Cell Injury, Adaptation, and Cell Death

Flashcards testing concepts of cell injury, mechanisms, reversible vs irreversible injury, necrosis patterns, and apoptotic pathways based on the lecture notes.

How is cellular homeostasis defined in the lecture notes?

Cellular homeostasis is the maintenance of a relatively stable internal environment, encompassing energy balance, ionic balance, water balance, protein and DNA integrity, and membrane integrity.

What are the six major causes of cell injury?

1. Oxygen deprivation (hypoxia and ischemia)
2. Physical agents
3. Chemical agents and drugs
4. Infectious agents
5. Immune-mediated injury
6. Genetic abnormalities, nutritional imbalance, and aging

What is the difference between hypoxia and ischemia, and why is ischemia generally more damaging?

Hypoxia is inadequate oxygen availability to cells/tissues. Ischemia is reduced blood flow causing oxygen and nutrient deficiency plus impaired waste removal. Ischemia is more damaging because it combines nutrient deficiency and waste accumulation with lack of oxygen.

What are the seven central mechanisms of cell injury?

1. ATP depletion
2. Mitochondrial damage
3. Loss of calcium homeostasis
4. Oxidative stress
5. Membrane damage
6. DNA and protein damage
7. Endoplasmic reticulum stress

What downstream cellular effects result from ATP depletion during ischemic cellular injury?

Failure of the $Na^+$ pump causing influx of $Ca^{2+}$, $H_2O$, and $Na^+$ (and efflux of $K^+$) leading to cellular swelling; increased anaerobic glycolysis causing lactic acid accumulation and decreased pH; and detachment of ribosomes leading to decreased protein synthesis.

How does increased cytosolic $Ca^{2+}$ contribute to cell injury?

Increased cytosolic $Ca^{2+}$ activates cellular enzymes: phospholipases (causing membrane damage), proteases (causing cytoskeletal/membrane damage), endonucleases (causing nuclear/DNA damage), and ATPases (causing further ATP depletion).

What are the three main cellular components targeted and damaged by Reactive Oxygen Species (ROS)?

1. Lipids: oxidation causes lipid peroxidation and disruption of plasma/organelle membranes.
2. Proteins: oxidation causes loss of enzymatic activity and abnormal folding.
3. DNA: oxidation causes strand breakage and mutations.

What are the two primary morphologic patterns of reversible cell injury visible under light microscopy?

Cellular swelling (hydropic change/vacuolar degeneration) and fatty change (lipid accumulation).

What ultrastructural (electron microscopy) changes characterize reversible cell injury?

Plasma membrane blebbing, mitochondrial swelling, endoplasmic reticulum dilation, and ribosomal detachment.

What events mark the 'point of no return' leading to irreversible cell injury and cell death?

Irreversible mitochondrial dysfunction (inability to generate ATP), severe plasma and organelle membrane damage, profound failure of ATP production, and leakage of intracellular contents/lysosomal enzymes.

What is the correct sequence of nuclear changes observed during necrosis?

Pyknosis (nuclear shrinkage and increased basophilia) $\rightarrow$ Karyorrhexis (fragmentation of the pyknotic nucleus) $\rightarrow$ Karyolysis (fading and dissolution of nuclear basophilia).

What are the six main types of necrosis described in the lecture notes?

1. Coagulative necrosis
2. Liquefactive necrosis
3. Fat necrosis
4. Gangrenous necrosis
5. Caseous necrosis
6. Fibrinoid necrosis

How do necrosis and apoptosis compare in terms of cell size, membrane integrity, cellular contents, and inflammation?

Necrosis: cell swelling, disrupted plasma membrane, cellular contents leak out, and inflammation is usually present. Apoptosis: cell shrinkage, intact plasma membrane, cellular contents packaged into apoptotic bodies, and inflammation is usually absent.

What are the key steps in the intrinsic (mitochondrial) pathway of apoptosis?

Cell stress $\rightarrow$ pro-apoptotic BCL-2 family signaling $\rightarrow$ mitochondrial outer membrane permeabilization $\rightarrow$ release of cytochrome c $\rightarrow$ apoptosome formation $\rightarrow$ activation of initiator caspase-9 $\rightarrow$ activation of executioner caspases.

What initiates the extrinsic pathway of apoptosis?

Ligand binding to death receptors (such as Fas or TNF-receptor family members), which recruits adaptor proteins to activate initiator caspase-8 or caspase-10, subsequently activating executioner caspases.

What membrane alteration acts as an 'eat-me' signal on apoptotic bodies for phagocytic clearance?

Translocation and exposure of phosphatidylserine on the outer leaflet of the plasma membrane.

Name and define four alternative forms of regulated cell death highlighted in the lecture.

1. Necroptosis: regulated necrotic cell death with membrane disruption and inflammation.
2. Pyroptosis: inflammatory programmed cell death associated with inflammasome/caspase signaling.
3. Ferroptosis: iron-dependent cell death driven by lipid peroxidation.
4. Autophagy: degradation and recycling of cellular components by lysosomal digestion that can lead to cell death when excessive.

What is endoplasmic reticulum (ER) stress and what is its eventual outcome if unresolved?

ER stress is caused by the accumulation of misfolded proteins in the endoplasmic reticulum. The unfolded protein response (UPR) attempts to restore normal folding; if persistent, pro-apoptotic pathways are activated.