patho 1. cell death & injury 1

The state wherein the cells are capable of handling physiologic demands, thereby maintaining a steady state.

Homeostasis

True or False: Cell adaptation occurs when cells are exposed to damaging insults and deprived of critical nutrients.

False. Cell injury occurs when cells are exposed to damaging insults and are deprived of critical nutrients.

True or False: Cell injury is an irreversible process.

False. Cell injury may be reversible or irreversible.

The device used to view the progression of cell injury.

Light microscope

True or False: Cell injury occurs from the inside-out, bit by bit.

TRUE

What is the most common cause of oxygen deprivation in cells, and how does it differ from hypoxia?

Ischemia. Unlike hypoxia, ischemia also limits the delivery of other substrates, impairing both aerobic and anaerobic metabolism.

How can extremes of temperature cause cell injury?

High temperatures = denature proteins and damage membranes; low temperatures = cause ice crystal formation and disrupt cell structures

Which types of microorganisms can cause cell injury?

Bacteria, fungi, parasites, and viruses.

What are the two main categories of immunologic reactions that can lead to cell injury?

Autoimmune diseases and immune reactions to external agents (microbes/environmental substances)

How can a genetic defect cause cell injury?

By producing deficient protein function, as in inborn errors of metabolism.

What happens when damaged DNA or misfolded proteins accumulate beyond repair?

They trigger cell death.

Give examples of diseases caused by genetic abnormalities.

Down syndrome, sickle cell anemia.

What are the two broad types of nutritional imbalances?

Deficiency and excess.

How does a high-fat diet contribute to atherosclerosis?

Excess dietary fats raise serum cholesterol, which deposits in arterial walls, triggering inflammation and narrowing of vessels.

Why might anorexia nervosa cause more than just weight loss?

Severe protein-calorie deficiency impairs immune function, wound healing, muscle strength, and organ function due to widespread nutrient shortages.

Mitochondria are highly susceptible to damage by

increase cytosolic Ca2+, ROS, oxygen deprivation (hypoxia)

Consistent feature of most forms of cell injury (except in apoptosis)

Membrane Damage

Damage to nuclear DNA activates sensors that trigger

p53-dependent pathways

p53 arrests cells in what phase to activate DNA repair mechanisms?

G1 phase

Chemical species that have a single
unpaired electron in an outer orbit which are highly reactive
and “attack” and modify adjacent molecules

Free radicals

ROS interact with membranes and
produce peroxides which are also
unstable and reactive causing an
autolytic chain reaction called

Propagation

Excess Ca2+ may cause cell injury through opening of the

Mitochondrial permeability transition
pore

Alterations of the cell that occur in early stages or mild forms of injury

Reversible Cell Injury

Reversible cell injury is correctable if?

Damaging stimulus is removed

What is the earliest manifestation of almost all forms of cell injury?

Hydropic/Cellular Swelling

Hydropic swelling occurs due to the disruption of what mechanism?

NA+/K+ ATPase pump

What accumulates in the cytoplasm during hypoxic, toxic, or metabolic injuries?

Fat/Triglyceride/Triglyceride-filled lipid vacuoles

What are the ultrastructural changes in reversible cell injury present under electron microscopy?

○ Plasma Membrane Alterations (Blebbing, blunting, loss of microvilli)
○ Mitochondrial Changes (swelling, appearance of small amorphous densities)
○ Accumulation of myelin figures (phospholipid from damaged cellular membranes)
○ Dilation of the ER with detachment of polysomes
○ Nuclear alterations (disaggregation of granular and fibrillar elements)

What are the features of reversible cell injury that are recognizable under light microscopy?

○ Cellular/Hydropic Swelling
○ Fatty change/Triglyceride accumulation

What organs are prone to fatty change?

Organs involved in lipid metabolism: liver, muscle

What are the pathways of cellular responses to stress and injury?

○ Integrated Stress Response (ISR)
○ Unfolded Protein Response (UPR) & Endoplasmic Reticulum (ER) Stress
○ Autophagy

TRUE or FALSE: Integrated Stress Response (ISR) is considered as the least basic initial pathway when there is cell injury.

FALSE

An early response pathway consisting of a network of
intracellular signaling pathways that respond to different
stressors

Integrated Stress Response (ISR)

ISR is activated by _________ which phosphorylates the eucharyotic translation inititation factor (eIF2a)

stress-sensing protein kinases (PKR, PERK, GCN2, HRI)

This triggers changes in protein synthesis that allow an injured cell to conserve ___________ and maintain ____________.

○ energy
○ homeostasis

What are the other roles of ISR?

○ antioxidant response
○ protein folding
○ activation od autophagy

TRUE or FALSE: Dysfunctional ISR has been linked to cancer, autoimmune disease, type 2 diabetes, and neurodegenerative diseases.

TRUE

These are located in the endoplasmic reticulum (ER) and control the proper folding of newly synthesized proteins during protein translation.

chaperone proteins

TRUE or FALSE: Some misfolded proteins are toxic to the body, causing and leading to cell injury.

TRUE

TRUE or FALSE: UPR triggers decreased proteasomal degradation of abnormal proteins.

FALSE

TRUE or FALSE: Cystic fibrosis and Tay-Sachs disease are some of the diseases caused by misfolded proteins.

TRUE

Included in the list of diseases caused by misfolded proteins is the deficiency of __-antitrypsin.

α1

Aside from the production of chaperones and enhanced proteasomal degradation of abnormal proteins, another event triggered by UPR during ER stress due to the load of misfolded protein accumulation is the ________ of protein ___________.

slowing, translation

UPR occurs during ER stress due to the accumulation of?

misfolded or unfolded proteins

Which group of enzymes deals with misfolded or unfolded proteins in the cytoplasm?

proteases

TRUE or FALSE: Familial hypocholesterolemia is one of the diseases caused by misfolded proteins.

FALSE

Cell injury or cell death is triggered via _________ if the cell is unable to cope with ER stress as the misfolded proteins accumulate in endoplasmic reticulum.

apoptosis

What is the term for the process in which a cell degrades and recycles its own contents to maintain cellular integrity?

Autophagy

What is the initial structure formed during autophagy that eventually becomes an autophagosome?

Phagophore

Which organelle fuses with the autophagosome to degrade its contents?

Lysosome

Name two stress conditions under which autophagy functions as a survival mechanism

Nutrient deprivation and hypoxia (low oxygen levels)

List two diseases or conditions that have been associated with dysregulated autophagy.

Cancer and neurodegenerative disorders (e.g., Alzheimer’s disease)

A pathologic process that is the consequence of severe
injury

Necrosis

What is necrosis is characterized by?

○ Denaturation of cellular proteins
○ Leakage of cellular contents through damaged
membranes
○ Local inflammation
○ Enzymatic digestion to the lethally injured cell

__________ happens on H&E stains due to loss of cytoplasmic RNA and accumulation of denatured cytoplasmic proteins

Increased eosinophilia

Necrosis has a glassy homogenous appearance due to ________

loss of glycogen particles

Architecture of dead tissue is preserved for a span of at
least some days

Coagulative necrosis

This structure in coagulative necrosis denote where the normal
cells used to be

Eosinophilic tombstones

Most common etiology of coagulative necrosis due to obstruction of a supplying vessel

Ischemia

Localized area of coagulative necrosis

Infarct

Transformation of tissue into a viscous liquid due to
digestion of dead cells

Liquefactive necrosis

Creamy yellow necrotic material which contains dead
leukocytes

Pus

Hypoxic death of cells within the _____ often manifests as
liquefactive necrosis

CNS

A term used in clinical practice to describe necrosis applied to a limb

Gangrenous necrosis

Dry gangrene is mostly made up of ______
necrosis while wet gangrene produces ______ necrosis

coagulative; liquefactive

On a slide, the glassy homogenous appearance is due to loss of _____ particles.

Glycogen

Unlike the nucleus in an apoptotic cell, the nucleus in a cell undergoing necrosis is _____.

Pyknotic

In necrosis, the plasma membrane will be ____.

Disrupted

In necrosis, ____ inflammation will frequently occur

Adjacent

What is programmed cell death induced by a tightly regulated suicide program.

Apoptosis

Is apoptosis physiologic, pathologic, or both?

Both

In apoptosis, what enzymes do dying cells activate?

Intrinsic enzymes that degrade the cell’s DNA and nuclear/cytoplasmic proteins.

Does apoptosis elicit an inflammatory reaction?

No

What are apoptotic bodies?

Plasma membrane–bound fragments of apoptotic cells containing cytoplasm and nuclear portions.

What is the role of apoptosis in physiologic situations?

Eliminates cells no longer needed and maintains constant cell numbers in tissues (homeostasis).

Give 3 examples of physiologic situations where apoptosis occurs.

1. Removal of excess cells during development.

2. Involution of hormone-dependent tissue upon hormone withdrawal.

3. Cell turnover in proliferating cell populations.

How are self-reactive lymphocytes eliminated to prevent autoimmune reactions?

By apoptosis

What are two main triggers for apoptosis in physiologic situations?

Deprivation of survival signals and pro-apoptotic signals from other cells or the environment.

In pathologic situations, what is the main benefit of apoptosis?

Eliminates irreversibly injured cells without eliciting an inflammatory response.

List 4 pathologic causes of apoptosis.

1. DNA damage (radiation, anticancer drugs, free radicals)

2. Accumulation of misfolded proteins (ER stress)

3. Infections (especially viral)

4. Pathologic atrophy after duct obstruction

What is ER stress, and how does it relate to apoptosis?

ER stress results from accumulation of misfolded proteins, activating the unfolded protein response, which can trigger apoptosis.

How can viral infections induce apoptosis?

Directly (e.g., adenovirus, HIV) or via immune response (e.g., viral hepatitis).

T or F: Chromatin condensation is the most characteristic feature of apoptosis.

TRUE

T or F: Cell shrinkage during apoptosis is associated with an increase in cell size

FALSE, decrease

Extensive membrane blebbing during apoptosis leads to the formation of ________.

Apoptotic bodies

The process where apoptotic bodies are rapidly ingested and degraded by phagocytes.

Efferocytosis

The immune cells that usually perform efferocytosis of apoptotic bodies.

Macrophages

The mitochondrial (intrinsic) pathway of apoptosis is primarily triggered by loss of survival signals, DNA damage, or protein misfolding.

TRUE

In the extrinsic pathway, the best-known death receptors are Fas (CD95) and Type 1 TNF receptor (TNFR1)

TRUE

In the extrinsic pathway, the best-known death receptors are Fas (CD95) and Type 1 TNF receptor (TNFR1)

Caspase-8

The caspases responsible for the final phase of apoptosis, such as caspase-3 and caspase-6.

Executioner caspases

The pro-apoptotic protein released from mitochondria that triggers the caspase cascade.

Cytochrome c

This mechanism of cell death is also known as "programmed necrosis"

Necroptosis

Necroptosis is similar to necrosis due to what mechanism?

Plasma membrane disruption

Process of Necroptosis

Ligation of TNFR1 → formation of multiprotein complex → phosphorylation of MLKL, a cytoplasmic protein that disrupts the plasma membrane → leakage of cell contents → inflammation, tissue damage, and cell death

Remember: Ligation --> Formation --> Phosphorylation --> Leakage --> Cell Death

This mechanism of cell death is commonly seen in conditions such as: steatohepatitis, acute pancreatitis,
ischemia-reperfusion injury, and neurodegenerative diseases
(Parkinson disease)

Necroptosis

A form of apoptosis accompanied by the release of interleukin-1 (IL-1)

Pyroptosis

This mechanism of cell death is characterized by release of inflammatory mediators, unlike classical apoptosis

Pyroptosis

Two pathways of pyroptosis

Canonical & Non-canonical

Process of Pyroptosis

Activation of caspases-1, 4, and 5 → activation of gasdermins → pores in the plasma membrane are formed → release of IL-1β and proinflammatory mediators → recruitment of leukocytes and induction of fever