619 9/28 GLA Cellular Injury, Adaptation, and Death

3 Cellular Outcomes

adaptation

reversible injury

irreversible injury

Homeostasis

normal healthy steady state maintained by the cell

Cellular Adaptations

allow for the survival and continued function of a cell in an altered steady state

stimuli may be either pathologic or physiologic

generally reversible if the stimulus is removed

can be one cell or all the cells in an organ

Cell Adaptations and Mechanism Table

3 Types of Cellular Adaptations

increased demand or stimulation

decreased nutrients and/or stimulation

chronic irritation

Increased Demand or Stimulation: Adaptive Mechanism

hyperplasia (increase in number of cells)

hypertrophy (increase in size of cells)

Hypertrophy

increase in size of cells due to increased demand, leads to an increase in size of affected organ

physiologic or pathologic

Mechanism of Hypertrophy

due to the synthesis/assembly of additional intracellular structural componenets

Where does hypertrophy occur?

typically in cells that are not capable of self-replication, such as skeletal and cardiac muscles

Physiologic Uterine Hypertrophy

normal growth of uterus during pregnancy, caused by hypertrophy of smooth muscle cells that make up the walls of the uterus

Pathologic Cardiac Hypertrophy

cariomyocytes respond to increased demand by undergoing hypertrophy, and hypertrophy makes it more susceptible to ischemia or heart failure

although function initially improves, over time this adaptation often fails leading to heart disease

Boxcar Nuclei

seen in hypertrophy myocardium, larger boxy shaped nuclei

Hyperplasia

increase in number of cells, can lead to increase in size of the affected organ

occurs in tissues composed of cells that have the capacity to divide

What drives hyperplasia?

increased stimulation by hormones or growth factors

Decreased Nutrients/Stimulation: Adaptive Mechanism

atrophy (decrease in size and number of cells)

Atrophy

decrease in size and number of cells that leads to a decrease in organ size due to a decreased demand

physiologic or pathologic

Physiologic Cause of Atrophy

less/decrease in hormonal stimulation

ex: post-menopausal breast atrphy and uterine atrophy following parturition

Pathologic Causes of Atrophy

decreased workload

loss of innervation

diminished blood supply

inadequate nutrition

Pathologic Atrophy

can also be unilateral renal atrophy, where one kidney shrinks because of reduced blood flow

Histological Pathologic Atrophy

skeletal muscle showing denervation atriphy, where the cells on the right are normal and the cells on the left are atrophic myocytes

Chronic Irritation: Adaptive Mechanism

metaplasia (change in cell type)

Metaplasia

change in cell type, often in response to change in environment or stress

metaplasic cell type is better able to withstand the adverse environment

Adaptive Mechanisms Gland Example

Atherosclerosis

a buildup of lipid materal in the wall of our blood vessels

Physiologic Hyperplasia

occurs when functional capacity needs to be increased

also seen in some tissues in response to damage/deficiency

Physiologic Hyperplasia: Increase Functional Capactiy Example

proliferation of breast glandular epithelium during puberty or pregnancy

Physiologic Hyperplasia: Response to Damage/Deficiency Examples

compensatory hyperplasia during liver regeneration

bone marrow in response to deficiency of blood cells

Pathologic Hyperplasia

occurs when the actions of hormones or growth factors are excessive or innapropriate (begning prostatis hyperplasia, endometrial hyperplasia)

also seen in response to certain viral infections (skin warts seen in hpv infection)

Pathologic Hyperplasia Indications

may stabilize or regress if stimulus is eliminated

some of these proliferations are precursors to cancer

Pathologic Hyperplasia Due to HPV Infection

hpv causes skin cell proliferation, some areas of the skin become thicker because the keratinocytes undergo hyperplasia

Metaplasia Mechanism

occurs through reprogramming of stem cells to induce replacement of the native cell type with another that is better suited to handle the new stress

Columnar to Squamous Metaplasia

commonly occurs in respiratory tract in response to chronic irritation (ex- smoking)

respiratory cells are usually cilliated pseudocolumnar, but become squamous cells that are more hardy (but we have a loss of normal structure)

Price of Columnar to Squamous Metaplasia

predisposes to infection because mucous secretion and ciliary action lost

cancers can arise from metaplastic epithelium

Squamous to Comulnar Metaplasia

reflux of gastric acid causes squamous cells to become columnar epithelium that are similar to digestive cells with goblet cells (secrete mucus) so they can resist acids

also a precursor to cancer

Cell Changes Overall Diagram

Causes of Cell Injury

oxygen deprivation, genetic derangements, infectious agents, immunologic reactions, nutritional imbalances, chemical agents and drugs

Progression of Cell Injury and Death

2 Types of Cell Death

necrosis

apoptosis

Reversible Cell Injury Process

cell injury common occurs due to ischemia (inadequate blood flow) which causes hypoxia and local reduction in oxygen

without oxygen, mitochondria are unable to create atp by oxidative phosphorylation

insufficent atp production leads to an intracellular ion imbalance

as ions accumulate in the cell, water preferentially diffuses in from the extracellular space, leading to cellular swelling, the first manifestation of cellular injury

cellular swelling can be difficult to discern via light microscopy and often is more noticeable when looking at the entire organ

What is the first manifestation of cellular injury?

cellular swelling

Reversible Injury - Ultrastructural Changes

generalized swelling of the cell and organelles (ER and mitochondria)

plasma membrane alterations (blebbing and loss of microvilli)

Reversible Injury - Light Microsope Changes

cellular swelling caused by failure of energy-dependent ion pumps in plasma membrane, vacuoles appear in cytoplasm

increased eosinophilia (redness) due to decreased cytoplasmic RNA (increases with progression to necrosis

fatty change in tissues involved with fat metabolism

Hydropic Change/Vacuolar Degeneration

appearance of vacuoles in the cytoplasm of reversible cell injury, visible through light microscopic changes

Fatty Change

in the setting on hypoxia or toxin exposure, the cell cannot break down fat which accumulates within cells and is visible in reversible injury

droplets of fat are visible as clear round spaces

Ischemic Heart Disease

the cardiac cells need lots of oxygen from the coronary arteries

if the coronary artery is occluded, initially the cardiomyocytes are reversibly injured

but with time it will become more severe and irreversible, causing muscles cells to die resulting it myocardial infarction

this is why it is important to start treatment quickly, because restoration of blood flow during the window of time when cell injury is still reversible will prevent myocardial infarction

Necrosis

a pathologic process that is the end result of something that went wrong, cell falls apart

commonly associated with ischemia, exposure to toxins, various infections, and trauma

Apoptosis

may be physiologic or pathologic, may be a result of disease/injury or a normal process

leverages a proleaded cellular “death script” which is activated by certain signals

What should we associate membrane damage with?

necrosis

What should we associate protein misfolding and DNA damage with?

apoptosis

Principle Forms and Sites of Damage in Cell Injury

What do ROS trigger?

it can lead to necrosis or apoptosis, depending on what the pathologic effect is

3 Nuclear Changes in Irreversible Injury (Occur in Step-Wise Direction)

pykosis

karyorrhexis

karyolysis

Pyknosis

nuclear shrinkage and increased basophilia, used to diagnosie irreversible injury

Karyorrhexis

fragmentation of the nucleus, used to diagnosie irreversible injury

Karyolysis

fading of basophilia due to DNA degredation, necrosis only, used to diagnosie irreversible injury

4 Characteristics of Necrosis

denaturation of cellular proteins

leakage of cellular contents through damaged membranes

local inflammation

enzymatic digestion of the injured cell

4 Light Microscopic Changes of Necrosis

increased eosinophilia due to loss of cytoplasmic rna and accumulation of denatured proteins

cytoplasm becomes more vacuolated due to continued swelling

pyknosis, karyorrhexis, karyolysis

can have various morphologic patterns

Neutrophils

polylobic nuclei, attracted to necrosis so they will be seen in histological sections of it

6 Patterns of Tissue Necrosis

coagulative

liquefactive

gangrenous

caseous

fibrinoid

fat

Coagulative Necrosis

results in every organ (besides the brain) from blood loss

architecture of the tissue is preserved for a period of time, and the affected area may be pale with firm texture and wedge-shaped

Histology of Coagulative Necrosis

retention of eosinophilic, anucleate cells

cell architecture is preserved for a span of days, but is lost as inflammation increases

Liquifactive Necrosis

seen in infection (bacterial or fungal) and brain infarctions

enzymes digest dead cells and the tissue becomes liquified

Histology of Liquifactive Necrosis

cavity becomes filled with liquid cells, no structural integrity remains

Caseous Necrosis

cheese-like appearance, liquified tissue that has become thickened by an infectious agent (common with tuberculosis)

associated with granuloma formation

Caseating Granuloma

pink necrosis in the center of the granuloma, macrophages, giant cells, and small lymphocytes (mostly at periphery)

Why do we form granulosas?

when there is a bacteria we have a hard time getting rid of, we form circular structures around them to wall it off, making granulosas

Non-Caseating Granuloma

has giant cells, macrophages, and lymphocytes

NO necrosis in the middle

Fibrinoid Necrosis

seen in autoimmune reactions involving blood vessels (vasculitis), antigen-antibody complexes and fibrin deposit into blood vessel wall causing damage

appears in pink ring due to large amount of proteinaceous substances accumulated in blood vessel wall (arrow)

Fat Necrosis

focal areas of fat desctruction, most commonly associated with acute pancreatitis becasue lytic enzymes leak out and digest adjacent fat cells

grossy appears white and chalky

What gives fat necrosis its chalky white apperance?

fatty acids combining with calcium, aka fat saponification

Gangrenous Necrosis

ischemic tissue death with coagulative and liquefactive elements, usually applied to a limb that has lots its blood supply

Dry vs Wet Gangrene

dry: usually coagulative

wet: superimposed infection causes liquefactive necrosis