Unit 2 Pathphysiology - Chapter 2 Altered Cellular and Tissue Biology Flashcards
Dysplasia
Cellular Adaptation
atypical hyperplasia
abnormal change - size, shape, and organization of mature tissues cells; may not progress to cancer, if they do not involve entire epithelium may be reversible
Metaplasia
Cellular Adaptation
reversible replacement of one mature cell type by another, sometimes less differentiated, cell type; asssociated w/ tissue damage, repair, and regeneration; can develop from reprogramming stem cells (epithelial or connective tissue/bone marrow stem cells) d/t cytokines and growth factors in cell environment
e.g. smoker => lungs replaced with stratified squamous epithelial cells (no mucus or cilila)
Causes of cellular injury?
Cellular Injury
Hypoxia (most common?), free radicals, toxic chemicals, infections, injury, immune response, genetic factors, lack of nutrients, trauma
ultimately cell stress
What is necrosis, apoptosis, autophagy, accumulation, and pathologic calcification?
Cellular Injury
- necrosis - severe cell swelling and breakdown of organelles
- apoptosis - cellular self-destruction (programmed)
- autophagy - recycling factory; degrades organelles
- accumulation - water, pigments, lipids, glycogen, protein
- pathologic calcifcation - accmulation of calcium
Biochemical themes for cell death
Cellular Injury
A. ATP depletion (swelling; loss of cell integrity)
B. Lowered levels of oxygen + increased levels of oxygen-derived free radicals (destroy cell membranes and structures)
C. Increased intracellular Ca++ & loss of calcium steady state (d/t ischemia and chemicals)
D. Defects in membrane permeability (early loss of membrane d/t all forms of cell injury)
Sequence of events l/t cell death
Cellulary injury
- Decreased ATP production
- failed active transport mechanisms
- cellular swelling
- ribosomes detach from ER
- mitochondrial swelling (calcium accumulation)
- vacuolation
- leaked digestive content from lysosomes
- autodigestion
- lysis of plasma membrane
- death!
One particular sx that hypoxia can cause?
cellular injury
Inflammation (inflammed lesions can eventually become hypoxic)
First thing after hypoxic injury?
cellular injury
Ischemia
Reperfusion injury
cellular injury
Restoration of o2 after ischemic injury can result futher injury d/t the oxygen intermediates or radicals
Inherent reactive oxygen species (ROS)
cellular injury
Aerobic metabolism; important in cell function + communication, signaling pathways; regulates protein expression, posttranslational modifications, alteration of protein stability => protein stability, dictating protein fx, alter location or interactions
This includes redox-dependent regulation as well; proliferation and differentiation, immune fx, stem cell renewal, autoimmunity
What can cardiac ischemia and reperfusion injury cause cellwise?
cellular injury
- ROS
- pH alterations
- Osmotic changes
- gap junciton changes
- Inflammatory signaling
- Calcium overload of mitochondria
Mitochondrial permeability transition pore (MPTP)
cellular injury
D/t rapid pH restoration in cell b/c of the reperfusion, causes large pore to appear on mitochondria leaking many ATP+ and solutes l/t apoptosis.
What happens in low, moderate, or high levels of ROS?
cellular injury
- Low (normal immune system)
- Moderate (stem-cell differentiation and renewal via signal pathways)
- High (hyperactive signal pathways => inflammation, cancer, cell death)
Free radical
cellular injury
a molecular species of independent existence that contains a single unparied electron in outer orbit
Oxidative stress
cellular injury
disturbance in balance between the production of and antioxidant defenses important in membrane damage process induced by free radicals; this process can active signaling pathways b/c ROS controls enzymes + transcription factors
Oxidative stress is an important mechanism in which general conditions? (4)
cellular injury
- cell injury
- cancer
- degenerative diseases (alzheimer’s)
- aging
What processes create free radicals?
cellular injury
- redox reactions in metabolic processes (transferring of electrons)
- absorb extreme energy sources (UV, radiation)
- enzyme metabolism of exogenous (external) chemicals, drugs, and pesticides
- processing of transition metals (e.g Iron, copper)
- nitric oxide “NO” (chemical mediator, can act as independent radical)
Effects of free radicals? (3)
cellular injury
- liquid peroxidation (destruction of unsat. fatty acids)
- alter proteins + protein loss + misfolding
- DNA mutations
How are ROS created and deactivated?
cellular injury
- mitochondria or enzymes in cytoplasm (xanthine oxidase or cytochrome p-450)
- inactivated by enzyme superoxide dismutase (SOD or O) or spontaneously
Hydrogen peroxide (H2O2)
cellular injury
cellular signaling molecule (free radical); created from SOD enzyme
Hydroxyl radicals
cellular injury
hydrolysis of water d/t ion radiation or interact w/ metals (mainly Fe and Cu) l/t macromolecule modification and toxicity
Nitric Oxide
cellular injury
important mediator and act as a free radical; in neuronal cells (neurotransmission), endothelial cells (vessel relaxation), neutrophils/macrophages (vessel relaxation + pathogen suppression)
Antioxidant and list of them?
cellular injury
blocks synthesis + inactivates free radicals; vitamin E, vitamin C, cysteine, gluathione, albumin, ceruloplasmin, transferrin
Enzymes important for terminating free radicals?
cellular injury
Superoxide dismutase (converts superoxide to h2o2)
catalase (in peroxisomes) decomposes h2o2
glutathione peroxidase (decompases h2o2 and OH-)
Hydrogen peroxide and hydroxide
What is the greatest source of ROS?
cellular injury
mitochondria
Aside from energy (ATP) production, what else is mitochondria responsible for?
cellular injury
- intracellular ca++ regulation
- ROS production/scavenging
- regulate apoptotic cell death
- activate caspace proteases (control inflammation and cell death)
Does mitochondria contain own DNA? Does it have an new emerging role?
cellular injury
- Yes, mtDNA (mitochondrial DNA) and it encodes various enzymes involved in oxidative phosphorylation (delivery of electrons via NADH + FADH2, electron transport + proton pumping, form water by splitting o2, ATP Synthesis) for CNS, skeletal muscle, cardiac muscle, liver, and kidneys.
- role of mediating environmental changes and genomic responses
Excessive hydrogen peroxide and OH radicals can cause what?
cellular injury
Damage lipids, proteins, and mtDNA => cell death
Specific conditions implicated when Mitochondrial oxidative stress occurs?
cellular injury
Alzheimer’s, parkinson’s, prion disease (infectious brain disease), amyotrophic lateral sclerosis (ALS or loss of muscle control), aging
List the toxicity pathways or cellular stress response pathways
cellular injury
- hypoxia
- ER stress
- mental stress
- inflammation
- osmotic stress
Effects of chaparral and ma huang on liver?
cellular injury
Dietary supplements that are hepatotoxins
Liver responsible for conversion of toxins to intermediates that can adversely affect body?
cellular injury
true
Phytochemicals
cellular injury
Being investigated for benefits amongst select fruts + plants: chamomile (sleepiness, anxiety, GI - flower), silymarin, carrot, ginger root, milk thistle seed, rosemary, tumeric
Large envirnomental health risk?
cellular injury
air pollution
Risks of air polluation
cellular injury
stroke, heart disease, lung disease, respiratory disease, including asthma
Heavy metals common in toxicity?
cellular injury
lead, mercury, arsenic, cadmium
What is the recommended medical tx for children w/ high blood lead levels?
cellular injury
chelation therapy when greater than or equal to 45 mcg per deciliter
Iron (Pb) exposures affects what most in body?
cellular injury
alteration of cellular ion status (cations, transport mechanisms, metal enzyme cofactors)
Minamata Disease
cellular injury
Causes deafness, blindness, intellectual disability, cerebral palsy (disorder of muscle, tone, and posture), and CNS defects in children exposed in utero; leaked methylmercury from industry into water
How are iron (Pb) and mercury similar?
cellular injury
Iron and mercury both bind to sulfhydral groups (delineating or describe general role and structure of proteins and enzymes) in some proteins l/t CNS and kidney damage.
What can slow down absorption of alcohol? And recommended drinking amount for men + women?
cellular injury
Milk and fatty foods
two drinks per day for men; one drink per day for women (12 oz beer, 4 oz wine, 1.5 oz 80 proof spirit, 1 oz 100 proof spirit)
What is alcohol converted into?
cellular injury
acetylaldehyde
Most common chemical asphyxiant? Other gases?
cellular injury
- Carbon monoxide
- Others: cyanide (genetic trait for smell - most population lack), hydrogen sulfide (sewer gas)
dry-lung drowning
cellular injury
in 15% drowning little or no water enters lungs b/c vagal nerve-mediated laryngospasms.
conditions for potential of disease producing microorganism (3)
cellular injury
- invade and destroy cells
- produce toxins
- produce damaging hypersentivity rxns
What one of the main systems is responsible for membrane alterations during immunologic injury?
cellular injury
complement
opsonization (enhancing phagocytosis of antigens); chemotaxis (attracting macrophages and neutrophils); cell lysis (rupturing membranes of foreign cells); and clumping (antigen-bearing agents).
Antibodies can cause immunologic damage in what conditions? (Membrane wise)
cellular injury
Interfere w/ membrane by occupying receptors in diabetes mellitus and myasthenia gravis (autoimmune cause weakness in skeletal or voluntary muscles)
Autoantibodies in diabetes 1 against insulin or islet cells
Myasthenia gravis (MG) is a disease of the postsynaptic neuromuscular junction (NMJ) where nicotinic acetylcholine (ACh) receptors (AChRs) are targeted by autoantibodies. Causing muscle weakness and fatigue (autoimmune)
Genetic d/o can injure cells by altering following: (4)
cellular injury
Plasma membrane’s structure, shape, receptors, or transport mechanisms
Vitamin A purpose
cellular injury
metabolism of visual pigments
vitamin K purpose
cellular injury
prothrombin synthesis
Prothrombin is a protein made by the liver. Prothrombin helps blood to clot. The “prothrombin time” (PT) is one way of measuring how long it takes blood to form a clot, and it is measured in seconds
vitamins E and C purpose
cellular injury
antioxidation rxn’s
pyroxidine (vitamin b6) purpose
cellular injury
affects amino acid transfer rxn’s
flavin (FAD/FMN)
nicotinamide (NAD)
Purpose of them?
cellular injury
help transfer electrons in various reactions
vitamin d purpose
cellular injury
calcium and phosphate metabolism
Primary accidental hypothermia
cellular injury
previously health person exposed to the changes that occur w/ cold; can commonly happen in warmer regions; neonates and eldery great risk groups; homeless or even climbers
secondary hypothermia
cellular injury
occurs d/t systemic d/o; e.g - hypothyrodism, hypoglycemia, adrenal insuffciency, metabolic alterations w/ uremia (high waste products in blood d/t kidney filter failure), neurolgic injury, extensive burns, acute MI, skin diseases, hepatic failure
risks of cold water diving?
cellular injury
submersion into cold water inducing high incidence of cardiac dysrhythmias
cold-shock response and diving response?
cellular injury
- triggers tachycadria from sympathetic nervous system
- while the diving response promotes a parasypathetically mediated bradycardia
- both happening l/t automatic conflict > dysrhythmias
Frostbite
cellular injury
Continued exposure to cold; vasodilation => swellling l/t affected nerves // thrombosis as well
When the body is exposed to very low temperatures, it tries to prevent heat loss by redirecting the blood away from the extremities such as fingers and toes.
If exposure is prolonged, ice will start to form inside and around skin cells. The ice crystals block the movement of blood through the fine mesh of capillaries, which means the tissue is deprived of oxygen and nutrients. The longer the tissue remains frozen, the greater the amount of damage.
Heat cramp
result of exercise d/t sweat; tx - salt replacement
heat exhaustion
cellular injury
most common; loss of salt + h2o; hypotension secondary to hypovolemia
heat stroke
cellular injury
high environmental temp and humidity; core temp of 106 f (41 c) is life threatening; vasodilation and decreased blood volume
Malignant hyperthermia
cellular injury
elevated temp, increased muscle metabolism, muscle rigidity/spasm, rhabdo, acidosis, CV alterations, tachycardia and tachypnea, respiratory and metabolic acidosis, brown urine, hyperkalemia, elevated CK and myoglobulin, DIC, patchy, discolored skin (mottled) - lack of blood flow!, sweating
inheritied d/o of skeletal muscle sarcoplasmic reticulum in response to inhalation anesthetics (halothane, isoflurane, sevoflurane, desflurane or succinylcholine. MH is a genetic disorder passed down through families) or succinylcholine (depolarizing muscle relaxant - anectine and suxamethonium)
Inherited rxn to certain drugs used during surgery
dantrolene (Dantrium, Revonto, Ryanodex) is used to treat the reaction by stopping the release of calcium into muscles.
Sudden infant death syndrome (SIDS) - recommendations to prevent
cellular injury
position supine, use firm sleep surface, breast feed, room-sharing w/o bed-sharing, routine immunizations, use of a pacifier
avoid soft bedding, overheating, exposure to smoke
Decompression sickness
cellular injury
Decompression sickness occurs when rapid pressure reduction (eg, during ascent from a dive, exit from a caisson or hyperbaric chamber, or ascent to altitude) causes gas previously dissolved in blood or tissues to form bubbles in blood vessels. Symptoms typically include pain, neurologic symptoms, or both.
slowly reintroduce gas bubbles to blood if not then ischemia d/t gas emobli causing cellular hypoxia
blast injury
cellular injury
sudden increase or decrease in atmospheric pressure transmitted via air or water onto human body
3 types of high altitude illnesses
cellular injury
high altitude pulmonary edema (HAPE), high altitude cerebral edema (HACE), acute mountatin sickness (AMS)
High altitude cerebral edema vs High altitude pulmonary edema
cellular injury
cerebral edema version - hypoxia induced cerebral vasodilation and increased in blood flow, which leak too; pulmonary edema version - hypoxic pulmonary hypertensive response (vasoconstrict l/t leakage from blood vessels to lungs to air sacs)
Cellular swelling
cellular injury
shift of extracellular water into cells; in hypoxia, reduced ATP and ATPase levels permit sodium to enter cell (usually transported out), where as K+ diffuse out, this increased na+ l/t increased osmotic pressure, whichc draws more water
Vacuolation
cellular injury
Cisternae of ER distend, rupture, and coalesce (form one mass) => form large vacuoles that isolate water from cytoplasm
Progressive vacuolation resulting in cytoplasm swelling is called ____ ?
cellular injury
vacuolar degeneration
Mucopolysaccharidoses (MPSs)
cellular injury
carbohydrate excess d/o
Mucolipidoses (MLs)
cellular injury
carbohydrates and lipids excess accmulation
MPSs and MLs are classified as ……..?
Mucopolysaccharidoses (MPS) and mucolipidosis (ML)
celluar injury
lysosomal storage disease; they involve increased storage of carbohydrates or lipids or both
glycosaminoglycans, present in mucus or fluid around joints (muco-) — polysaccharidoses
Carbohydrate, lipids, or both accmulation concern which conditions?
cellular injury
Tay-sachs (absence of enezyme beta-hexosaminidase A that breakdown fatty acid => accmulate gangliosides affecting brain and spinal cord) // flaw in hexa gene when passed on
Muscular: muscle weakness, problems with coordination, rhythmic muscle contractions, or stiff muscles
Whole body: feeling faint or wasting away
Also common: difficulty speaking, difficulty swallowing, hearing loss, seizures, or vision loss
fabry disease (enzyme alpha-glactosidase-A cannot breakdown fatty materials or lipids)
Episodes of pain in the hands or feet.
Gaucher diease (cannot breakdown lipids d/t lacking enzyme glucocerebrosidase b/c GBA recessive gene - affect bone marrow, liver, spleen // affect jewish population)
Enlarged spleen.
Enlarged liver.
Eye movement disorders.
Yellow spots in the eyes.
Not having enough healthy red blood cells (anemia)
Extreme tiredness (fatigue)
Bruising.
Lung problems
**Niemann-Pick disease ** (lack ASMD, unable to metabolize fat, collect in macrophages)
Acid sphingomyelinase deficiency (ASMD) is a rare progressive genetic disorder that results from a deficiency of the enzyme acid sphingomyelinase, which is required to break down (metabolize) a fatty substance (lipid) called sphingomyelin. Symptoms may include:
enlarged liver and spleen (hepatosplenomegaly) difficulty coordinating movement (ataxia) abnormal eye movements (vertical supranuclear gaze palsy) poor muscle tone (hypotonia) severe liver disease. frequent respiratory infections. difficulty with speech. difficulty with swallowing and feeding.
Pompe disease (buildup of glycogen in the body’s cells) — progressive weakness to heart and skeletal muscle
Classic type:
Weak muscles Poor muscle tone Enlarged liver Failure to gain weight and grow at the expected rate (failure to thrive) Trouble breathing Feeding problems Infections in the respiratory system Problems with hearing
Non-classic type:
Motor skills delayed (such as rolling over and sitting) Muscles get steadily weaker Abnormally large heart Breathing problems
mucopolysaccharidoses (corneal clouding, joint stiffness, intellectual disability)
steatosis
cellular injury
intracellular lipid accmulation in liver
Two ways protein accmulation can harm body?
cellular injury
- Metabolites from protein digestion can affect other organelles when released from lysomsomes
- Excessive proteins push against organelles
What is present in multiple myeloma in terms of proteins?
celluar injury
russell bodies d/t excess proteins in B lymphocytes
Any small intracellular body found within another (accmulute in ER inside cytoplasm) – Russell bodies
Cancer of WBC
What color does lipofuscin (aging pigment) give to cells undergoing atrophic changes?
cellular injury
yellow-brown
Most common exogenous pigment
cellular injury
carbon or coal dust
What condition causes the rare bronze or hyperpigmentation appearance?
cellular injury
Addison’s disease (melanogenesis)
Does not produce steroid hormones: cortisol; aldosterone => hypoglycemia, hypotension, wt loss, GI disturbance (n/v, abdominal pain), weakness, hair changes
Adrenal crisis:
profound fatigue, dehydration, low bp, serum NA down, serum K+ (d/t renal failure) elevated
Albinism
cellular injury
inherited d/o; decrease in melanin production
Iron enters blood from what 3 major sources?
cellular injury
- tissue stores
- intestinal mucosa
- macrophages digesting RBC
How does hemoprotein accmulation occur?
cellular injury
excessive iron stored
How does brusing appearance change in regards to hemosiderin (greater levels of iron)?
cellular injury
initial bruise/hemorrhage starts red-blue then lysis of RBC causing hemosiderin to build up (yellow-brown pigment) causing that yellow-brown appearance
Condition for repeated transfuion or prolonged iron administration?
cellular injury
hemosiderosis
an excess of billirubin, bile derived from hemoglobin, can cause what?
cellular injury
jaundice or icterus (bilirubin level exceed 1.5 -2 mg/dl rather than 0.4 - 1) // yellowing of skin
Hyperbilirubinemia
cellular injury
build up of bilirubin in blood; d/t hemolytic jaundice, liver diesase, or gallstones/pancreatic tumors
Since unconjugated billirubin can damage membrane and proteins, what can provide some protection?
cellular injury
Albumin can bind to them
Dystrophic calcifcation
cellular injury
occurs in dead tissues of necrosis
Metastatic calcification
cellular injury
occur in undamaged tissues d/t hypercalcemia // hyperparathyroidism (osteoclast and calcium reabsorption via kidney and phosphate excreted, hyperthyroidism (thyroid causes more bone resorption and excretion), addison disease (volume depletion and renal not excreting Ca++), toxic lvl vitamin D (intestinal and renal absorption)
How is urate produced?
cellular injury
end product of purine (animal products from liver, intestine, muscles [exoogenous] and endothelium; dead cells from DNA/RNA [endogenous] — adenine and guanine) catabolism; missing enzyme urate oxidase then urate must be removed via bowel and urine
Tophus
cellular injury
firm nodular subq deposits of urate crystals surrounded by fibrosis
Uric acid is a normal body waste product. It forms when chemicals called purines break down. Purines are a natural substance found in the body. They are also found in many foods, such as liver, shellfish, and alcohol. They can also be formed in the body when DNA is broken down.
When purines are broken down to uric acid in the blood, the body gets rid of it when you urinate or have a bowel movement. But if your body makes too much uric acid, or if your kidneys aren’t working well, uric acid can build up in the blood. Uric acid levels can also increase when you eat too many high-purine foods or take medicines like diuretics, aspirin, and niacin. Then crystals of uric acid can form and collect in the joints. This causes painful inflammation. This condition is called gout. It can also lead to kidney stones.
Niacin – vit b3 (made and used by body to turn food into energy)
Lactate dehydrogenase (LDH)
cellular injury
released from RBC, liver, kidney, skeletal muscle
Tissue damage
Creatine kinase (CK)
cellular injury
release from skeletal muscle, brain, heart
Increased amounts of CK are released into the blood when there is muscle damage such as a heart attack, skeletal muscle injuries, certain muscle disorders, or strenuous exercise. A CK level may also rise when excessive alcohol, cocaine, and certain medications are taken, such as a statin for elevated cholesterol.
When CK adds phosphates to creatine, it turns the creatine into the high-energy molecule, phosphocreatine, which your body uses to generate energy (muscles)
aspartate aminotransferase (AST)
cellular injury
release from heart, liver, skeletal muscle, kidney, pancreas
Metabolize amino acids aspartate w/ glutamate important
Aspartate non essential + glutamate (NT)
alanine aminotransferase (ALT)
cellular injury
liver, kidney, heart
alkaline phosphatase (ALP)
cellular injury
liver, bone
ALP is an enzyme found in the liver and bone and is important for breaking down proteins. Higher-than-normal levels of ALP may indicate liver damage or disease, such as a blocked bile duct, or certain bone diseases.
amylase
cellular injury
pancreas
An amylase is an enzyme that catalyses the hydrolysis of starch into sugars. Amylase is present in the saliva of humans and some other mammals, where it begins the chemical process of digestion.
aldolase
cellular injury
skeletal muscle, heart
enzyme helps the body break down sugars to produce energy.
troponins
cellular injury
heart
Necroptosis
cellular death
necrosis driven by regulated or programmed molecular pathways
difference between necrosis and apoptosis?
cellular death
- necrosis: swelling; disrupted membrane; leak out; inflammation; pathologic
- apoptosis: reduced size; fragmented nucleosomes; intact membrane; no inflammation; physiologic; apoptotic bodies remove cellular content
gas gangrene
cellular death
cause gas bubbles to form in muscle cells via enzymes and toxins - clostridium; lyse RBC can be fatal
ER stress
cellular death
excessive accmulation of misfolded proteins => apoptotic cell death // linked to CNS degenerative disease
Liquefactive necrosis
cellular death
ishcemic injury to neurons and glial cells in the brain => cyst + pus
coagulative necrosis
cellular death
kidneys, heart, adrenal glands - hypoxia caused by severe ischemia or chemical injury (mercuric chloride) => opaque state (protein albumin => gelatinous state)
caseous necrosis
cellular death
TB pulmonary infection (combination of coagulative and liquefactive necrosis) => clumped cheese
Fat necrosis
cellular death
breasts, pancreas, abdominal structures =? creates soap b/c free fatty acids from breakdown bind with ca++, mg, na+ (saponification)
caspace
cellular death
aspartic acid-specific proteases; amplify suicide cascade; cleave other key proteins => killing cell quickly and neatly
mitochondrial pathway
cellular death
intrinsic pathway
death receptor pathway
cellular death
extrinsic pathway
The extrinsic pathway involves the binding of ligands to cell surface ‘death receptors’ (DR) which in turn initiates the caspase cascade.
gangrenous necrosis caused by
cellular death
caused by hypoxia and subequent bactieral invasion
Autophagy
cellular death
important in homeostasis; lysosomes breakdown cyatoplasmic parts and organelles and then salvage key metabolite
senescense
aging
the process of aging; permanent proliferative arrest
inflammaging
aging
increased levels of body cytokines and proinflammatory markers; changes with aged immune system
Frality
aging
common clinical syndrome in OA
Somatic death
Somatic Death
death of entire organism
Manifestations of somatic death
Somatic Death
cessation of resp/circ, low temp, dilation of pupils, loss elasticity, loss transparency in skin, rigor mortis (muslce stiffening), discoloration (livor mortis)
Putrefaction is obvious after how long (rotting)?
somatic death
24-48 hours after death
sarcopenia
somatic death
loss of muscle mass
