Patho ch4 cell injury and death
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3 general ways cells respond to environmental changes or injry?
- 1. withstand and completely return to normal if change is mild or short-lived
- 2. change structure of function to adapt to a persistent but nonlethal injury
- 3. death if the injury is too severe or prolonged
What are the 2 processes in which cell death may occur?
necrosis and apoptosis
cell death caused by external injury
triggered by intracellular signaling cascades that result in cell suicide
What occurs within a cell in reversible injuries and the early stages of irreversible injuries?
What causes this?
swelling and accumulation of excess substances within the cell
insufficient cellular energy/ATP or dysfunction of associated metabolic enzymes
What is usually the first manifestation of most forms of reversible cell injury?
What is it?
hydropic swelling - cellular swelling due to accumulation of water
Why does hydropic swelling occur?
malfunction of the Na-K pumps that normally maintain ionic equilibrium of the cell
What are the results of malfunction of the Na-K pump?
accumulation of Na ions within the cell that creates an osmotic gradient = water into the cell
Why will any injury that result in insufficient energy production cause hydropic swelling?
because the Na-K pump depends on ATP
The Na-K pump works by _____ transport.
The Na-K pump pumps ___ Na ions out of a cell for every ____ K ions it pumps in.
The malfunctioning of the Na-K pump changes the resting potential of a cell and can affect the functioning of ____ and _____ cells.
nerve and muscle
Effect of generalized swelling in the cells of an organ on that organ?
How is this described?
organ will increase in size and weight
EX: hepatomegaly, splenomegaly
3 categories of intracellular accumulations
- 1. normal intracellular substances in excess amounts
- 2. abnormal substances produced by the cell because of faulty metabolism or synthesis
- 3. accumulation of substances the cell is unable to degrade
4 normal substances that tend to accumulate in injured cells?
- 1. lipids
- 2. carbs
- 3. glycogen
- 4. proteins
cell is unable to metabolize them
A common site of intracellular lipid accumulation is the ____ where many fats are normally stored, metabolized, and synthesized.
2 genetic disorders where enzymes needed to metabolize lipids are impaired?
Where do the lipids accumulate?
Tay-Sachs disease and Gaucher disease
group of genetic diseases in which the enzymatic degradation of glycosaminoglycans in the cells are impaired and cause them to accumulate in the cell
mental disabilities and connective tissue disorders may result
Common cause of excessive glycogen storage?
Cellular stress may lead to accumulation and aggregation of _____ proteins.
How are denatured proteins dealt with within a cell?
What happens if they are allowed to accumulate?
chaperone proteins bind and refold them
they form complexes with the protein ubiquitin that assists in having them digested into fragments less harmful to the cell
Endogenous and exogenous?
endogenous - produced within the body
exogenous - comes from outside the body
5 common adaptive responses made by cells?
- 1. atrophy
- 2. hypertrophy
- 3. hyperplasia
- 4. metaplasia
- 5. dysplasia
cells shrink and reduce their differentiated functions
6 general causes of atrophy?
- 1. disuse
- 2. denervation
- 3. ischemia
- 4. nutrient starvation
- 5. interruption of endocrine signals
- 6. persistent cell injury
What is the purpose of cells' atrophying?
minimize energy requirements of the cell
A person who is on bed rest is at risk for ____ atrophy.
4 common sites of ischemia?
heart, brain, kidneys, and lower leg
3 atrophic changes that may occur with ischemia in the lower leg?
- 1. thin skin
- 2. muscle wasting
- 3. hair loss
Atrophy that results from persistent cell injury is most commonly r/t ____ & ____.
inflammation and infection
increase in cell mass acoompanied by an augmented functional capacity
Why do cells hypertrophy?
in response to increased physiologic or pathophysiologic demands
Cellular enlargement results primarily from a net increase in cellular ____ content.
Organ enlargement may be a result of both ______ and _______.
hypertrophy and hyperplasia
increased number of cells
3 reasons hyperplasia usually occurs?
- 1. increased physiologic demands
- 2. hormonal stimulation
- 3. persistent cell injury
An increase in RBC number in response to high altitude is an example of cell _____.
Increase in skeletal muscle in response to exercise is primarily the result of _____.
the replacement of one differentiated cell type with another
What usually causes metaplasia to occur?
persistent injury causes an adaptation that replaces the more injured cells with those better able to tolerate the stimulation
The replacement of ciliated columnar epi cells with stratified squamous epi cells in the bronchial mucosa of a smoker is an example of _______.
What may be caused by metaplastic cells?
disorganized appearance of cells because of abnormal variations in size, shape, and arrangement
Where is dysplasia most often seen?
in hyperplastic squamous epi
may be seen in mucosa of intestine
Dysplastic cells have significant potential to transform into _____ cells and are usually regarded as preneoplastic lesions.
Dysplasia that is severe and involves the entire thickness of the epi is called ___ ___ ___.
carcinoma in situ
Necrosis usually occurs as a consequence of ____ or ____.
ischemia or toxic injury
3 characteristics of necrosis?
- 1. cell rupture
- 2. spilling of contents into the ECF
- 3. inflammation
How does apoptosis occur?
An injury does not kill the cell but triggers cellular cascades that activate cellular suicide. Cells usually do not rupture. They are ingested by neighboring cells with minimal disruption of the tissue and without inflammation
Is apoptosis a pathologic process?
swollen cell volume
4 typical morphologic changes that occur in necrotic cells?
- 1. pyknotic - shrunken & degraded nucleus
- 2. karyolysis - swollen cell volume
- 3. dispersed ribosomes
- 4. disrupted plasma and organelle membranes
5 local and systemic indicators of cell death?
- 1. inflammation - fever, elevated WBC count, malaise
- 2. increased heart rate
- 3. decreased appetite
- 4. elevated serum enzyme levels
- 5. loss of function
What are 2 ways that may be used to identify the location and extent of cellular death?
1. testing for the presence of cellular enzymes in the blood that may have been dumped by the burst cells - different cells contain different enzymes
2. location of pain
4 types of tissue necrosis?
How do they differ?
- 1. coagulative
- 2. liquifactive
- 3. fat
- 4. caseous
primary by type of tissue affected
___ necrosis is the most common.
What are the 4 manifestations of coagulative necrosis regardless of the cause of cell death
(1) ischemic cellular injury, leading to (2) loss of the plasma membrane's ability to maintain electrochemical gradients, which results in (3) an influx of Ca ions and mitochondrial dysfunction (4) and degradation of plasma membranes and nuclear structures
The area of coagulative necrosis is composed of ______ _____ and is relatively solid.
How is coagulative tissue preserved for weeks?
the coagulated area is slowly dissolved by proteolytic enzymes
2 ways liquefactive occurs?
- 1.dissolution of dead cells occurs quickly and a liquefied area of lysosomal enzymes and dissolved tissue may result and form an abscess or cyst
- 2. bacterial infection that triggers a localized collection of WBC's that contain potent degradative enzymes that may cdigest dead cells and result in liquid debris
Liquefactive necrosis may be seen in the ____ because it is rich in degradative enzymes and contains little supportive connective tissue.
Fat necrosis refers to the death of _____ tissue and usually results from _____ or _____.
trauma or pancreatitis
How does fat necrosis occur?
Activated digestive enzymes are released from the pancreas or injured tissue. They attack the cell membranes of fat cells, causing release of their stores of triglycerids. Pancreatic lipase hydrolyzes the triglycerides to free fatty acids and glycerol which cause the appearance of fat necrosis
What does fat necrosis look like?
chalky white area of tissue
_____ necrosis is characteristic of lung tissue damaged by tuberculosis.
What do areas of caseous necrosis look like?
white, soft, and fragile resembling clumpy cheese
How does the body isolate caseous necrosis?
What are cells in the center like?
dead cells are walled off from the rest of the tissue by inflammatory WBC's
the dead cells in the center lose their cellular structure but are not totally degraded
What happens to necrotic debris in caseous necrosis?
may persist indefinitely
term used to describe cellular death involving a large area of tissue
What usually causes gangrene?
interruption of the major blood supply to a particular body part
3 types of gangrene?
wet, dry, and gas
form of coagulative necrosis characterized by black-ended, dry, wrinkled tissue that is separated from adjacent healthy tissue by an obvious line
Dry gangrene typically occurs only in ____.
gangrene that may occur due to liquefactive necrosis
Wet gangrene is typically found in ____ _____, appears _____ & _____, and may have a _____ smell due to the invasion of bacteria.
black and cold
2 reasons wet gangrene is a life-threatening problem?
1. rapid spread of tissue damage
2. the release of toxins into the blood
What causes gas gangrene and what indicates it?
infection of necrotic tissue by anaerobic bacteria of the genus clostridium
How do clostridium bacteria cause gas gangrene?
produce toxins and degradative enzymes that allow the infection to spread rapidly through the necrotic tissue
What 2 types of gangrene may be rapidly fatal?
wet and gas
What is the major difference in apoptosis and necrosis?
apoptosis does causes little tissue damage and does not elicit the inflammatory response
Death of cancer cells in response to radiation or chemotherapy is most likely due to ______.
____ cell death is recognized as a primary factor in heart failure and dementia.
2 types of environmental or extrinsic signals that may induce apoptosis?
1. withdrawwal of "survival"signals that normally suppress the apoptotic pathways
2. extracellular signals bind to the cell and trigger the death cascade through activation of "death receptors"
What occurs if a cell loses signals from neighboring cells?
the cell death cascade is initiated
How may apoptosis be triggered by intrinsic pathways?
cells monitor their condition and usefulness internally and will trigger their own death if they become too damaged to repair
A large number of cancers are associated with a mutation in the _____ gene which allows cancer cells to escape the intrinsic apoptotic monitoring system.
____ is important in preventing the proliferation of cells with damaged DNA and will cause apoptosis if its levels in a cell become high.
A family of enzymes called _____ is the main component of the proteolytic cascade that degrades key intacellular structures leading to cell death
How are caspases activiated?
initiator caspases are activated and causes a apid domino effect of caspase activation
When caspases destroy a cell what happens to the contents of the cell?
the contents are destroyed within the plasma membrane of the cell and the cell remnants are assimilated by neighboring cell
How are apoptotic cells ingested by neighboring cells?
a phospholipid normally on the cytoplasmic side of a healthy cell flips to the outside of the lipid bilayer and signals neighbors and tissue macrophages to bind and assimilate the cell components and suppresses the inflammatory response that normally accompanies phagocytosis
Heart tissue exhibits ____necrosis, brain tissue exhibits _____necrosis, lung tissue exhibits _______ necrosis, and pancreatic tissue exhibits ______ necrosis.
5 common causes of cellular injury?
- 1. hypoxic injury
- 2. nutritional injury
- 3. infectious and immunologic injury
- 4. chemical injury
- 5. physical and mechanical injury
4 causes of tissue hypoxia?
- 1. interruption of bloodflow to an area
- 2. heart failure
- 3. lung disease
- 4. RBC disorders
_____ is the most common cause of cell injury in clinical medicine and injures cells faster than hypoxia alone.
Why does ischemia injure cells more quickly than hypoxia alone?
It doesn't just cut off oxygen supply to the area. It also cuts off waste removal and nutrient supply
What are the results of hypoxia?
Eecreased oxygen supply to the mitochondria decreases ATP production. ATP dependent pumps in the cell fail. (Na-K and Ca pumps) Na builds up in the cell and draws water into the cell by osmosis and causes hydropic swelling. Excess extracellular Ca builds up in the mitochondria and further inhibits their functioning
When the mitochondria of a cell is not able to produce enough ATP what occurs?
Anaerobic glycolytic pathways metabolize cells stores of glycogen. The pyruvate end products of glycolysis accumulate and are converted to lactate and cause cellular acidification.
lactate escapes into the bloodstream as a result of the end products of glycolysis
How does the pH drop due to anerobic glycolysis affect the functioning of the affected cells?
cellular proteins and enzymes become progressively more dysfunctional as pH falls
When does ischemic injury become irreversible?
when the plasma, mitochondrial, and lysosomal membranes are critically damaged
How long does it take ischemia to occur?
When does most ischemia occur?
many minutes to hours
most cellular damage occurs after the blood supply to the tissues has been restored
damage to cells that have the blood flow restored after they have been ischemic
3 critical components of ischemia - reperfusion?
- 1. Ca overload
- 2. formation of reactive oxygen molecules (free radicals)
- 3. subsequent inflammation
Why does a Ca overload occur during restoration of blood flow to an ischemic area?
fluids high in Ca bathe the cell which has a non-functioning Ca pump due to lack of ATP production
What can the accumulation of Ca ions in the cytoplasm of a previously ischemic cell cause?
may trigger apoptosis or activate enzymes that degrade lipids in the membrane
What do reactive oxygen molecules in a cell do?
they steal hydrogen atoms and form abnormal molecular bonds in a destructive cascade
What are the 4 effects of reactive oxygen molecules in a cell?
- 1. damage cell membranes
- 2. denature proteins
- 3. disrupt cell chromosomes
- 4. may initiate the inflammatory cascade
What is the result of the inflammatory response that occurs in an ischemic cell when the blood flow is returned?
may cause ongoing cellular and organ damage for up to weeks following the initial event b/c WBC's release enzymes and other chemicals that further damage the cells in the area
4 causes of cell nutritional deficiencies?
- 1. poor intake
- 2. altered absorption
- 3. impaired distribution by the circulatory system
- 4. inefficient cellular uptake
5 common causes of malnutrition?
- 1. poverty
- 2. chronic alcoholism
- 3. acute and chronic illness
- 4. self-imposed dietary restrictions
- 5. malabsorption syndromes
The virulence of a particular biological agent depends on what 2 things?
its ability to gain access to the cell and its success in altering cellular functions
2 causes of damage when a biological agent is present?
1. damage done directly by the agent
2. damage incurred due to the body's immune response
Most _____ do not gain entry into the cell and accomplish their injurious effects from the outside.
Why do some bacteria produce and secrete powerful destructive enzymes?
to digest cellular membranes and connective tissues
toxin produced by a bacteria that interferes with specific cellular functions
Exotoxins are generally _______ and are usually susceptible to extremes of heat.
Certain gram-negative bacteria have an _____ in their cell wall that is released upon lysis of the bacteria and causes fever, malaise, and even circulatory shock.
Why does the inflammatory response cause damage to cells?
WBC's secrete enzymes and chemicals meant to destroy invading organism that can damage normal body cells that are close by
6 substances that may be secreted by WBC's during the inflammatory response?
What may WBC's cause to be produced?
- 1. histamines
- 2. kinins
- 3. complement
- 4. proteases
- 5. lymphokines
- 6. protaglandins
free radicals that attack host cell membranes
What is a virus?
small piece of genetic material that is ale to gain entry into a cell
What do viruses do within the body?
invade the cells and use the cell's functioning to survive
How may cells infected with a virus trigger their own destruction?
express viral proteins on the cell surface that are recognized by the immune system
How does the hepatitis B virus replicate and cause immune mediated cell death?
It becomes incorporated into the host cell's nucleus where it is transcribed by the normal DNA plymerases. The viral genes are transported to the cytoplasm and translated into structural proteins and enzymes which are used to make more copies of the virus.
2 ways that toxic chemicals cause cellular injury?
2. chemical is metabolized into reactive chemical within the body
What is carbon tetrachloride?
What can it do within the body?
chemical that is converted to a highly toxic free radical by liver cells and forms abnormal chemical bonds in the cell
ultimately destroys cell membranes of liver cells and causes liver failure
What common household drug acts similarly to carbon tetrachloride within the body if taken in high doses?
How does carbon monoxide cause damage?
binds selectively to Hgb and prevents RBC from carrying sufficient O2
5 injurious physical and mechanical factors?
- 1. extremes of temp
- 2. abrupt changes of atm pressure
- 3. mechanical deformation
- 4. electricity
- 5. ionizing radiation
Extremes of cold result in the hypothermic injury known as _____.
What may damage cells that experience frostbite even before they actually freeze?
ischemia due to extreme vasoconstriction and increased blood viscosity
With continued exposure to cold, a ___ ___ response may occur leading to intense _____ and _____ _____ ____.
swelling and peripheral nerve damage
Frostbit generally affects the ____, ____, and ____ and is often complicated by ______ necrosis.
extremities, ears, and nose
What are the effects of high temp?
microvascular coagulation and may accelerate metabolic processes in the cell
4 possible effects of abrupt changes in pressure?
- 1. interference with gas exchange in the lungs
- 2. formation of gas emboi in the bloodstream
- 3. collapse the thrax
- 4. rupture internal organs
Electrical current damages tissues in what 2 ways?
1. disruption of neural and cardiac impulses
2. hyperthermic destruction of tissues
Where does an electrical current usually go in the body?
follows path of least resistance through neurons and body fluids
3 manifestations of electrical cell damage?
- 1. violent muscle contractions
- 2. thermal injury
- 3. coagulation in BV's
2 ways radiation can injure cells?
1. directly by breaking chemical bonds
2. indirectly by generating free radicals
How does radiation damage DNA?
breaks apart DNA bonds
the ability of the radiant energy to split water molecules by knocking off orbital electrons
What is the result of ionization?
free radicals are created that steal electrons from other molecules and disrupt chemical bonds
2 primary effects of radiation at the cellular level?
- 1. genetic damage
- 2 acute cell destruction
The vulnerability of a tissue to radiation-induced genetic damage depends on its rate of _____.
Which cells are the most vulnerable?
cells that divide slowly will have time to repair the DNA damage done by radiation, but rapidly dividing cells may pass the damaged DNA info from cell to cell
What is radiation-induced cell death most attributed to?
radiolysis of water with resulting free radical damage to the plasma membrane
How is radiation therapy used?
kills cancer cells in an area by b/c it induces death in rapidly proliferating cells
What damage to normal cells can occur due to radiation therapy and where does it occur?
usually localized to the irradiated area
small arteries and arterioles may be damaged and cause blood clotting and fibrous deposits that compromise tissue perfusion
What is cellular aging?
cumulative result of a progressive decline in the proliferative and reparative capacity of cells coupled with exposure to environmental factors that cause accumulation of cellular and molecular damage
3 mechanisms believed to be responsible for cellular aging?
- 1. DNA damage
- 2. reduced proliferative capacity of stem cells
- 3. accumulation of metabolic damage
How is DNA caused in aging?
damage to DNA occurs due to various factors and is corrected by repair mechanisms in the cell which work less efficiently with age resulting in inhibited cell replication or apoptosis initiated due to DNA damage
Programmed senescence theory?
aging is the result of an intrinsic genetic program in which cells are programed to replicate a certain number of times and then stop
In programmed senescence theory why is it believed cells stop dividing at some point?
when telomeres get short enough the cell stops dividing
Progressive loss of _____ gene expression with aging may contribute to reduced proliferative capacity because telomeres are not repaired when they are shortened.
Free radical theory of aging?
accumulated metablic cell damage over time
In free radical theory what determines the life span?
rate of metabolism
2 factors that may cause cells to age more quickly?
- 1. DNA repair mechanisms are faulty
- 2. reduced antioxidant activity
death of the entire organism
Characteristics of somatic death that occur immediately? (3)
- 1. body temp falls
- 2. skin becomes pale
- 3. blood and body fluids collect in dependent areas
When does rigor mortis begin in somatic death?
within 6 hours
What causes rigor mortis?
accumulation of Ca and depletion of ATP result in actin-myosin cross-bridge formation in muscle cells
When does rigor mortis progress to limpness as tissues of the body begin to deteriorate?
24 to 48 hours after death
release of lytic enzymes in tissues throughout the body that causes putrefaction
6 criteria for determining brain death?
- 1. unresponsiveness
- 2. flaccidity
- 3. absence of brainstem reflexes (swallowing, gagging, pupil and eye movements)
- 4. absence of respirtory effort when the subject is removed from the ventilator
- 5. absence of electrical brain waves
- 6. lack of cerebral blood flow
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