619 9/28 GLA pt 2 Cellular Injury, Adaptation, and Death

Apoptosis

atp dependent, enzyme mediated cell death whereby cells activate pre-programmed instructions for self destruction in response to physiologic or pathologic stimulus

Physiologic Apoptosis

involution of hormone-dependent tissues

elimination of potentially harmful self-reactive lymphocytes

death of inflammatory cells following an immune response

Pathologic Apoptosis

following fatal dna damage (radiation)

accumulation of misfolded proteins (er stress response)

cell death in certain infections (mainly viral)

Molecular Mechanisms of Apoptosis

intrinsic (mitochondiral) or extrinsic (death receptor) pathway depending on initiation, results in the activation of enzymes called caspases

2 Phases of Apoptosis

initiation phase

execution phase

Initiation Phase of Apoptosis

first step where some capsases are activated and unleash a cascade of other capsases

Execution Phase of Apoptosis

second step where terminal caspases trigger cellular fragmentation

Intrinsic (Mitochondiral) Apoptosis Pathway

activated in response to a trigger such as dna damage, infection, or loss of survival signals

pro-apoptotic proteins (bax/bak) overcome the signals of the anti-death proteins (bcl-2) initiating the apoptosis cascade

bax/bak proteins cause the mitochondrial membrane to become leaky, allowing cytochrome c to escape into the cytosol

cytochrome c (and other proteins) activate the caspase cascade inducing cell death

External (Death Receptor) Apoptosis Pathway

activated by engagement of plasma membrane death receptors such as fas/fal receptor and tnf receptor

Apoptosis as “Silent” Cellular Death

apoptotic bodies break cells into fragments for phagocyte digestion, their breakdown releases factors that recruit phagocytes, it is a controlled pathway

the end result is that apoptosis limits inflammatory reactions, even when extensive

Unfolded Protein Response and ER Stress

when the protein folding demand outweighs the protein folding capacity of the ER

can be mitigated by decreasing protein synthesis, increase production of chaperones

if the cell does not adapt, it undergoes apoptosis

Follicular Lymphoma

type of cancer caused by a genetic aberration whereby the cancer cells overexpress bcl-2 (anti-apoptotic protein), allowing cancer cells to evade apoptosis

Apoptosis Morphological Changes Diagram

Apoptosis Morphological Changes

cell shrinks with and increasing eosinophilia and nuclei become pyknotic

nucleus breaks into fragments (karyorrhexis) accompanied by dissolution of the nuclear membrane, surface membrane blebs form

eventually apoptotic bodies containing organelles and nuclear material form, apoptotic bodies are ingested by phagocytes

Unique Nuclear Features of Apoptosis

as the chromatin condenses, it accumulates peripherally and forms crescent-shapes

only on electron microscopy

Light Microscopic Features of Apoptosis

cell shrinkage (cell becomes smaller and the cytoplasm becomes dense and eosinophilic)

involves isolated cells with minimal inflammatory response

Necrosis vs Apoptosis

Cell Changes Diagram

Pathologic Calficiation

abnomal tissue deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral salts

2 Forms of Pathologic Calcification

dystrophic

metastatic

Dystrophic Pathologic Calcification

deposition occurs locally in damaged and/or necrotic tissue, normal serum ca levels

Metastatic Pathologic Calcification

may occur in normal tissues, almost always due to hypercalcemia

Examples of Dystrophic Pathologic Calcification

3 Reasons Metastatic Calficiation Occurs

parathyroid tumors due to excessive pth

cancer (due to pthrp secretion or bone metastasis)

vitamin-d disorders including intoxication and sarcoidosis

Where does metastatic calcification occur most often and why?

principally effects interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins

these tissues have an internal environment that predisposes them to form calcifications

Calcific Deposits Histology

dark basophilic character with cleft-like spaces, dystrophic and metastatic look the same histologically

4 Mechanisms fo Abnormal Intracellular Accumulations

inadequate removal of a normal substance secondary to defects in packaging and transport

accumulation of an endogenous substance, due to genetic or acquired defects, that impair its folding, packaging, transport, or secretion

failure to degrade a metabolite due to an inherited enzyme deficiency

deposition and accumulation of abnormal eogenous substance that cannot be degraded or removed becasue the cell lacks both the enzymatic machinery required for its breakdown and the means to transport it elsewhere

Example of Inadequate Removal of a Normal Substance Secondary to Defects in Packaging or Transport

hepatic steatosis (fatty change) in the liver

Hepatic Steatosis

fatty change where alcohol use disorder, diabtes, and obesity cause triglycerides to accumulate within vacuoles of hepatocytes

gives liver a yellow color

Hepatic Steatosis Histology

fat vaculoes accumulate in the hepatocyte as clear circular spaces of various sized

Example of Accumulation of and Endogenous Substance, Due to Genetic or Acquired Defects, that Impair its Folding, Packaging, Transport, or Secretion

A1AT deficiency

misfolded a1at protein accumulates in the liver

A1AT Deficiency

inherited disorder where a mutation causes the aiat protein to misfold and accumulate in hepatocytes

A1AT Deficiency Histology

round-to-oval cytoplasmic globular inclusions in hepatocytes

best visualized using PAS

What does A1AT Deficiency lead to?

lung and liver disease

Example of Failure to Degrade a Metabolite due to an Inherited Enzyme Deficiency

von gierke disease

accumulation of glycogen in hepatocytes

Von Gierke Disease

mutation in enzyme that mobilizes glucose from liver glycogen, lack of enzyme leads to accumulation of glycogen within hepatocytes

Von Gierke Disease Histology

optically clear nuclei and pale cytoplasm caused by accumulation of glycogen

Example of Accumulation of an Abnormal Exogenous Substance that Cannot be Degraded or Removed Because the Cell Lacks Both the Enzymatic Machinery Required for Its Breakdown and the Means to Transport it Elsewhere

anthracosis

carbon dust in macrophages

Anthracosis of the Lung

blackening caused by inhalation of carbon dust, dust is picked up by macrophages where it remains in perpetuity due to its indigestible nature

Intracellular Accumulations vs Storage Diseases

intracellular accumulations may be reversible, but inherited storage diseases typically lead to progressive tissue injury