Chapter 2: Cell response to stress Flashcards
define hyaline change
alteration within a cell or ECM that causes a homogenous, glassy, pink appearance on histology stain.
-is not a particular pattern of accumulation and can be seen in connection to protein accumulation
difference of cellular response between cell injury by low O2 perfusion (hypoxic injury) or infection at the initial stage and late stage?
if acute= cell injury
initially: reversible, causes cellular swelling and increase fatty change (more adipose)
if chronic= cell death
late stage progression including DNA damage: irreversible, cell death by necrosis or apoptosis
what is hypoxic injury? and what are the 3 underlying mechanisms that cause it ?
hypoxic injury- result of low oxygen delivery to tissues (hypoxia) which decreases oxidative phosphorylation and decreases ATP production resulting in injury
- ischemia: low blood flow through organ
causes: 1 blocked arterial flow (atherosclerosis)
2. blocked venous drainage
3. shock (low blood tissue perfusion from decreased cardiac output) - low oxygen carrying capacity of blood
causes: 1. anemia (low RBC and therefore low Hgb)
2. CO poisoning (CO Hgb affinity > O2)
3. methemoglobinemia ( amount of Fe3+ > Fe2+) - hypoxemia: low oxygen content in blood due to hemoglobin loss or dysfunction (PaO2< 60mmHg)
casuses: 1. high altitude (decreased PAO2)
2. hypoventilation (increased PACO2)
3. COPD (increased PACO2)
what is a big indicator of irreversible cell injury that will progress to cell death
leakage of cellular proteins into blood causing an increase in blood levels that can be seen in lab work
two big characteristics that mark irreversibility of cell injury
- inability to reverse mitochondrial dysfunction
2. profound disturbances of plasma membrane
example of abnormal lipid accumulation
xanthomas
atheroscelrosis
cholesterolosis
neiman pick disease type C
pathologic effects of ROS formation
- lipid peroxidation –> membrane damage
- protein modification –> breakdown and misfolding
- DNA damage –> mutation
*Please Don’t Look
disorders of excessive cell death
- neurogenerative disorder
- ischemic injury
- stroke
- death of virally infected cell
hyperplasia is ____ driven
growth factor
what are the 2 types of pathologic calcification
- dystrophic calcification
2. metastatic calcification
define metastatic calcification
- calcium deposition in normal tissues (not necrotic) due to increases calcium (hypercalcemia) from Ca2+ metabolic dysfunctions
- usually not harmful unless severely progressive
- increased risk of tissues with alkaline compartments
cause of hemosideren accumulation
(hemosiderin = iron storage form)
excess iron being turned into hemosiderin granules by ferritin
- localized = tissue hemorrhage (causes bruising)
- systemic = hemosiderosis (caused by hemolytic anemia, hemochromatosis, or repeated blood transfusion )
*can be seen in coagulative necrosis by red infarction (organs with dual blood supply)
cellular swelling is seen in
reversible cell injury
and
necrosis
pathologic effects of defects in membrane permeability and membrane damage
- mitochondrial membrane damage (caspace activation)
- plasma membrane damage (leakage of cell content)
- lysosomal membrane damage (leakage of enzymes causing digestion of RNA, DNA, and glycogen leading to necrosis)
examples of exogenous pigment accumulation
carbon (can darken LNs and lungs)
tattoos
Key features and mechanisms of coagulative necrosis
- most commonly seen with extensive tissue injury due to ischemic infarction (all tissues except brain)
- firm; maintenance of cell/shape structure
- nucleus disappears
- can be red infarction (due to venous thrombi induced congestion and hypoxia) or white infarction (due to arterial thrombi induced occlusion and hypoxia)
- **wedged shaped pattern
function of glutathione peroxidase
removal of OH free radical
most dangerous ROS
define cholesterolsis
cholesterol- macrophages complex build up in lamina propria of the gall bladder
what are ways that the mitochondria can become damaged and cause progression of cell injury ? and what are the 3 major consequences of mitochondrial damage?
causes:
increased intracellular Ca2+ , ROS, toxins, or decreased O2 levels by hypoxic or chemical injury
consequences:
- formation of mitochondrial permeability transition pore (which contains cyclophilin D) leading to ox phos failure and depletion of ATP and necrosis
- abnormal Ox phos leads to ROS formation and necrosis
- leakage of cytochrome C which activates apoptosis
Atrophy results in decreased cell size in two ways. what are the differences between the mechanism of ubiquitin degradation pathway and autophagy ?
ubiquitin
- decrease in protein content of the cell by tagging with ubiquitin and activating lysosomal degradation activity
authophagy
- destruction of “self” cell organelles in 3 ways
1. macroautophagy: requires de novo formation of phagophore–>autophagosomes–>autolysosome which degrades cell.
2. microautophagy: direct lysosomal membrane invagination of cell organelle
3. chaperone mediated: chaperone transport of misfolded protein across lysosomal membrane
types of necrosis
coagulative liquefactive gangrene caseous fatty fibrinoid
mechanism of metaplasia ?
List common clinical examples
stem cell reprogramming causing surface epithelium or mesenchymal cells (cartilage, bone, blood vessels) to change cell types.
*can cause malignant transformation of metaplastic epithelium if the the reversible stimuli is not removed
Squamos metaplasia (from chronic smoking): respiratory tract columnar cells –> squamous cells
Barrets esophagus (from chronic GERD): lower esophageal squamous –> conciliated columnar with goblet (mucous secreting) cells
myosistiits ossificans: (from skeletal muscle inflammation by intermuscular hemorrhage) muscle –> boney cell types
Vitamin A deficiency: squamous metaplasia of respiratory tract, or keratomalacia (thicked eye conjunctiva by squamous cells)
what 2 types of adaptation are associated with malignant transformation
- metaplasia
- pathologic hyperplasia (common in response to viruses) - bc increased cell proliferation can occur if mutation of regulation occurs
function of catalase
decomposes H202 to H20 and O2
*removes H202
what is the cellular response to cell injury by cumulative sublethal/chronic injury over life span
cellular aging
Key features and mechanisms of fat necrosis
- necrosis of fat tissues with dystrophic calcification
- caused by trauma to adipose tissue resulting in release of fatty acids. release of FA combines with the Ca2+ deposition in saponification process.
- seen in pancreatitis when pancreatic enzymes degrade the surrounding peri-pancreatic fat (not parenchyma)
- *feature: chalk white look (bc of calcium deposits)
reduction of ATP levels is fundamental cause of _____? and what is the principle mechanism causing reduction in ATP?
necrotic cell death (starts reversible but progresses)
-main result of hypoxic or and chemical cell injury
due to mitochondrial damage or reduced O2 supply for ox phos
clinical signs of CO poisoning
- pt exposure to fire smoke, car exhaust, or gas heater
- cherry red skin
- early = severe headache
- middle = confusion
- late = coma/death
**labs: normal PaO2, but low SaO2
what is the cellular response caused by cell injury from chronic metabolic alterations
intracellular accumulations; calcifications
what are the types of cellular adaptations in response to increased stress, decreased stress, changing changing stress
- increased stress
1. hypertrophy (increase in cell size)
2. hyperplasia (increase in cell number) - decreased stress
3. atrophy (decrease cell number by apoptosis, and cell size by ubiquitin pathway or autophagy) - change in stress
4. metaplasia (change in cell type)
discuss the 2 mechanism of chemical injury and gives an example of each
- mainly affects the liver
1. direct toxicity: chemical causes direct damage to critical molecular components of tissues
ex: cyanide alters cytochrome oxidase which inhibits oxidative phosphorylation
- toxic metabolite conversion: metabolites from degradation of the chemical causes ROS production and lipid peroxidation usually by p450 enzyme in liver
ex: CCl4 (carbon tetrachloride) seen in laundry mats becomes CCl3 by p450 in the liver. CCl3 damages hepatocytes which impairs apolipoprotein synthesis causing FATTY LIVER
define anthracosis
carbon build up in lungs causing dark appearance, can progress to lung disease
altered physiological stimuli ( increased need, change in stress levels/type, irritation) that cause cell injury result in what cellular response
REVERSIBLE cellular adaptation
what are the 4 over arching aspects of the disease process
- etiology (cause)
- pathogenesis (cellular mechanisms following exposure)
- morphologic changes (structural/functional alterations of organs)
- clinical manifestation (presentation of signs and symptoms)
discuss the mechanism of re-perfusion injury
irreversible ischemic cell injury (marked with leakage of enzymes into blood) occurs followed by re-entering of blood with inflammatory cells and calcium to the site of injury. the irreversible injury damage to the mitochondria results in ROS generation by the inflammatory cells and calcium which increases extent of damage and amount of protein leakage. IgM also activates complement to increase inflammatory state.
*seen with cardiac enzyme troponin. continued elevation of cardiac enzymes following blood return indicates reperfusion injury
define dystrophic calcification
calcification deposition that occurs in necrotic tissues by normal serum Ca2+ that entered the injured cell
(no Ca2+ metabolic dysfunction present)
-can lead to increase organ dysfunction
mechanism of hypertrophy
increased gene activation of protein synthesis and organelle production
define xanthomas
*lipid accumulation
cholesterol build up in macrophages that cause accumulation of lipid foamy cells in connective tissue (usually seen in eye)
4 pathways in which result in abnormal accumulation of intracellular content
- impaired removal of normal endogenous substances from packaging/transport dysfunction (ex: steatosis of liver)
- accumulation of abnormal endogenous substances from packaging/transport dysfunction (ex: antitryspin mutation)
- accumulation of abnormal exogenous substances with no intracellular degradation enzyme
- accumulation by storage diseases (genetic enzyme defect that results in failure to degrade metabolites for removal)
function of superoxide dismustase
convert superoxide (O2-) to H2O2 *removes superoxide
Key features and mechanisms of gangrene necrosis
dry gangrene
-widespread (not wedged shaped) coagulative necrosis with mummified dead tissue
wet gangrene
-superimposed coagulative necrosis with liquefactive necrosis from infection of tissue
*usually involving ischemia of LE (seen in diabetics) and GI tract
define pyknosis, karyorrhexis, and karyolysis
*seen in histology slide of necrosis
pyknosis: nuclear shrinking
karryohexxis : nuclear fragmentation of pyknotic nucleus
karyolysis: nuclear fading/disappearance due to loss of DNA
Key features and mechanisms of fibrinoid necrosis
- necrosis of blood vessels (immune system mediated)
- Antigens and antibodies adhere to blood vessel wall and result in destruction of endothelium
- associated with malignant HTN (causing turbulent flow) or vasculitis
- *features bright pink fibrinoid staining
what is the microscopic sign seen in gangrenous necrosis
- gangrene is not a microscopic finding, just a clinical one.
- will see coagulative if dry
- will see liquefactive and coagulative is wet
a REVERSIBLE functional or structural change undergone to increase cellular ability to survive to change in stress
adaptation
ROS is largely produced by activated ______ during inflammatory reactions aimed at destroying microbes and cleaning up dead cells
lymphocytes
(particularly neutrophils and macrophages)
**Production of rapid ROS is termed “oxidative burst”
what type of necrosis is caused by pre-eclampsia
fibrinoid necrosis of the placenta
examples of causes of abnormal protein accumulations
- Renal disease cause of reabsorption of droplets in proximal renal tubules and proteinuria
- russell bodies indication of protein accumulation in ER
- antitrypsin deficicnecy = transport defect and protein accumulation
- alzheimers accumulation of amyloid
- cytoskeletal protein accumulation of intermediate filaments
- alcoholic hyaline accumulation
mechanism of hyperplasia
by stem cell production of new cells
or
growth factor initiation of proliferation of mature cells
examples of physiologic and pathologic causes of apoptosis
physiologic
- during embryogenesis
- cell loss in proliferating cell tissues
- elimination of self reactive lymphocytes
- endometrial shedding
- normal destruction of used/aged host cell
pathologic
- DNA damage
- misfolded protein accumulation
- infection and cell death by CD8/MHC1 T-cell killing
- atrophy of organs from obstruction
- loss of growth factor
list the ways ROS can be generated
- lymphocytes
- normal metabolic proceses
- radiant energy absorption
- re-perfusion
- transition metals (iron and copper)
- metabolism of certain drugs (CCl4)
- NO made by endothelial cells, macrophages, neurons, etc
causes and effects related to cellular aging
- DNA damage by end/exogenous exposure (carcinogen, ROS, etc) –> mutations
- decreased cellular replication by cellular senescence (telomere shortening) –>cell loss
- decreased protein levels by misbalance in protein folding maintenance (loss of protein homeostasis) –> decreased cell function
- in short:
causes: DNA damage, decreased cell replication, decreased protein content
results: mutations, cell loss, loss of function
definite pyroptosis
-programmed cell death associated with fever and IL-1
**inflamasome activation of caspase 1 and 11 that induces cell death by swelling, plasma membrane disruption, and inflammation
define necroptosis
- hybrid of apoptosis and necrosis
- trigged by apoptotic extrinsic pathway with TNF; however there is NO caspase involvement
- results in same effects as necrosis (loss of ATP, cellular swelling and increased size, ROS formation, plasma membrane disruption)
- also termed “programmed necrosis”
necrosis vs apoptosis
necrosis (pathologic)
- large group cell death because cellular injury
- followed by acute inflammation
- neutrophlils present
- enlarged cell size, nucleus shrinks fragments and then disappears, plasma membrane is disrupted, cell components get digested and may leak
apoptosis (pathologic and physiologic)
- energy dependent programmed cell death
- no inflammation associated
- cell shrinks in size, fragmented nucleus, intact/ altered plasma membrane, apoptotic body release with macrophage removal
explain mechanism of reperfusion injury
when blood returns to site of ischemic injury it carries inflammatory cells (lymphocytes) and calcium that will induce ROS formation and continued damage of cell.
also IgM antibodies activate complement.
-result is increased plasma levels of enzymes (in terms of heart injury you would see a continued elevation of troponin cardiac enzyme)
counteractions of cellular aging
dysfunction in nutrient sensing
- eating less increases life span by reducing insulin and IGF-1 levels (anabolic hormones) which reduces growth and chance of mutation formation
- sirtuins - NAD dependent protein deacetylases that help metabolic adaption of calorie restriction by increasing insulin sensitivity and induce DNA repair by acetylation to decrease cell death
what are the pathologic causes of increased intracellular calcium? and what are the consequences?
causes:
ischemia or certain toxins
consequences:
- opening of mitochondrial permeability transition pore
- activation of degradation enzymes (phospholipase, proteases, endonuclease, ATPases)
- direct activation of caspar resulting in apoptosis
Key features and mechanisms of caseous necrosis
- friable, pale combination of liquefactive and coagulative necrosis featured with granulomatous inflammation (type of chronic inflammation) with granuloma formation
- caused by TB or fungal infections
- *feature: cheesy appearance
cell injury vs cell death
injury
-reversible; decreased oxidative phosphorylation and ATP production; cellular swelling, fatty change of membrane lipids (loss of microvilli, membrane blebbing) RER swelling (decreased protein synthesis)
cell death
-late stage progression of cell injury, irreversible. plasma membrane damage, protein leakage, increased intracellular Ca2+, mitochondrial membrane damage = cytochrome C leakage and caspase activation of apoptosis, lysosomal damage and organelle degradation
what are the 3 apoptotic pathways
- intrinsic (mitochondrial) pathway
- cell injury, DNA damage, and decreased hormonal stimulation of growth factor causes inactivation of BCL2 which allows cytochrome C leakage and subsequent caspase activation for apoptosis
* BCL2 keep cytochrome C in mitochondria; BAX / BAK are pro-apoptotic regulators triggered by p53) - extrinsic pathway
- FAS ligand and FASR (CD95) used for negative selection of T-cells in thymus
- TNF and TNF receptor binding on target cell - cytotoxic CD8/MHC1 T-cell pathway
- APC presentation and activation of cytotoxic t-cell
- death by granzymes entering perforin made pores in cell membrane which initiate caspase activity
examples of endogenous pigment accumulation
lipofuscin brown granules (from ROS injury of lipid peroxidation and membrane destruction)
*is not dangerous to cell but is a sign of ROS injury
melanin (from oxidation of tyrosine)
hemosiderin (from local or systemic excess of iron resulting in ferritin formation of hemosiderin granules)
Key features and mechanisms of liquefactive necrosis
- most commonly seen in hypoxic injury/infarction of brain or other CNS tissues
- results from enzymatic digestion of dead tissue to liquid mass
- CNS degradation is by microglial cells, Abscess formation is by neutrophils, and pancreatitis is by pancreatic enzyme digestion of pancreas parenchyma
- *feature: creamy yellow with pus
