Cell Injury, Cell Death, and Adaptations Richard D. Boucher

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Cell Injury, Cell Death, and Adaptations

• Richard D. Boucher, MD
• Clinical Medicine I
• Adjunct Faculty, SCCO

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Introduction to Pathology

• Vocabulary
• Pathology
• Literally it is the study of suffering
• What happens to tissues/organs of the body in the
  presence of disease
• Disease
• Literally a lack of ease
• Pathological process of the body organ(s) with
  its own signs and symptoms
• Dysfunction of significant number of cells in the
  organ must occur first

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• Disorder
• Organ is normal but malfunction of the organ
  exists
• Disease may or may not be present
• Sickness
• The physical and/or mental state of being
  unwell
• Can be due to emotions, background, inheritance
  self image, presence or absence of psychiatric
  problems, etc.

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Introduction to Pathology

• Vocabulary
• Health
• Well being state indicating normality of body,
  mind and spirit
• Origin in health cells in tissues and organs
• Sign
• Observable objective or measurable physical
  manifestations of disease(s) or disorder(s)

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Introduction to Pathology

• Symptom
• Subjective evidence of a disease or disorder
• Diagnosis
• Attachment of a specific name to a specific
  disease or disorder
• Summation of signs, symptoms, tissue changes,
  chemistry, physiology or function changes unique
  to that disease or disorder

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Introduction to Pathology

• Vocabulary
• Prognosis
• Making a prediction of the outcome of a disease
  or disorder
• Therapy
• Treatment of a disease or disorder
• Several components
• Supportive lenses
• Restorative VT
• Physical agents laser
• Chemical medications
• Surgical

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Introduction to Pathology

• Etiology
• The cause of a disease or disorder
• Pathogenesis
• Underlying mechanisms resulting in the signs and
  symptoms of the patient
• Morphology
• Gross or microscopic appearance of cells and
  tissues
• For a disease or disorder to become manifested
  clinically, there first must be a dysfunction of
  a significant number of cells in an organ or
  tissue

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Overview of Cellular Responses to Stimuli

• Cells operate in a very narrow range of
  physiologic parameters they maintain
  homeostasis
• Homeostasis equilibrium of the microenvironment
  of the cell
• Chemical electrolytes, glucose, pH, etc.
• Physical temperature, etc.

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Overview of Cellular Responses to Stimuli

• Constantly adjust their structure and function
  adapting to their altered environment
• Adaptation adjusting to a new situation to
  preserve viability and function
• Stress pathological definition any demand on
  the cell requiring it to adapt

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Overview of Cellular Responses to Stimuli

• Inability to adapt will compromise the cell and
  result in injury and possibly death
• Principle adaptive responses
• Hypertrophy
• Hyperplasia
• Atrophy
• Metaplasia

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Overview of Cellular Responses to Stimuli

• If the adaptive capability of the cell is
  exceeded or the stress inherently harmful, cell
  injury occurs
• Reversible return to baseline
• Irreversible
• Cell death causes include ischemia, infections,
  toxins, and immune reactions
• Cell death can be a normal and essential process

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Stages in cellular response to stress and
injurious stimuli
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Cell reaction to stimuli
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Overview of Cellular Responses to Stimuli

• Other factors that affect stress on the cell
• Vulnerability - by location
• Differentiation by specific cellular function,
  i.e., different cells do different things which
  may predispose to protection or problems
• Blood supply better supply, better chance of
  survival
• State of nutrition
• State of cellular health at the time of stress

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Overview of Cellular Responses to Stimuli

• Molecular and biochemical levels that stress may
  affect
• Maintenance of cellular membrane
• Cell and its components
• Trauma, acids, etc.
• Maintenance of ionic/osmotic balance
• Water, medications, etc.
• Energy production by the cell
• Protein synthesis
• nutrition
• Genetic apparatus
• Viruses, radiation, etc.

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Cellular Adaptations to Stress

• Adaptations are reversible changes in the number,
  size, metabolic activity, and functions of cells
• Two basic types
• Physiologic
• Cellular response to normal stimulation
• e.g. - hormones
• Pathologic
• Modified cellular response to avoid injury

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Hypertrophy

• Increase in the size of cells resulting in
  increase in the size of the organ
• No new cells, just bigger cells
• Occurs in cells that cannot divide
• Physiologic weight lifter
• Pathologic - cardiac enlargement hypertension,
  aortic valve stenosis
• Cardiac failure adaptation to stress can lead
  to functionally significant cell injury

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Hyperplasia

• Increase in cell number
• Occurs in cells capable of replication
• Can occur with hypertrophy
• Physiologic
• Hormonal breast during puberty and pregnancy
• Compensatory part of tissue is removed kidney,
  liver

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Hyperplasia

• Pathologic
• Caused by excessive hormonal (abnormal menstrual
  bleeding) or growth factor stimulation (viral
  infection causing warts)
• If stimulation abates, hyperplasia disappears.
  Not so with cancers

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Atrophy

• Shrinkage in the size of the cell by loss of cell
  substance
• Tissue or organ size diminishes in size
• Function diminishes not death

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Atrophy

• Causes
• Immobilization
• Loss of innervation
• Diminished blood supply
• Inadequate nutrition
• Loss of endocrine stimulation
• Aging
• Autophagy can occur
• Physiologic and pathologic

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Metaplasia

• Reversible change in which one adult cell type is
  replaced by another adult cell type
• Cells sensitive to a certain stress are replaced
  by another cell type capable of better
  withstanding that stress

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Metaplasia

• It is a genetic reprogramming of stem cells and
  not changing of already differentiated cells
• Function can be reduced
• Increased chance of malignant transformation
• Examples
• Cigarette smoking
• Gastric reflux

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Metaplasia of columnar to squamous epithelium
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Cell Injury and Death

• Occurs when cells are unable to adapt to stress
  or when they are exposed to damaging agents or
  suffer intrinsic abnormalities
• Reversible cell injury
• Damage reversed when stimulus removed

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Cell Injury and Death

• Cell death
• Injury is irreversible
• Two types
• Necrosis enzymes leak out of lysosomes and cell
  is digested. Leakage through cell membrane
  elicits inflammation. Due to ischemia, toxins,
  infections, trauma
• Apoptosis cell kills itself, no membrane leakage

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Necrosis vs. Apoptosis
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Causes of Cell Injury

• Iatrogenic
• Doctor caused disease or disorder medication
  reaction
• Fomite
• Object capable of transmitting a disease
  improperly cleaned instrument
• Stress factors
• Hypoxia oxygen deficiency
• Ischemia decreased blood supply
• Inadequate oxygenation of blood - pneumonia
• Reduction in oxygen-carrying capacity of blood
  anemia, CO poisoning

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Causes of Cell Injury

• Chemical agents
• Alter membrane permeability, osmotic homeostasis,
  enzyme damage
• Examples glucose, salt, oxygen
• Infectious agents
• Viruses, bacteria, fungi, protozoans, etc.

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Causes of Cell Injury

• Stress factors
• Immunologic reactions
• Defend against pathologic organisms
• Autoimmune reactions against ones own tissues
• Allergic reactions
• Genetic defects
• Can cause cell injury by inborn errors of
  metabolism
• Accumulation of damaged DNA

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Causes of Cell Injury

• Nutritional imbalances
• Protein-calorie insufficiency
• Vitamin deficiencies
• Excesses in nutrition
• Obesity diabetes mellitus, atherosclerosis

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Causes of Cell Injury

• Stress factors
• Physical agents
• Trauma
• Extremes of temperature
• Radiation
• Electrical energy
• Changes in atmospheric pressure

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Causes of Cell Injury

• Aging
• Alterations in replication and repair abilities
• Long term accumulation of toxins, radiation,
  injuries, etc.?

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Cell and Tissue Injury

• Cellular function may be long lost before cell
  death occurs
• Example of myocardial cells
• Reversible injury
• Cellular swelling
• Fatty change
• Liver and heart
• Irreversible injury
• Inability to reverse mitochondrial dysfunction
• Profound disturbances in membrane function

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Necrosis

• Degradative action of enzymes on lethally injured
  cells
• Membrane integrity is lost and contents leak out
  causing inflammation
• Enzymes come from cellular lysosomes or from the
  lysosomes from recruited leucocytes
• Enzymes given off from a particular organ can
  indicate damage to that organ
• Heart CPK, troponin
• Liver alkaline phosphatase, transaminases (ALT,
  AST)

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Necrosis

• Types
• Coagulative tissue necrosis in which component
  cells are dead but basic architecture is
  preserved for a short while
• Liquefactive complete digestion of the cell
• Caseous - friable yellow-white appearance
  (cheese-like), architecture completed
  obliterated. Has an inflammatory border giving
  the appearance of a granuloma.

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Cell injury
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Subcellular Responses to Injury

• Certain agents and stresses can affect only
  subcellular organelles
• Some are seen in lethal injury, some in adaptive
  responses

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Subcellular Responses to Injury

• Lysosomes cytoplasmic bodies that contain
  hydrolytic enzymes used to breakdown phagocytosed
  material
• Autophagy digestion of cells own components
• A survival mechanism in times of nutrient
  deprivation
• Heterophagy ingestion of outside material for
  intracellular destruction
• Example - macrophage

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Subcellular Responses to Injury

• Induction (hypertrophy) of smooth endoplasmic
  reticulum
• Involved in metabolism of chemicals
• Hypertrophy is adaptive response to chemical
  stimuli

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Subcellular Responses to Injury

• Example barbiturates and cytochrome P-450
  system swelling occurs to better metabolize
  medication but may better metabolize other
  medications as well (alcohol)
• Mitochondrial alterations
• Energy producers in the cell

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Subcellular Responses to Injury

• Cytoskeletal abnormalities
• Consists of actin and myosin filaments,
  microtubules and various filaments that are
  altered
• These structures are responsible for
• Intracellular transport of organelles and
  molecules
• Maintenance of cell architecture

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Subcellular Responses to Injury

• Maintenance of mechanical strength for tissue
  integrity
• Cell mobility
• phagocytosis

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Mechanism of Cell Injury

• Cellular response to injurious stimuli depends on
  the type of injury, its duration, and its
  severity
• Consequences of the injurious stimulus depends on
  the type, status, adaptability, and the genetic
  make-up of the injured cell
• Striated versus cardiac muscle

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Mechanism of Cell Injury

• Cell injury results from functional and
  biochemical abnormalities in one or more of
  several essential cellular components
• Mitochondria
• Cell membranes
• Protein synthesis
• Cytoskeletal
• Genetic apparatus

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Principle Sites of Damage in Cell Injury
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Examples of Cell Injury and Necrosis

• Ischemia and hypoxic injury
• Ischemia
• Diminished blood flow to a tissue
• Most common cause of cell injury
• Compromises delivery of substrates for glycolysis
• Hypoxia
• Decreased oxygen delivered

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Examples of Cell Injury and Necrosis

• Ischemia-reperfusion injury
• Restoration of blood flow can cause exacerbated
  and accelerated injury
• Chemical (toxic) injury
• Chemical may combine with a component of the cell
• Inactive chemical is converted to a reactive
  toxic metabolite

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Apoptosis

• Cell destroys its own nuclear DNA and nuclear and
  cytoplasmic proteins
• Plasma membrane remains intact
• Membrane altered inducing phagocytosis but no
  leakage
• No inflammation

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Apoptosis

• Physiologic
• Death of specific cell types at defined times
  during development of the organism
• Involution of hormone-dependent tissues upon
  hormone deprivation
• Cell loss in proliferating cell populations
• Intestinal crypt epithelia

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Apoptosis

• Death of cells that served their purpose
• Neutrophils in an acute inflammatory response
• Elimination of potential harmful self-reactive
  lymphocytes
• Prevents reaction against ones own tissue

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Apoptosis

• Pathologic
• Eliminates cells that are genetically altered or
  injured
• DNA damage
• Cell injury in certain infections viruses

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Apoptosis

• Examples
• Growth factor deprivation
• Hormone-sensitive cells deprived of the hormone
• Lymphocytes not stimulated by antigens
• Neurons deprived of nerve growth factor

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Apoptosis

• DNA damage
• Exposure to radiation or chemotherapeutic agents
• Self-reactive lymphocytes
• Lymphocytes that encounter self antigens
• Failure of apoptosis here causes autoimmune
  diseases

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Cellular Aging

• Result of a progressive decline in the
  proliferative capacity and life span of cells and
  the effects of continuous exposure to exogenous
  factors that cause accumulation of cellular and
  molecular damage
• Responsible mechanisms
• DNA damage
• Occurs during normal replication
• Defects in DNA repair mechanisms
• DNA repair mechanisms can be activated by caloric
  restriction

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Cellular Aging

• Decreased cellular replication
• All normal cells have a limited capacity for
  replication
• Reduced regenerative capacity of stem cells
• Accumulation of metabolic damage
• Cellular life span is a balance between damage
  from metabolic events and molecular response that
  repair the damage