Cell Injury, Adaptation, & Death

Tonde Matsungo
B.Sc (UZ). M.Phil (UZ)

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Cells

Tissues

Organs

Systems

Organism

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 How is meiosis different?

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 Tumor suppressor genes

synthesize growth inhibition proteins p53

Proto-oncogenes
stimulate cell growth

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Proliferation of Cells
Labile
continuous reproduction

Stable
reproduce slowly until injured

Permanent
no division

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Biologic Aging
Apoptosis
Programmed cell death

Necrosis
Death caused by disease

As cells age, functioning decreases Genetically, telomeres influence cell aging

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 All diseases occur because of cell injury

Either because of the injury itself or the repair process that follows

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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 tmatsungo@gmail 14 in the organ must occur first

 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 tmatsungo@gmail

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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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Causes of Cell Injury

Hypoxia

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Hypoxia
Inadequate oxygenation Most common cause of cell injury Usually due to ischemia Causes chemical & acidbase imbalances Reversible if O2 restored or death if not

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Causes of Cell Injury

Hypoxia Direct physical action

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Direct Physical Action

Major problems are hemorrhage & ischemia

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Causes of Cell Injury

Hypoxia Direct physical action Ionizing radiation

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Ionizing Radiation
Ionizes H2O into H+ & OH OH- attaches to DNA & prevents cell reproduction

DNA mutations

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Causes of Cell Injury

Hypoxia Direct physical action Ionizing radiation Toxic molecular injury

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Toxic Molecular Injury

Dose related

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Causes of Cell Injury

Hypoxia Direct physical action Ionizing radiation Toxic molecular injury Microbes

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Microbes
Toxins can interfere with protein synthesis or utilization of O2

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Causes of Cell Injury

Hypoxia Direct physical action Ionizing radiation Toxic molecular injury Microbes Inflammatory & immune reactions

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Inflammatory & Immune Reactions

Due to cell injury & then in turn causes injury

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Causes of Cell Injury

Hypoxia Direct physical action Ionizing radiation Toxic molecular injury Microbes Inflammatory & immune reactions Nutritional imbalances Genetic defects Aging
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Mild Cell Injury

Hydropic change
Na/K pump damaged so Na+ increases in the cell & H2O moves in causing swelling

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Intracellular Accumulations
Some due to phagocytosis or other normal physiologic mechanisms

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Fat

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Cholesterol
Most extensive & damaging accumulation Atherosclerosis

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Protein

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Glycogen

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Pigments

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Adaptations
Change in size Change in number of cells Change into another type of cell

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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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Atrophy
Decreased size & function Metabolic processes shut down to conserve energy Due to
decreased demand ischemia lack of nerve or hormonal stimulation chronic inflammation
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Hypertrophy
Increased size & functional capacity Due to
hormonal stimulation increased functional demand

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Hyperplasia
Increase in number of cells Due to
hormonal stimulation increased functional demand chronic stress or injury

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Dysplasia
Disorderly overgrowth of cells Premalignant Reversible

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Metaplasia
One cell type to another Reversible

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Necrosis
Pathologic cell death Usually in a collection of cells fed by a single artery

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Coagulative Necrosis
Most common Dead cells form a gellike consistency No anatomic disruption so cells or tissues are left with a ghostly outline Infarction most common cause
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Liquefactive Necrosis
Dead tissue dissolves into liquid Dead cells disrupted faster than it can be cleaned up

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Caseous Necrosis
TB cheesy Cellular detail gone

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Fat Necrosis
May due to trauma Triglycerides digested & free fatty acids precipitate as calcium salts One type of dystrophic calcification
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Gangrene
Dry
part is dry & shrinks skin wrinkles dark brown or black slow spread line of demarcation form of coagulation necrosis extremities part cold, swollen, pulseless moist, black, & under tension liquefaction occurs foul odor no line of demarcation spreads rapidly death if not stopped organs & extremities
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Wet (moist)

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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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 P450 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

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