ADAPTATION - MODULE 1

What is pathophysiology?

• study of functional changes in cells, tissues, and organs altered by disease or injury

What is disease?

• acute or chronic illness

• acquired or congenital

• causes physiologic dysfunction in one or more body systems

How is disease characterized?

• signs and symptoms which characterize pathology and etiology

What are manifestations?

• signs + symptoms

What is cell adaptation, injury, and death?

• alteration in cell or tissue function underlies EVERY disease

How can cells be altered?

1. adaptation (reversible)

2. injury (reversible / irreversible)

3. death via necrosis or apoptosis

4. aging

5. neoplasia

What are cellular adaptations?

• changes in size, number, or type of cell for survival and maintenance of function under stress

• occurs as a result of normal or adverse conditions

What is an example of normal cellular adaptations?

• uterine cells increase in size and number as a result of pregnancy

What is an example of adaptation from adverse conditions?

• heart muscle cells increase in size due to chronically elevated blood pressure

What are the 5 types of cell adaptation?

1. atrophy

2. hypertrophy

3. hyperplasia

4. metaplasia

5. dysplasia

What is atrophy?

• decrease in size

• may be normal (e.g. thymus gland)

• may be pathological (e.g. muscles or brain)

What is hypertrophy?

• increase in size

• in skeletal muscle and heart muscles which cannot do mitosis

• adapts to increased workload by increasing size

What is hyperplasia?

• increase in cell number (normal cells)

• occurs in tissue with cells capable of mitosis

What are examples of hyperplasia?

• the liver which can reduce by 50-60% and completely regenerate in a month

• breast growth at puberty

• wound healing

What is metaplasia?

• reversible replacement of one mature cell type by another

• due to reprogramming of undifferentiated stem cells

  • e.g. replacement of ciliated simple columnar cells with stratified squamous epithelial cells in smokers

    • is a tradeoff between ciliated cell function and protection offered by stratified cells

What is dysplasia?

• abnormal changes in size, shape, and organization of mature cells

• precursor to cancer

• mitosis rate often increased but not required for dysplasia

• can be reversed if stimulus is removed

  • e.g. cancerous cells in cervix or respiratory tract

What is intracellular accumulation?

• the buildup of material that the cell cannot metabolize

• can be endogenous (normally produced by cell)

• can be exogenous (external sources like coal dust or tattoo pigment

What happens when substance is produced faster than it is used?

• e.g. in alcoholics, impaired liver is unable to process all fatty acids

• storage of excess triglycerides = fatty liver

What happens with pigment during endogenous intracellular accumulation?

• e.g. lipofuscin

  • yellow / brown pigment in liver, heart, and neurons from accumulation of undigested material

  • material is produced during normal cell structure turnover

  • aka wear and tear pigment

What is calcification?

• buildup of calcium salts in tissue

• can occur in damaged and normal tissue

How does calcification occur in damaged tissue?

• damaged heart valves, healed TB lesions, advanced atherosclerosis

• excess calcium comes from damaged / dead cells or circulation

How does calcification occur in normal tissue?

• due to excess serum calcium levels (e.g. hyperparathyroidism)

• can occur in lung, kidney, and blood vessels

What is cell injury?

• cell can no longer maintain homeostasis / cannot adapt

• most diseases begin after cell injury

• reversible or not

• caused by any factor that disrupts the structure or deprives the cell of oxygen and / or nutrients

What are the physical agents that cause cell injury?

• mechanical

• electrical

• radiation

What are the chemicals that cause cell injury?

• drugs

• alcohol

• heavy metals

What are the miological microorganisms that cause cell injury?

• viruses

• bacteria

• parasites

What are the nutritional deficiencies / excess that cause cell injury?

• macronutrients like fats or carbs

• micronutrients like vitamins and minerals

What are the 3 mechanisms of cell injury?

1. hypoxia

2. impaired calcium homeostasis

3. free radicals

What is hypoxia?

• lack of sufficient oxygen for cells

• most common cell injury cause

What is the most common cause of hypoxia?

• ischemia which is reduced blood supply to cells in one area

• gradual narrowing of arteries (e.g. ateriosclerosis)

• sudden acute anoxia (e.g. thrombi, embolisms)

What are the other causes of hypoxia?

• hypoxemia

  • decreased oxygen in air

  • loss of hemoglobin or RBC

  • diseases of respiratory and cardiovascular systems

  • poisons / toxins

What are the pathophysiological effects of hypoxia?

• reduced O2 availability decreases ATP production which results in:

  • increased anaerobic respiration

  • reduced activity of ATP dependent enzymes

  • reduced activity of ATP dependent sodium potassium pump

  • reduced activity of ATP dependent calcium pump

What happens during increased anaerobic respiration?

• lactic acid buildup

• decrease pH

• DNA clumping and decreased activity of many enzymes

What occurs during reduced activity of ATP dependent enzymes?

• phospholipid synthesis reduced

• damaged membranes

  • lysosome daamge

  • mitochondrial damage

  • plasma membrane damage

What happens during lysosome damage?

• leakage of degradative enzymes into cell

• breaks down macromolecules

• results in necrosis

What happens during mitochondrial damage?

• leads to change in membrane permeability

• decreased ATP synthesis

• results in necrosis

What occurs during plasma membrane damage?

• leads to influx of fluids and ions

• loss of cellular contents

• results in necrosis

What happens during the reduced activity of ATP dependent sodium potassium pumps?

• intracellular ion concentrations are altered

• water enters the cell following the increase in intracellular sodium

• causes cellular edema or swelling)

What does cellular edema lead to?

• rough endoplasmic reticulum swelling

• loss of ribosomes

• no protein synthesis

What happens in the reduced activity of ATP dependent calcium pumps?

• results in increased intracellular levels of Ca

• Ca also released from damaged intracellular sources

What is impaired calcium homeostasis?

• increase of intracellular calcium (e.g. via toxins)

• may result in activation of inappropriate enzymes

• may cause increased mitochondrial permeability

What happens during the activation of inappropriate enzymes?

• overall cell damage

• membrane damage in phospholipase and protease

• nuclear damage in endonuclease

• decreased ATP in ATPase

What happens during increased mitochondrial permeability?

• decreased ATP production

What are free radicals?

• unstable molecules

• contains unpaired outer electrons that are highly reactive

• e.g. reactive oxygen species (superoxide anion)

What is free radical injury?

• free radicals non specifically attack atoms in macromolecules

• causes cell damage and disease

  • e.g. cancer, heart disease, and neurodegeneration

What are types of free radicals?

• may be exogenous or endogenous

What are exogenous free radicals?

• environmental agents

• generated by absorption of radiation from X rays or UV light

• also exposure to cigarette smoke or air pollution

What are endogenous free radicals?

• metabolism byproducts

• naturally generated during the general metabolism, drug breakdown, or produced by phagocytes

  • e.g. ROS

How does the body protect itself from ROS?

• ROS scavengers

  • enzymes such as superoxide dismutase

  • antioxidants like vitamins E and C

What are levels of injury dependent on in different people?

• type of cell and how well it adapts to change

• severity and duration of stimulus

• general health, age, and nutritional status

What is apoptosis?

• programmed cell death caused by normal and pathological tissue changes

• ATP dependent

• affects selected cells

• cell shrinks

• no inflammation involved

What are examples of apoptosis?

• intestinal epithelia turnover

• endometrial cell breakdown in the menstrual cycle

• cell death induced by cytotoxic T lymphocytes

What are the steps in apoptosis?

1. cell structures shrink

2. nucleus is destroyed by regulated enzymes (caspases) and turn into DNA fragments

3. membrane protrudes and enclosed fragments pinch off as apoptotic bodies

4. apoptotic bodies are engulfed and cleared by phagocytes

What is necrosis?

• unregulated and passive cell death due to injury

• cell swells and bursts

• leakage of enzymes and self digestion = autolysis

• causes damage to nearby tissues

• brings about an inflammatory response

• often interferes with tissue regeneration

What is coagulative necrosis?

• caused by hypoxia and characteristic of infarcts

• protein denaturation or coagulation occurs

• tissue becomes firm and opaque

• occurs in kidneys, heart, and adrenal glands

What is liquefactive necrosis?

• occurs in focal bacterial or fungal infections (neutrophils release hydrolytic enzymes)

• tissues soften and liquefy, cells are completely digested

• an abcess forms

• can occur in brain via ischemia

What is caseous necrosis?

• cheese like, has crumbly yellowish appearance

• combination of coagulative and liquefactive necrosis

• often enclosed with a granuloma

• often seen in lungs due to tuberculosis infections

What is fat necrosis?

• areas of fat destruction

• results from leakage of pancreatic lipases into peritoneal cavity

• peritoneal fat digested into glycerol and fatty acids which liquefy

• fatty acids combine with ions in tissue to make soap (saponification)

• tissue appears opaque and white

What is gangrene or gangrenous necrosis?

• results from severe hypoxic injury

• refers to significant tissue area whose cells have undergone necrosis

What is dry gangrene?

• due to coagulative necrosis

• skin becomes dry, wrinkled, and dark

• usually due to interference with arterial blood supply

• typically occurs in extremities

What is wet gangrene?

• due to liquefactive necrosis

• usually in internal organs

• area becomes cold, swollen, and black

• has foul odour due to bacterial action

• can easily spread to other tissues

What is gas gangrene?

• specific condition caused by infection with a species of bacteria (clostridium species)

• bacteria produce enzymes that destroy connective tissue

• causes bubbles of gas to form

How does aging work?

• inevitable and normal

• causes structural and functional changes that lead to cellular death by apoptosis

• biological basis is poorly understood

What are the programmed / molecular theories of aging?

• changes that occur with aging and programmed genetically

  • e.g. fruit flies with INDY gene that doubles lifespan

What are the damage / senescence theories of aging?

• changes result from an accumulation of DNA damage due to random events

  • e.g. effects of free radical damage