(M1-7) LEC MLSHPATC

except infectious dsx

When a cell undergoes stress, the response is ____________.

Adaptation, reversible injury, irreversible injury, or cell death.

What are some causes of cell injury?

- hypoxia

- physical damage

- chemicals

- infectious agents

- immunologic reactions

- genetic defects

- nutritional imbalances

What are some types of adaptive responses?

Hypertrophy, hyperplasia, atrophy, and metaplasia.

**All of these may be physiologic or pathologic!!

______________ is an increase in cell size (not number!!)

Hypertrophy.

What is an example of physiologic hypertrophy? Pathologic hypertrophy?

-Physiologic: enlargement of skeletal muscle cells secondary to weight lifting/steroids.

-Pathologic: enlargement of cardiac muscle cells secondary to HTN or valvular stenosis.

______________ is an increase in cell number (not size!!)

Hyperplasia.

** What is an example of physiologic hyperplasia? Pathologic hyperplasia?

- Physiologic: compensatory hyperplasia of liver or female breast during puberty and pregnancy.

- Pathologic: squamous papilloma or focal fibrous hyperplasia/fibroma (both of these are benign)

** What is an example of when hypertrophy and hyperplasia may develop concurrently and both contribute to an overall increase in organ size?

Hypertrophy of uterus during pregnancy occurs as a consequence of both smooth muscle hypertrophy and hyperplasia.

Pathologic hyperplasia sometimes creates an environment conducive to _____________ development.

Cancer/malignant neoplasm.

_______________ is a decrease in cell size (ie: cells retreat to smaller size in order to survive).

Atrophy.

If enough cells are involved, the entire tissue or organ may become atrophic, such as in _______________.

Alzheimer's disease.

What are some causes of atrophy?

- Decreased workload

- Loss of innervation (ie: spinal muscular atrophy II)

- Decreased blood supply

- Inadequate nutrition

- Loss of endocrine stimulation

- Aging

______________ is the change from one adult cell type to another.

Metaplasia.

In metaplasia, cells under stress are replaced by another cell type that is _____________.

Better able to withstand the adverse environment.

**cell becomes tougher but protective mechanisms are lost.

What are some examples of metaplasia?

- Squamous metaplasia (in trachea of smokers)

- Oncocytic metaplasia (of salivary ducts)

- Osseous and cartilaginous metaplasia (under ill-fitting denture)

- Gastric metaplasia (in esophagus, Barrett esophagus)

In certain cases, the influences that induce metaplastic transformation, if persistent, may induce ______________ in the metaplastic epithelium.

Cancer transformation (ie: squamous metaplasia in smokers and Barrett esophagus).

______________ is the failure of an organ to develop during embryonic growth due to absence of primordial tissue

Agenesis.

_____________ is the defective development or congenital absence of a structure or organ but primordial tissue is present

Aplasia.

Underdevelopment of a structure or organ due to inadequate or below normal number of cells is called ______________.

Hypoplasia.

_______________ is the reduction of oxygen supply to a cell or tissue.

Hypoxia.

_____________ is the loss of blood supply to a cell or tissue.

Ischemia.

** What is the most common cause of cell injury?

Ischemia.

** ____________ results form hypoxia induced by reduced blood flow (usually mechanical arterial obstruction).

Ischemia.

**inadequate blood supply to the area.

During ischemia, anaerobic glycolysis (can/cannot) continue.

Cannot.

Ischemia causes (more/less) rapid and severe cell and tissue injury than hypoxia.

More severe.

Aside from ischemia, hypoxia can also result from inadequate _____________. Examples?

- amount of oxygen reaching the tissues.

- Anemia, CO poisoning, and pneumonia

** During ___________ blood flow is maintained and anaerobic glycolysis can continue.

Hypoxia.

**This cannot occur during ischemia.

No matter what type of stress the cell experiences, it undergoes ______________.

Biochemical and molecular changes --> functional changes --> morphologic changes .

Cellular injury occurs when the stimulus ______________

Exceeds cells ability to adapt.

What are some examples of reversible cell injury?

Cellular swelling and fatty change.

Irreversible cell injury leads to ______________.

Cell death.

What are some examples of irreversible cell injury?

Necrosis and apoptosis.

** _____________ is seen in nearly all forms of reversible cell injury.

Cellular swelling.

** In cellular swelling, there is a failure of _______________.

Energy-dependent ion pumps (ie: allows influx of Na and H2O into cell in an attempt to maintain homeostasis).

** Fatty change is [more or less] severe than cellular/cloudy swelling and involves the build-up of _____________ in the cell cytoplasm.

More, lipid vacuoles.

**occurs in organs that are actively involved in lipid metabolism (liver).

Fatty change is most often seen in the _____________.

Liver, kidney, and heart.

What are the cause of fatty change?

1. Excessive triglyceride synthesis

2. Decreased utilization of fatty acids

3. Impaired exportation of fats

Irreversible cell injury (and eventually cell death) is consistently characterized by _____________.

-Inability to restore mitochondrial function

-Loss of structure and function of plasma membrane and intracellular membranes

-Loss of DNA and chromatin structural integrity

What are 2 mechanisms of cell death?

Necrosis and apoptosis.

Necrosis is almost ALWAYS ______________.

Pathologic.

What happens in necrosis?

Cell membrane disrupted --> cell contents leak out --> inflammatory response with eventual digestion of cell

Determine if necrosis or apoptosis is occuring:

Cell swells, plasma membrane is distrupted, cellular contents leak out, inflammation.

Necrosis.

Determine if necrosis or apoptosis is occuring:

Cell shrinks, nucleus fragments, no inflammation, altered but intact plasma membrane.

Apoptosis.

Which has inflammation? Apoptosis or Necrosis?

Necrosis.

_____________ is a consequence of severe injury such as ischemia, microbial toxins, or chemical/physical injury (burns).

Necrosis.

In necrosis, intranuclear proteins leak out of necrotic cells and into the circulation, this my help identify exactly which tissues are necrotic by serology.

Give examples of this.

1) Creatinine kinase, troponin → cardiac muscle

2) Alkaline phosphatase → bile duct

3) Transaminases → liver

In coagulative necrosis, necrotic cells retain their _____________ for a period of time.

Morphologic shape.

Coagulative necrosis is an indication of ____________ in all tissues except those in the ______________.

Hypoxic death, CNS.

What are some examples of coagulative necrosis?

- MI (most common!!).

- Kidney infarct.

- Necrotizing sialometaplasia (oral cavity).

In liquefactive necrosis, necrotic cells are digested by _____________, resulting in transformation of tissue into _____________.

- Catabolic enzymes.

- A viscous liquid.

Liquefactive necrosis leaves a cavity filled with ____________ forming ______________.

- Cellular debris, neutrophils, and fluid/pus.

- Abscess.

What is an example of liquefactive necrosis?

Bacterial infections.

Hypoxic death in the CNS is due to ______________.

Liquefactive necrosis.

**In all other tissues coagulative necrosis!!

Gangrenous necrosis is most common in ______________ and is typically seen in lower extremity that has lost its ____________ with a superimposed _____________ that causes liquefactive necrosis.

Uncontrolled diabetics, blood supply, bacterial infection.

** ____________ is a specific type of necrosis that is seen most often in TB.

Caseous necrosis.

In caseous necrosis, the necrotic debris has a _____________-like gross appearance.

"Cheese".

Caseous necrosis is usually seen in the center of a collection of _____________.

Epithelial histiocytes.

**True granuloma/ granulomatous inflammation.

Fat necrosis is seen most often in association with _______________.

Acute pancreatitis.

In acute pancreatitis, pancreatic enzymes leak out of the pancreas and cause ______________ with formation of ______________ in the peritoneal cavity and mesentery.

Lipid breakdown, calcium soaps.

Fibrinoid necrosis is seen with ______________.

Immune reactions involving BVs (ie: vasculitis... Ag-Ab complexes combine with fibrin in BV walls).

**special form of vascular damage.

Intranuclear proteins that leak out of necrotic cells into the circulation may provide a means to identify _____________.

Which tissues are necrotic (by using serology).

An increase of creatine kinase or troponin in the circulation may be indicative of _____________ necrosis.

Cardiac muscle.

An increase in alkaline phosphatase in the circulation may be indicative of _____________ necrosis.

Bile duct.

An increase in transaminases in the circulation may be indicative of _____________ necrosis.

Liver.

** Apoptosis is _____________.

Programmed cell death.

Apoptosis is ___________-dependent and [tightly or loosely] regulated.

Energy-dependent, tightly.

What happens in apoptosis?

Cellular enzymes degrade DNA and cytoplasmic proteins then cell is phagocytosed and cleared.

In apoptosis the cell membrane ______________.

Remains intact.

Is apoptosis physiologic or pathologic? Is there inflammation with apoptosis?

May be either.

No inflammatory response.

** What is physiologic apoptosis?

- Eliminates cells that are no longer needed.

- Maintains steady number of various cell populations.

- Death of cells that have served their purpose --> inflammatory cells.

- Elimination of self-reactive lymphocytes (prevents immune reactions).

** What is pathologic apoptosis?

- Eliminates cells that are genetically altered or injured beyond repair.

**Ex: cells with damaged DNA, misfolded proteins, cell injury from certain viral infections.

What are some important targets of injurious stimuli?

- Mitochondria (ATP generation)

- Cell membranes

- Protein synthesis

- Cytoskeleton

- Genetic apparatus (DNA)

What are 3 major consequences of mitochondrial damage?

1. ATP deletion

2. Plasma membrane energy-dependent sodium pump action is reduced --> cell swelling and ER dilation.

3. Cellular energy metabolism is altered.

Membrane defects due to ATP depletion and calcium-mediated activation of phospholipases can result in ______________.

- ROS

- decr phospholipid synthesis

- incr phospholipid breakdown

- cytoskeletal abnormalities.

How can DNA be damaged?

Exposure to radiation therapy, chemotherapy, ROS, and mutations.

DNA damage can trigger cell death via ______________.

apoptosis.

Calcium ions are normally second messengers in several signaling pathways, but in excessive amounts it can cause injury to the cell by _____________.

interfering with ATP generation or activating injurious enzymes.

What are some examples of cell injury and necrosis?

Ischemic and hypoxic injury, ischemia-reperfusion injury, and chemical (toxic) injury

Which is worse, ischemia or hypoxia? Why?

Ischemia, does not allow for anaerobic glycolysis.

Ischemic and hypoxic injury causes decreased ATP production due to _____________.

Mitochondrial damage, ROS accumulation, and Ca2+ influx.

Ischemic and hypoxic injury causes failure of _____________ and leakage of ______________.

Protein synthesis, lysosomal contents.

In ischemia-reperfusion injury, restoration of blood flow to ischemic but still viable tissue exacerbates _____________.

Cell death.

Ischemia-reperfusion injury may be caused by _______________.

ROS accumulation in cells during reoxygenation.

What are some examples of ischemia-reperfusion injury?

Myocardial ischemia (not MI) and cerebral ischemia.

Oxidative stress includes cellular abnormalities that are induced by _____________.

ROS .

What is the cellular source of oxidative stress/ROS?

Neutrophils and macrophages.

Oxidative stress causes damage to the ____________ and crosslinking/fragmentation of _____________ resulting in damage to _____________.

Plasma membrane, proteins, nuclear and mitochondrial DNA.

Toxic injury may be direct by ____________ or indirect by _____________.

- Combining with critical molecular component/cellular organelle.

- Being converted to metabolites and then acting on target cells.

**know for exam!!

Acetaminophen toxicity affects the ______________.

Liver and kidneys.

** What is an example of direct toxic injury? Indirect toxic injury?

-Direct: mercury poisoning from contaminated seafood and chemotherapy drugs.

-Indirect: acetaminophen toxicity.

**know for exam!!

In ER stress, an accumulation of ___________ puts stress on the ER leading to _____________.

Misfolded proteins, cell death via apoptosis.

What are some examples of ER stress?

Alzheimer disease, Huntington disease, and Parkinson disease.

Normally, cells with damaged DNA are arrested in the cell cycle by ___________, but some _____________ can allows cells with damaged DNA to escape apoptosis which can lead to ____________.

p53 protein, p53 mutations, neoplastic transformation.

____________ is an inflammatory reaction that is induced by microorganisms, necrotic cells, allergies, and autoimmune disease and can cause injury to cells.

Inflammation.

Inflammatory cells secrete products that destroy microbes and other pathogens, but can also ____________.

Damage host tissues.

______________ is lysosomal digestion of cell's own contents.

Autophagy (ie: "self-eating").

Autophagy is a survival mechanism during times of ____________, but it will eventually signal ______________.

Nutrient deprivation, cell death via apoptosis.

What are the 4 pathways of intracellular accumulations?

1. Normal substance accumulates due to inadequate metabolic rate of removal (Ex: fatty liver)

2. Normal or abnormal substance accumulates due to acquired or genetic defects in its folding, packaging, transport, or secretion (Ex: AAT deficiency)

3. Normal or abnormal substance accumulates due to inherited defects in enzymatic metabolism (ie: enzyme deficiency) (Ex: Tay-Sachs disease)

4. Abnormal substance accumulates because cell cannot degrade or transport it (Ex: anthracosis/"coal workers pneumoconiosis")

What is an example of when a normal substance accumulates due to inadequate metabolic rate to remove it?

Fatty liver/steatosis.

What is an example of when a normal or abnormal endogenous substance accumulates due to acquired or genetic defects in its folding, packaging, transport, or secretion?

AAT deficiency.