Cell Injury, Adaptations, and Death I and II

Question 1

Name the cellular response to:

Altered physiological stimuli or nonlethal injurious stimuli ⇒

1. Increased demand, increased stimulation (e.g., by growth factors, hormones) ⇒
2. Decreased nutrients, decreased stimulation ⇒
3. Chronic irritation (physical or chemical) ⇒

Answer 1

⇒ Cellular adaptations

1. ⇒ Hyperplasia, hypertrophy
2. ⇒ Atrophy
3. ⇒ Metaplasia

Question 2

Name the cellular response to:

Reduced oxygen supply, chemical injury, microbial infection ⇒

1. Acute and transient ⇒
2. Progressive and severe (including DNA damage) ⇒

Answer 2

⇒ Cell injury

1. ⇒ Acute reversible injury (cellular swelling and fatty change)
2. ⇒ Irreversible injury (cell death)
   
   • Necrosis
   • Apoptosis

Question 3

Name the cellular response to:

**Metabolic alterations, genetic or acquired, chronic injury ⇒ **

Answer 3

⇒ Intracellular accumulations, calcification

Question 4

Name the cellular response to:

Cumulative sub-lethal injury over long life span ⇒

Answer 4

⇒ Cellular aging

Question 5

How are tissues grouped based on their proliferative properties?

Answer 5

1. Labile cells
   
   • Continuously dividing cells
   • Hematopoietic cells, surface epithelia (ex.: linings of upper airways, gastrointestinal tract, skin, etc.)
2. Stable tissues
   
   • Quiescent; minimal replicative activity normally
   • Proliferate in response to injury
   • Parenchyma of most solid organs (liver, kidney, pancreas)
   • Endothelial cells, fibroblasts, smooth muscle cells
3. Permanent tissues
   
   • Non-proliferative
   • Neurons, cardiac muscle cells

Question 6

Cellular Adaptations: Hypertrophy

Answer 6

• Increase in size of cells = increase of size of organ
  
  • Increased amounts of proteins and organelles
  • Mechanisms: trophic or mechanical triggers to cell
• Occurs in cells that have limited or no capacity to divide

Question 7

1. Physiological Hypertrophy
2. Pathological Hypertrophy​​

Answer 7

1. Physiological Hypertrophy
   
   • Increased functional demand or hormonal stimulation
   • Examples: Skeletal muscle hypertrophy in weight lifting athlete and uterus in pregnancy
2. Pathological Hypertrophy​​
   
   • Example: Cardiac muscle hypertrophy seen in hypertension

Question 8

Generally describe left ventricular hypertrophy:

Answer 8

1. Thick left ventricle & increased mass
2. Adaptation in response to increased work load in hypertension (chronic hemodynamic overload)
   
   • Also occurs with aortic valve stenosis
3. Myofibers enlarge: synthesis of more filaments
4. Clinical manifestations:
   
   • initially no clinical signs, but eventually, heart reaches a limit beyond which enlargement of muscle mass cannot compensate for increased work & heart failure occurs.

Question 9

Cellular Adaptations: Hyperplasia

Answer 9

Increase in cell number

• Occurs in cells capable of division
  
  • labile and stable cells

Question 10

1. Physiologic Hyperplasia
2. Pathologic Hyperplasia

Answer 10

1. Physiologic Hyperplasia
   
   • Hormonal hyperplasia of female breast at puberty and in pregnancy
   • Compensatory hyperplasia of liver after partial resection
   • Connective tissue response with wound healing
2. Pathologic Hyperplasia
   
   • Excessive stimulation by growth factors or hormones
   • Example:
     
     • Hormonal imbalance stimulates endometrial hyperplasia
     • Skin warts and mucosal lesions associated with viral infections
       
       • papilloma viruses
   • Reversible
   • Cells respond to normal regulatory mechanisms
   • Clinical significance: Increases risk for cancer

Question 11

Describe benign prostatic hyperplasia. What makes it different from other hyperplasias?

Answer 11

• Very common in men > 50 years old
• Results in formation of nodules in prostate gland in the periurethral region ⇒ varying degrees of urinary obstruction
• Underlying cause is unknown
• Mechanism: androgen-induced release of growth factors increases proliferation of stromal cells ⇒ decreases death of epithelial cells
• Differs from endometrial hyperplasia in that it is not associated with increased risk of prostate cancer

Question 12

Give a clinical example of both hyperplasia and hypertrophy:

Answer 12

Enlargement of uterus during pregnancy (gravid)

Question 13

Cellular Adaptations: Atrophy

Answer 13

Decrease in size of a cell due to loss of cell substance

• If severe ⇒ decreased organ size
• Decreased protein synthesis & increased degradation
• Decreased function, but not death

Question 14

1. Physiologic Atrophy
2. Pathologic Atrophy

Answer 14

1. Physiologic Atrophy
   
   • ​​Loss of hormonal stimulation
   • ex: endometrium at menopause
2. Pathologic Atrophy
   
   • Decreased functional demand
     
     • ex: broken arm in cast
   • Loss of innervation
     
     • ex: trauma to peripheral nerve
   • Inadequate nutrition
     
     • calorie or protein deficit

Question 15

Cellular Adaptations: Metaplasia

Answer 15

One adult cell type is replaced by another adult cell type (that is better able to handle the stress)

• Adaptive process to chronic stress +/or persistent cell injury
  
  • Examples: Chronic smokers, Chronic gastric acid reflux
• Cells are “reprogrammed”
  
  • Stem cells differentiate along a new pathway
• Reversible
• May be associated with risk of cancer

Question 16

Describe the two types of metaplasia:

Answer 16

1. Epithelial metaplasia
   
   • Ciliated columnar epithelium becomes squamous epithelium
     
     • _​_ex. Trachea/bronchi of smokers
   • Squamous epithelium becomes gastric/intestinal type epithelium
     
     • ex. Distal esophagus in those with reflux
2. Mesenchymal metaplasia
   
   • Bone formation in soft tissue (muscle/connective tissue) at sites of injury

Question 17

Describe squamous metaplasia of trachea & bronchi in smokers:

Answer 17

• Respiratory epithelium:
  
  • ciliated columnar epithelium
    ⇒ squamous epithelium
• Stimulus that causes metaplasia may predispose to development of malignant neoplasm (squamous cell carcinoma)

Question 18

Describe the process of Barrett Esophagus:

Answer 18

Squamous epithelium (distal esophagus) ⇒ glandular epithelium (stomach)

• protects against reflux of stomach acid
  
  • predisposes to development of glandular carcinoma (adenocarcinoma)

Question 19

What happens with squamous metaplasia in the endocervix?

Answer 19

• columnar becomes squamous
• increases risk of HPV infection

Question 20

What are the 2 types of oxygen deprivation?

Answer 20

hypoxia and ischemia

Question 21

What is the difference between hypoxia and ischemia?

Answer 21

1. Hypoxia
   
   • Inadequate oxygenation of blood
     
     • ex: lung disease, lack of oxygen in ambient air
   • Reduced oxygen-carrying capacity of blood
     
     • ex: anemia, cyanide
2. Ischemia
   
   • lack of blood supply to site
     
     • ex: coronary artery disease/heart attack, stroke

Question 22

Besides oxygen deprivation, what are the other etiologies of cell injury?

Answer 22

• Physical agents
  
  • Trauma, temperature extremes, radiation, etc.
• Chemical agents
  
  • Chemicals (sodium, glucose), poisons, asbestos, etc.
• Infectious agents
  
  • Viruses, fungi, bacteria, parasites, etc.
• Immunologic reactions
  
  • Autoimmune diseases, hypersensitivity
• Genetic derangements
  
  • Point mutations, polymorphisms, etc.
• Nutritional imbalances
  
  • Protein / calorie imbalance, vitamin & mineral deficiencies, etc.
• Aging: decreased ability to repair damage

Question 23

What is cell injury a result of?

Answer 23

Continued severe stress (intrinsic and extrinsic) to a point that the cell reaches its limit and can no longer adapt

Question 24

Irreverisble Cell Injury (cell death):

Causes and Types (2)

Answer 24

• Inability to reverse mitochondrial dysfunction
  
  • lack of oxidative phosphorylation & ATP generation
• Disturbance of membrane function

​Two Types:

1. Necrosis
2. Apoptosis

Question 25

**Cell Death: Necrosis vs. Apoptosis** 1. **Cell size:** 2. **Nucleus:** 3. **Plasma Membrane:** 4. **Cellular Contents:** 5. **Adjacent Inflammation:** 6. **Physiologic or Pathologic Role:**

Answer 25

**Necrosis** 1. Cell size: **Enlarged** 2. Nucleus: **Pyknosis, karyorrhexis, karyolysis** 3. Plasma Membrane: **Disrupted** 4. Cellular Contents: **Enzymatic digestion: may leak out of cell** 5. Adjacent Inflammation: **Frequent** 6. Physiologic or Pathologic Role: **_Invariable pathologic_** **Apoptosis:** 1. ​Cell size: **Reduced** 2. Nucleus: **Fragmentation into nucleosome-size fragments** 3. Plasma Membrane: **Intact: altered structure** 4. Cellular Contents: **Intact: may be released in apoptotic bodies** 5. Adjacent Inflammation: **No** 6. Physiologic or Pathologic Role: **_Often physiologic: elminating unwanted cells. May be pathologic_**

Question 26

**Morphology of Reversible Cell Injury** * **Fatty change** * **Cellular Swelling**

Answer 26

* **Fatty change** * _Lipid vacuoles_ in cytoplasm * Occurs with _toxic and hypoxic injury_ * _Primarily in cells dependent on fat metabolism_ * Example: fatty liver secondary to toxins (_alcohol_) * **Cellular Swelling** * _Hydropic change or vacuolar degeneration_ * Results from failure of membrane pumps to maintain homeostasis: _membrane blebs_ * Vacuoles appear in cells corresponding to distended endoplasmic reticulum

Question 27

Describe the **pathogenesis and clinical manifestations of fatty liver:**

Answer 27

* Yellow color and “greasiness” indicates **steatosis** (_fat accumulation_) * Hepatocytes are injured resulting in an intracellular accumulation of triglycerides, liver enlargement and elevated liver enzymes * leak from injured hepatocytes * **Clinical manifestations:** depend upon specific cause & how severe the injury * It is **reversible** if cause is removed. * _Mild_: no effect on cell function. * _Severe_: impairs cell function, may lead to cell death, eventual cirrhosis if injury continues

Question 28

What are some causes of fatty liver? What other organs accumulate fat?

Answer 28

* **Common causes:** * _toxins_ (including **alcohol**) * obesity * malnutrition * carbon tetrachloride * anoxia * diabetes * viral infections * Other organs accumulate fat also: * heart, skeletal muscle, kidney

Question 29

Why would the liver accumulate fat?

Answer 29

1. impairment of microsomal & mitochondrial functions 2. decreased fatty acid oxidation 3. decreased apoprotein formation 4. increased mobilization of fatty acids from periphery

Question 30

**Describe Vacuolar (hydropic) Change:**

Answer 30

**Hydropic change (cellular swelling) of kidney tubules:** * First manifestation of many types of cell injury * Corresponds to distended endoplasmic reticulum * Also seen: * plasma membrane blebs * swollen mitochondria * clumped nuclear chromatin * When many cells in an organ are affected ⇒ organ weight is increased and appears swollen

Question 31

**Morphologic Features of Necrosis**

Answer 31

* increased eosinophilia * nuclear shrinkage * fragmentation * breakdown of plasma membrane & organelle membranes

Question 32

**List the types of necrosis (6):**

Answer 32

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

Question 33

**Coagulative Necrosis:** * **Etiology:** * **Morphology:** * **Areas affected:**

Answer 33

* **Etiology:** * **​**Results from _hypoxic or anoxic injury_ due to **ischemia (infarct)** * **Morphology:** * Persistence of dead cells with _intact outlines but with loss of cellular details_ * _Injury denatures both cellular proteins and enzymes_ (no proteolysis takes place) * **Areas affected:** * **​**Occurs in all solid organs (**except for the brain**)

Question 34

**Liquefactive Necrosis** * **Etiology:** * **Pathogenesis:** * **Morphology:**

Answer 34

* **Etiology:** * ​Complete digestion of the dead cells * **Pathogenesis:** * _Commonly seen with bacterial and fungal infections_ * Microbes stimulate accumulation of WBC * WBCs release digestive enzymes * _Necrotic cells together with acute inflammatory cells_ = **pus** * **EXCEPTION:** _brain infarcts results in liquefactive necrosis_ (reasons not understood) * **Morphology:** * Tissue is semi-liquid as it has been dissolved by hydrolytic enzymes * from lysosomes in WBCs attracted to the area

Question 35

Caseous Necrosis: * **Etiology:** * **Morphology:**

Answer 35

* **Etiology:** * **​Characteristic of tuberculous infection** * **Morphology:** * Gross appearance resembles cheese * Crumbly (friable) appearance of necrosis * Fragmented and coagulated cells with loss of tissue architecture (_no cell outlines_) * Usually surrounded by a border of inflammatory cells forming a distinctive pattern (_granuloma_)

Question 36

**Gangrenous Necrosis** * **Dry gangrene vs. wet gangrene**

Answer 36

* Not a specific type of necrosis but a term used for **ischemic coagulative necrosis of lower or upper extremity** * **Dry gangrene vs. wet gangrene:** * _When a bacterial infection is also present_, the necrosis has _liquefactive characteristics_ (**wet gangrene**) * Also used for severe necrosis of other organs: * Ex: gangrenous bowel, gangrenous appendix, gangrenous gallbladder

Question 37

**Fat Necrosis:** * **Areas affected:** * **Pathogenesis:**

Answer 37

* **Areas affected:** * **​**Typically seen in the pancreas in _acute pancreatitis_ * **Pathogenesis:** * **​**Injury to pancreas _releases lipase_ which _liquefies fat_ and _splits triglycerides_ * _Fatty acids combine with calcium_ to form chalky white material (saponification) * Can also occur as a result of trauma to fatty tissue with release of lipases and triglycerides * Example: Fat necrosis of breast

Question 38

**Fibrinoid Necrosis:**

Answer 38

* **Deposition of immune complexes** (antigens & antibodies) **in vascular wall** * Fibrin-like (suffix “-oid” means “like”) * _Bright pink amorphous appearance_ * _Occurs in vasculitis syndromes_ * Polyarteritis nodosa, giant cell arteritis, etc.

Question 39

What are the principal targets for cellular injury? By what mechanism are the targets affected?

Answer 39

* **Mitochondria** * depletion of ATP & ↑ reactive oxygen species-ROS * **Calcium homeostasis** * intracellular entry of calcium * **Cellular membranes** * increase permeability * **DNA & cellular proteins** * damage to DNA, protein misfolding

Question 40

Mitochondrial damage results in ___ \_\_\_\_\_\_\_\_. * **Major Causes:**

Answer 40

**ATP depletion** * **Major Causes:** * Decreased oxygen * Decreased nutrients (glycogen) * Specific toxins (cyanide) * ATP: required for synthetic & degradative cell processes

Question 41

What happens as a **result of ATP depletion in the mitochondria**?

Answer 41

**Production of reactive oxygen species (ROS)**

Question 42

**Effects of increased intracellular calcium:**

Answer 42

Question 43

**Accumulation of Oxygen-derived Free Radicals (Oxidative damage)**

Answer 43

Question 44

What are the mechanisms of membrane damage? What are the etiologies of membrane damage?

Answer 44

* **Causes:** 1. ischemia 2. microbial toxins 3. complement 4. other physical/chemical agents

Question 45

**Ischemic vs. Hypoxic Injury**

Answer 45

* **Ischemia** (decreased blood flow) _injures tissues faster than hypoxia_ (decreased oxygen level) * No delivery of substrates for glycolysis * _Both aerobic & anaerobic glycolysis cease_ * No removal of metabolites by blood flow * **Most common cause of cell injury** * **Hypoxia:** _anaerobic glycolysis continues_ * **In each:** reduced supply of oxygen * Results in reduced production of intracellular ATP * Leads to failure of other energy dependent systems

Question 46

* *Factors affecting cell injury and death** * *Cell response depends upon:**

Answer 46

1. **Type of injury** * Ischemia vs. hypoxia; toxins, infection, etc. 2. **Duration & severity of insult** * Example: * IF complete ischemia: death in 15 to 20 minutes * IF blood flow reduced by half: it takes 3-4 hours for cell death

Question 47

**Factors affecting cell injury and death** **Outcome depends upon:**

Answer 47

1. **Cell type:** * Example: Neurons are particularly sensitive to lack of oxygen * In other tissues: skeletal muscle dies in 2-3 hours; cardiac muscle in 20-30 minutes, etc. 2. **Extent of collateral flow:** * from vessels around the area affected

Question 48

What are other factors that affect cell injury and death (besides injury and cell type)?

Answer 48

Additional factors: 1. genetics 2. hormones 3. nutritional status of cell/organ

Question 49

**Reperfusion Injury** * **Definition:** * **Mechanisms:**

Answer 49

* **Definition:** Restoration of blood flow to ischemic tissue may increase cell injury * Occurs most frequently in _brain and heart_ * _​_**Mechanisms:** 1. Increased free radical generation 2. **Incomplete reduction of oxygen occurs with ischemia** * _Restoration of oxygen allows production of free radicals_ which increase tissue damage 3. **Increased leukocytes, plasma proteins, & complement** (inflammation) * _Production of adhesion molecules and cytokines by damaged tissue attract inflammatory cells_ that increase extent of injury

Question 50

**Chemical (toxic) injury:** **Mechanims (2)**

Answer 50

Many drugs/toxins are metabolized in liver; it is often site of drug toxicity 1. **Direct toxins:** * Bind to cellular organelle or molecular component 2. **Toxic metabolites:** * Toxin is “activated” * Often by P-450 oxidases in liver smooth ER

Question 51

Give an example of a **direct toxin** that causes cell injury:

Answer 51

**Example:** * **Mercuric chloride** binds to cell membrane proteins * Results in **decreased membrane transport** and **increased membrane permeability**

Question 52

Give an example of a **toxic metabolite** that causes cell injury:

Answer 52

**Examples:** 1. **Acetominophen** (tylenol) 2. **Carbon tetrachloride** converted to toxic free radical which _breaks down ER membranes_

Question 53

**Apoptosis characteristics:**

Answer 53

1. The plasma membrane is **intact** 2. **No leakage** of cell contents 3. **No inflammation**

Question 54

**Causes of apoptosis:** **Physiologic Conditions**

Answer 54

1. during **embryogenesis** 2. **involution of hormone dependent tissues after hormone deprivation** (ex. pregnancy) 3. **cell loss in proliferating cells** maintains constant number (ex. GI epithelium) 4. **death of inflammatory cells** (neutrophils, lymphocytes) after completion of immune response 5. **elimination of self-reactive lymphocytes** 6. **death induced by cytotoxic-T lymphocytes**

Question 55

**Causes of apoptosis:** **Pathologic condtions**

Answer 55

1. **Eliminates cells with DNA damage** (ex. radiation, chemo, etc.) * If repair processes fail, apoptosis is activated and the cell dies * Radiation & many chemo drugs work via apoptosis 2. **Accumulation of misfolded proteins** (ex. Alzheimer disease) 3. **Cell injury induced by viral infections** (ex. HIV), induced by the virus or the host 4. **Organ atrophy with duct obstruction** (example: Pancreas)

Question 56

**Morphology of Apoptosis**

Answer 56

* **Cytoplasmic eosinophilia** * **Chromatin condensation & aggregation** * eventually karyorrhexis * Cell shrinkage with **cytoplasmic blebs & apoptotic bodies** * Phagocytosis without inflammation

Question 57

Describe the **intrisnic mitchonidrial pathway for apoptosis:**

Answer 57

**Intrinsic pathway:** **Bcl-2 proteins increase permeability** of the mitochondria ⇒ allow **cytochrome C** to enter cyotplasm ⇒ resulting in **caspase activation**

Question 58

Cystic fibrosis, familial hypercholesterolemia, Tay-Sachs disease, Creutzfeldt-Jakob disease, Alzheimer disease, Huntington disease, Parkinson disease are all caused by what process?

Answer 58

Unfolded protein response & diseases caused by mis-folding of proteins ⇒ leads to **apoptosis**

Question 59

**Subcellular responses due to cell injury:**

Answer 59

* Alterations of the cell resulting in _distinctive morphology involving specific organelles_ * **Occur in acute** (lethal) **& chronic** (on-going) **injury** as an adaptive response to injury * **Results may be accumulation of abnormal substances** * **Lipid accumulation** already discussed * May be seen in _lysosomes, endoplasmic reticulum, mitochondria_, etc. * Examples: **lipofuscin, carbon, iron**, etc.

Question 60

**Lipofuscin in heart muscle:**

Answer 60

* **Indigestible material** resulting from **lipid peroxidation** * “Wear & tear” pigment, **occurs predominantly with aging** * Particularly in **heart, liver, & brain**

Question 61

What type of disease of **Tay-Sachs Disease**?

Answer 61

**Lysosomal Storage Disease** * **Abnormal metabolism** * increased production of normal substance (gangliosides) because of lack of enzyme to degrade it

Question 62

**Anthracosis in lung:**

Answer 62

Inhaled in air ⇒ **phagocytosed by alveolar macrophages **⇒ transported to regional lymph nodes

Question 63

Give an example of hypertrophy of smooth ER in liver:

Answer 63

**adaptative response to barbiturates & alcohol in hepatocytes** (to maximize toxin removal)

Question 64

What could cause mitochondrial change?

Answer 64

1. mitochondria response to starvation (atrophy) 2. alcohol (enlarge) 3. myopathy due to respiratory chain enzyme abnormality (increase in number & show abnormal structure)

Question 65

**Cytoskeleton Abnormalities**

Answer 65

* Consists of actin, myosin, microtubules & intermediate filaments * **Accumulations occur with:** * Toxins: Alcohol - Mallory hyaline in liver * Unknown causes: Alzheimer’s disease - Neurofibrillary tangle * **Abnormal organization of microtubules** * Kartagener Syndrome: immotile cilia: sterility & lung infections

Question 66

Describe the **morphology** and **pathogenesis** of **hemosiderin in the liver**:

Answer 66

* **Hemoglobin-derived pigment containing iron:** * yellow to golden-brown * Occurs locally where there has been _hemorrhage_ * **Systemic deposition occurs:** * with increased absorption of iron, in anemias, with many transfusions, and in hereditary conditions * Hemosiderin is found in many organs * liver, bone marrow, spleen, lymph nodes

Question 67

**Pathologic Calcification: Dystrophic**

Answer 67

* _Non-viable, damaged or dying tissues_ * **Normal serum calcium** * **Examples:** * Atheromas * Aortic valves in elderly * Lymph nodes with old TB * **Gross:** white gritty deposits * **Microscopically:** basophilic

Question 68

**Pathologic Calcification:** **Metastatic**

Answer 68

* **Normal tissues** * **Hypercalcemia** * Increased parathyroid hormone * Destruction of bone * Vitamin D intoxication * _Renal failure_ (most common cause) * **Most common locations:** * **Interstitial tissues** (lung, kidney, gastric mucosa)

Question 69

**Cellular Aging**

Answer 69

* **DNA damage increases with age** * Possible role of free radicals * **Decreased cellular replication** (“progressive replicative senescence”) * _Progressive shortening of telomeres_ (short DNA sequences at ends of chromosomes) over time in each cell division * _Lack of telomerase_ (maintains telomere lengths) _in somatic cells_ * **Defective protein homeostasis** * Decreases cell survival, replication, & function