cellular adaptations to disease dmf2

8/11/2019 Cellular Adaptations to Disease Dmf2

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Cellular adaptations

to cell injuryand cell death

Banun Kusumawardani

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Definitions :

- Pathology :

- The study of disease- Clinical Pathology - Laboratory procedures

- Anatomic PathologyStructural 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 vasculature

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-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


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Diagrammatic illustration showing the structure of the membrane unit


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Reactions of cells to stimuli

- Adaptations to environment stress

- Cells can adapt to stimuli by eitherHypofunctioning or hyperfunctioning

- A persistent sublethal injury can cause ..

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

2- Hyperplasia = increase in the size of an organ ortissue caused by increase in the number of thecells 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 stress

Developmental causes of reduced cell mass :

1- Agenesis = failure of formation of embryonic cell mass2- 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 organ

4- Hypoplasia =

- Decrease in cell production that is less extreme than that found in aplasia failure ofgrowth to full size. Ex.: Turner syndrome & Klinefelter syndrome ; patient lack ofgrowth & maturation of gonadal structure.

5- Atrophy =

- Decrease in the size of an organ or tissue resulting from a decrease in the mass ofpre-existing cells.

- Results most often from disuse, nutritional or oxygen deprivation, diminishedendocrine stimulation, aging, & denervation

- Often marked by presence of autophage granules, i.e. intracytoplasmic vacoulecontaining debris from degenerated granules

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Adaptation to environmental stress

5a- General atrophyinvolves widespread atrophy of numerous tissues

- Starvation atrophy

- Senile atrophy

- reduced activity leads to reduction in size of the skeletal musclefibers

5b- 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 stimulation

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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 partum

7- Metaplasia :Replacement of one differentiated tissue by another in a hostileenvironment

- Squamous metaplasia

- Ex- change from columnar ciliated epithelium to squamous epithelium at thesquamocolumnar 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-fittingdentures

- 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 cellanemia

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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 facts1- Adaptable within physiological limits

2- Heat shockcan respond to injury by producingcell stress proteins, which protect from damage &help in recovery

3- Increased demands met by hypertrophy &

hyperplasia4- Reduced demand met by atrophy

5- Apoptosiscell loss from tissues can be achievedby programmed cell death

6- Tissues can adapt to demand by a change indifferentiation 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 death

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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 beforegross

morphologic changes appear.

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on a biochemical level

- Ubiquitin- Marks abnormal proteins for degradation

- Exheat 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 foldingabnormalities

- 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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on a biochemical level- Biochemical derangements

1- Oxygenderived 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 withinthe cell (cytosolic calcium)

- Calcium activates enzymes capable of degrading cellmembranes

4- Defects in membrane permeabilitySodium plus other accumulations change the osmoticbalance . 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 & accumulations

2- 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

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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

glomerulosclerosis

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Reversible cellular changes & accumulations

4- Accumulation of exogenous pigments

- Naturally colored substances not requiringtissue stain to be seen

1 - Pulmonary accumulations of carbon, silica

& iron dust2 - Plumbism (lead poisoning)

3 - Algeria (silver poisoning)

- May cause a permanent gray discoloration

of the skin & conjunctiva

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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

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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

- Ironcontaining pigment , aggregates of

ferritin- In tissue appears as goldenbrown amorphous

aggregates

- Prussian blue dyepositive blue color stainreaction

- Exists normally in small amounts as physiologic

iron stores within tissue macrophages of the bone

marrow, liver, & spleen

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HemosiderinMelanin

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c- Hemosiderin

- Found in

1 - Weekold haemorrhage

2 - Hemolysis

3 - Inborn errors of metabolism

affecting transport & absorption as in

the liver & pancreas

- Accumulates pathologically in tissue inexcess 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- Systemicgeneralized; from hemorrhage,

multiple blood transfusions,

hemolysis, excessive dietary intake,often accompanied by alcohol

consumption

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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 .

- Triadmicronodular cirrhosis, diabetes mellitus,bronzediabetes

- Elevated serum iron, decreased total iron-binding capacity

- Secondary type: most often caused by multiple bloodtransfusions for conditions such as beta- thalassemia major ( a

hereditary hemolysis anemia)

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Lipofuscin


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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 & atthe poles of nuclei of myocardial cells

Brown atrophy :

- accumulation of lipofuscin & atrophy of

organs

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Pathologic calcifications


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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 deposition

1- Metastatic calcification : caused by hypercalcemia

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

- Hypervitaminosis D

- Excess calcium intake

- E.g. milkalkali syndromenephrocalcinosis, renal stones

caused by milk & antacid self-therapy for peptic ulcer

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2 D hi l ifi i


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2-Dystrophic calcifications :

- Intracellular or extracellular; gritty

- Deposition of calcium in tissue altered by injury1- 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 normal

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cellular adaptations to disease dmf2

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