Cellular adaptations to cell injury

and cell death Banun Kusumawardani

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Definitions : - Pathology : - The study of disease - Clinical Pathology - Laboratory

procedures - Anatomic Pathology – Structural

abnormalities at the cellular & tissue levels - Etiology : - The cause or causes of any disease - Pathogenesis : - The mechanism for the development of the

disease - Homeostasis : - The “steady state“ that cells exist in normally - An equilibrium of the cells with their

environment for adequate function - When disturbed there is a predisposal for the

onset of pathology - Relationships exist between cells & with the

vasculature2

-Tissue changes may be from either of the following :

- Parenchyma - The specific, unique

functioning tissue of an organ - Stroma - The connective tissue

framework & blood vessels of an organ - Not specific to the

organ

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5 Diagrammatic illustration showing the structure of the membrane unit

6Diagrammatic illustration showing the structure of the membrane unit

Reactions of cells to stimuli - Adaptations to environment stress - Cells can adapt to stimuli by either Hypofunctioning or hyperfunctioning

- A persistent sublethal injury can cause …..

1- Hypertrophy = Increase in the size of an organ or tissue due to an increase in the size of the cells e.g. work hypertrophy of muscle

2- Hyperplasia = increase in the size of an organ or tissue caused by increase in the number of the cells e.g. uterine enlargement during pregnancy.

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The relationships between normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation depicted here is hypertrophy, and the type of cell death is ischemic necrosis. In reversibly injured myocardium, generally effects are only functional, without any readily apparent gross or even microscopic changes. In the example of myocardial hypertrophy, the left ventricular wall is more than 2 cm in thickness (normal is 1 to 1.5 cm). In the specimen showing necrosis, the transmural light area in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme leakage after cell death.

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Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus (left) compared with large plump cells in gravid uterus (right).

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Gingival Hyperplasia

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Adaptation to environmental stressDevelopmental causes of reduced cell mass :1- Agenesis = failure of formation of embryonic cell mass 2- Aplasia = - Failure of differentiation to organ specific tissues e.g.

kidney - Failure of cell production - During fetal development aplasia results in agenesis - Later in life; aplasia can be caused by permanent loss of

precursor cells in proliferative tissues such as bone marrow3- Dysgenesis = Failure to undergo structural organization of

tissues into an organ4- Hypoplasia = - Decrease in cell production that is less extreme than that

found in aplasia – failure of growth to full size. Ex.: Turner syndrome & Klinefelter syndrome ; patient lack of growth & maturation of gonadal structure.

5- Atrophy = - Decrease in the size of an organ or tissue resulting from a

decrease in the mass of pre-existing cells. - Results most often from disuse, nutritional or oxygen

deprivation, diminished endocrine stimulation, aging, & denervation - Often marked by presence of autophage granules, i.e.

intracytoplasmic vacoule containing debris from degenerated granules14

Adaptation to environmental stress5a- General atrophy – involves widespread atrophy of

numerous tissues - Starvation atrophy - Senile atrophy - reduced activity leads to reduction in size of

the skeletal muscle fibers5b- Local atrophy - Disuse atrophy - from inactivity of an organ or part - Ex. An arm in a cast results in loss of muscle

due to lack of use - Pressure atrophy - from prolonged pressure on a local area - Ex. Bed sores, atrophy of the submandibular

gland - Endocrine atrophy - from deprivation of hormonal stimulation - Ex. Lactating breast & uterus after menopause. - Denervation atrophy - Ex. Damage to axons supply muscle lack of

stimulation15

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Senile Atrophy

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A, Atrophy of the brain in an 82-year-old male with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply. The meninges have been stripped. B, Normal brain of a 36-year-old male. Note that loss of brain substance narrows the gyri and widens the sulci.

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ADAPTATION TO ENVIRONMENTAL STRESS

6- Involution - Physiological decrease in the number of cells to their

normal number - Ex- thymus gland involutes during adolescence - Ex- myometrium involutes during post partum7- Metaplasia : Replacement of one differentiated tissue by

another in a hostile environment - Squamous metaplasia - Ex- change from columnar ciliated epithelium to

squamous epithelium at the squamocolumnar junction of the cervix

- Associated with chronic irritation (e.g. bronchi with long term use of tobacco); and vitamin A deficiency

- Often reversible - Osseous ( cartilagenous ) metaplasia - Formation of new bone ( cartilage ) at sites of

tissue injury, such as ill-fitting dentures - Myeloid metaplasia ( extramedullary hematopoiesis) - Proliferation of hematopoietic tissue in sites

other than the bone marrow, such as the liver or spleen leads to hepatosplenomegaly such as during sickle cell anemia

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Thymus gland involutes during adolescence

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Metaplasia. A, Schematic diagram of columnar to squamous metaplasia .B, Metaplastic transformation of esophageal stratified squamous epithelium (left) to mature columnar epithelium (so-called Barrett metaplasia).

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Esophageal Mucosa Metaplastic to Stratified Squamous Epithelium

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Cell adaptation key facts 1- Adaptable within physiological limits2- Heat shock – can respond to injury by producing cell stress proteins, which protect from damage & help in recovery

3- Increased demands met by hypertrophy & hyperplasia

4- Reduced demand met by atrophy5- Apoptosis – cell loss from tissues can be achieved by programmed cell death

6- Tissues can adapt to demand by a change in differentiation known as metaplasia.

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Reaction of cells to injury - Reversible injury ( degeneration) - Cell functions impaired but cell can recover

- Irreversible injury - Cessation of all cell functions with cellular death

- Apoptosis : programmed cell death

- Necrosis : Sum of the degradative &

inflammatory reactions occuring after

tissue death31

Reaction of cells to injury on a biochemical level

- Functional (biochemical) changes occur before gross morphologic changes appear

- Ultrastructural changes occur before light microscopic changes appear

- Light microscopic changes occur before gross morphologic changes appear.

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Reaction of cells to injury on a biochemical level

- Ubiquitin - Marks abnormal proteins for degradation

- Ex – heat shock proteins induced by stress

- Chaperones - Specialized protein - Required for proper folding and/or assembly of another protein or protein complex

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Reaction of cells to injury on a biochemical level

- Disorders characterized by protein folding abnormalities

- two known pathogenetic mechanisms - Abnormal protein aggregation , examples

- Amyloidosis - Neurodegenerative diseases e.g. Alzheimer, parkinsonian diseases

- Abnormal protein transport & secretion , eaxmples :

- Cystic fibrosis - Alpha 1-antitrypsin deficiency

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Reaction of cells to injury on a biochemical level

- Biochemical derangements 1- Oxygen – derived free radicals affect cell structure

2- ATP depletion - Needed for energy of all cell functions

3- Loss of calcium homestasis - Calcium enters via membranes & also increases within the cell (cytosolic calcium)

- Calcium activates enzymes capable of degrading cell membranes

4- Defects in membrane permeability Sodium plus other accumulations change the osmotic balance ………. Water enters ………….cloudy swelling

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Reversible cellular changes & accumulations

1- Hydropic degeneration (hydropic change) - Only the cytoplasm is involved - Water accumulates & the cell swells - Large vacuoles in the cytoplasm

- Light microscopy - Cytoplasm is pink & granular

- Electron microscopy (ultrastructural) - Organelles are swollen - Ribosomes displaced - Lysosomal activity very apparent

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Reversible cellular changes & accumulations2- Fatty change/degeneration (steatosis, fatty metamorphosis)

- Characterized by accumulation of intracellular parenchymal triglycerides, nucleus is displaced & the cells swells

- Observed frequently in liver, heart, & kidney - Ex. in liver secondary to alcoholism, diabetes

mellitus, malnutrition, obesity, & poisoning - Results from imbalance among the uptake, utilization &

secretion of fat - Increased transport of triglycerides (fatty acids)

to affected cells - Decreased mobilization of fat from cells - Most often due to decreased production for

transport - Decreased use of fat by cells

- Overproduction of fat in cells 42

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Reversible cellular changes & accumulation

3- Hyaline change/degeneration - Homogenous, glassy, eosinophilic appearance in H & E stained tissue sections

- Caused most often by nonspecific accumulations of proteinaceous material

- Ex. Glomeruli tufts in diabetic

glomerulosclerosis46

Reversible cellular changes & accumulations

4- Accumulation of exogenous pigments - Naturally colored substances not requiring tissue stain to be seen

1 - Pulmonary accumulations of carbon, silica & iron dust

2 - Plumbism (lead poisoning) 3 - Algeria (silver poisoning) - May cause a permanent gray discoloration

of the skin & conjunctiva 47

5- Accumulation of endogenous pigments a- Melanin : - Most common; brown pigment - Formed from tyrosine via tyrosinase - Synthesized in melanosomes of melanocytes within the basement membrane of the epidermis & choroid of the eye

- Transferred by melanocytes to adjacent clusters of keratinocytes & macrophages (melanophores) in the subjacent dermis

- Seen also in neoplasm - Ex. Melanocytic nevus , melanotic macule

- Ex. Melanoma 48

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Pigmented Gingiva

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b- Bilirubin - Catabolic product of the heme moiety of hemoglobin & myoglobin

- In pathologic conditions, accumulates & stains the blood, sclera, mucosa, & internal organs producing a yellow discoloration ( jaundice)

- Hemolytic jaundice - Destruction of red blood cells - Obstructive jaundice - Intra or extrahepatic obstruction of the billiary tract

- Hepatocellular jaundice Ex. Parenchyma liver damage

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c- Hemosiderin - Iron – containing pigment , aggregates of ferritin - In tissue appears as golden – brown amorphous

aggregates - Prussian blue dye – positive blue color stain

reaction - Exists normally in small amounts as physiologic

iron stores within tissue macrophages of the bone

marrow, liver, & spleen

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Hemosiderin Melanin

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c- Hemosiderin - Found in 1 - Week – old haemorrhage 2 - Hemolysis 3 - Inborn errors of metabolism affecting transport & absorption as in

the liver & pancreas - Accumulates pathologically in tissue in

excess amounts ( sometimes massive) -Hemosiderosis vs. hemochromatosis

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Hemosiderosis - Accumulation of hemosiderin, primarily within tissue macrophages, without associated tissue organ damage - Local - most often from hemorrhage into tissue; derived from breakdown of hemoglobin

- Systemic – generalized; from hemorrhage,

multiple blood transfusions,

hemolysis, excessive dietary intake,

often accompanied by alcohol

consumption57

Hemochromatosis - extensive accumulation of hemosiderin , often within parenchymal cells , with accompanying tissue damage , scarring , & organ dysfunction

- Hereditary type (primary) - Most often caused by mutation of Hfe gene, chromosome # 6

- Characterized by liver, pancreas, myocardium, & multiple

endocrine glands damage; melanin deposition in skin …….

- Triad – micronodular cirrhosis, diabetes mellitus,”bronze diabetes”

- Elevated serum iron, decreased total iron-binding capacity

- Secondary type : most often caused by multiple blood transfusions for conditions such as beta- thalassemia major ( a hereditary hemolysis anemia)

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Lipofuscin - Yellowish to light brown, fat-soluble pigment; end product of membrane lipid peroxidation

- “Wear & tear” pigment- Commonly accumulates in elderly patients - Found most often within hepatocytes & at

the poles of nuclei of myocardial cells

Brown atrophy : - accumulation of lipofuscin & atrophy of organs

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Pathologic calcifications

- Abnormal deposition of calcium salts in soft tissue - Deep blue-purple in nondecalcified H & E stained tissue

- May stimulate further bone deposition1- Metastatic calcification : caused by hypercalcemia

- Most often from hyperparathyroidism - Osteolytic tumours with mobilization of Ca2+ & PO4

- Hypervitaminosis D - Excess calcium intake - E.g. milk – alkali syndrome – nephrocalcinosis, renal stones

caused by milk & antacid self-therapy for peptic ulcer

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2-Dystrophic calcifications : - Intracellular or extracellular; gritty- Deposition of calcium in tissue altered by injury

1- Areas of old trauma 2- Tuberculosis lesions 3- Affects crucial organs, heart valves, vessels

- Scarred heart valves - Atherosclerosis- Not caused by hypercalcemia but calcium attracted by released membrane phosphates

4- Serum calcium concentration normal63

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