phagocytosis
              Organization & fibrous repair
              Dystrophic calcification
Cell Injury:


         Examples of Cell Injury and Necrosis
        Hypoxia :
        State of reduced oxygen availability.
        Glycolytic energy production can continue.


        Ischemia :
        Caused by reduced blood flow, usually as a
        consequences of a mechanical obstruction in the
        arterial system.
Cell Injury:


         Ischemic injury
Mechanisms of Cell Injury
 Cell Injury:




  Ischemic injury
Cell Injury:


          Reperfusion injury

    Depending on the intensity and duration of the ischemic
      event additional cells may die as a result of reperfusion
      by necrosis as well as apoptosis.
     Prominent neutrophilic infiltration is associated with

      reperfusion injury.
     E.g. - myocardial infarction, stroke and acute renal

      failure.
Cell Injury:


           Mechanism
        Increased generation of oxygen free radicals from
        resident tissue cells and infiltrating WBCs. Antioxidant
        systems may also be compromised by the initial insult.

        Reactive O2 species promotes MPT which precludes
        mitochondrial recovery

        Ischemic related inflammation attracts neutrophils to the
        reperfused tissue causing additional injury.

        Some IgM antibodies bind to ischemic tissue and
        reperfusion results in the activation of complement
        proteins resulting in increased inflammation.
Cell Injury:


         Chemical injury
    Two general mechanisms
       Directly by binding a critical molecule (usually a
        protein)
            - Mercuric chloride poisoning
            - Cyanide poisoning

              Indirectly by conversion to a reactive, toxic metabolite
               which:
                 Directly binds a critical molecule

                 Forms a reactive free radical (more common)
Cell Injury:
                                                    Chemical
                                                     injury



                                               Figure: Sequence of
                                               events leading to fatty
                                               change and cell necrosis
                                               in carbon tetrachloride
                                               (CCl4) toxicity. RER,
                                               rough endoplasmic
                                               reticulum; SER, smooth
                                               endoplasmic reticulum.

               Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 19 October 2005 05:23 PM)
                                                                                            © 2005 Elsevier
Cell Injury:


         Apoptosis
       Cell death that is induced by a tightly regulated
        intracellular program.

       The cells destined to die activate enzymes that
        degrade the cells’ own nuclear DNA and nuclear
        and cytoplasmic proteins.

               “Programmed Cell Death”

       Causes of Apoptosis
          - Physiologic situations
          - Pathologic conditions
Cell Injury:
               Morphology of
                 Apoptosis
               Cell shrinkage

               Chromosome
               condensation

               Formation of
               cytoplasmic blebs
               and apoptotic
               bodies

               Phagocytosis of
               apoptotic cells or
               cell bodies
Cell Injury:
Cell Injury:




   No
Cell Injury:



               Microscopy

                Involves single cells
                or small clusters of
                cells.

                 Round /oval mass of
               intensely eosinophilic
               cytoplasm with dense
               nuclear chromatin
               fragments.
Cell Injury:   Apoptosis in Physiologic
               Situations
     Programmed destruction of cell during
      embryogenesis
     Hormone-dependent involution
         - endometrial cells (menstrual cycle)
     Cell deletion in proliferating cell population
     Death of host cells - neutrophils
     Elimination of self reactive lymphocyte
     Cell death induced by cytotoxic T-cells
          - viral infected or tumor cells
Cell Injury:
               Apoptosis in Pathologic
               Conditions
       Cell death produced by injurious stimuli –
        radiation, cytotoxic drug

       Cell injury in certain viral diseases – viral
        hepatitis

       Pathologic atrophy

       Cell death in tumors
Cell Injury:


         Examples of Apoptosis
       Apoptosis after Growth factor deprivation
         - lymphocytes that are not stimulated by antigens and
        cytokines
         - neurons deprived of nerve growth factor.


       DNA Damage – Mediated Apoptosis
           - exposure of cells to radiation or chemotheurapeutic
        agents
Cell Injury:


         Examples of Apoptosis
       Apoptosis induced by Tumor Necrosis
        Factor Family of Receptors
            - elimination of lymphocytes that recognize self-
        antigens causing Autoimmune diseases


       Cytotoxic T-Lymphocytes-Mediated
        Apoptosis
Cell Injury:




               Summary
Cell Injury:

                               Overview
                                + Stress
                Normal                       Adapted
                 cell           - Stress       Cell

                 Injury

               Reversibly
               injured cell


                                 Apoptosis
               Irreversibly
                                                Dead cell
                Injured cell
                                  Necrosis
Cell Injury:
Cell Injury:
               Reversible vs irreversible
               cell injury
         Reversible injury    Irreversible injury
    * Decreased ATP          * Amorphous
      levels                   densities in
    * Ion imbalance            mitochondria
    * Swelling               * Severe membrane
     Decreased pH
                               damage
     Fatty change
                             * Lysosomal rupture
      (liver)                 Extensive DNA

                               damage
Cell Injury:


         Cell Death
Morphology of
 Cell Injury:
                         Morphology of
   Necrosis                Apoptosis
 Cell
                         Cell shrinkage
 swelling
                         Chromosome
Pyknosis                 condensation
Karyorrhexis
                         Formation of
karyolysis
                         cytoplasmic blebs
                         and apoptotic
Formation of             bodies
cytoplasmic
blebs
                         Phagocytosis of
                         apoptotic cells or
Enzymatic
                         cell bodies
digestion and
leakage of
cellular contents
 Inflammatory reaction
Cell Injury:
               Features of Necrosis and Apoptosis


    Feature                  Necrosis                  Apoptosis


    Cell size                 Enlarged                 Reduced

    Nucleus         Pyknosis/karyorrhexis/karyolysis   Fragmentation

    Plasma membrane           Disrupted                Intact

    Cellular contents         Enzymatic digestion      Intact

    Inflammation              Frequent                 None

    Physiologic/pathologic    Pathologic               Physiologic
Cell Injury:


         Reversible injury
         1.    Reversible injury results from a decrease in ATP
               production

         2.    Irreversible injury occurs when ATP depletion and
               membrane dysfunction result in significant
               mitochondrial injury.

         3.    Reperfusion injury plays a significant role in the
               result of ischemic injury by:
               1. The induction of free radical formation.
               2. Eliciting an inflammatory response.
Cell Injury:




        Physiologic changes precede morphologic changes in all
        forms of cell injury.

        Reversible cell injury causes changes associated with
        decreased ATP production (cell swelling and fatty
        change)) that may be visible.

        Irreversible injury (necrosis) results in morphologic
        change due to
         1.    Denaturation of protein
         2.    Enzymatic digestion of cell components
Cell Injury:
Cell Injury:

               3 R’s of success:




         Respect for self,
      Respect for others and
  Responsibility for all your actions

				
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