Exam 1:cell injury Flashcards
cell injury
what is etiology
-causative mechanisms
-the why of the disease/what caused it to happen?
-it can be be simple, complex, unknown/idiopathic (cryptogenic) or iatrogenic “occurred as a result of a medical/surgical intervention”
an example iatrogenic etiology
vaginitis caused by candida albicans as a result from a tx with abx
epidemiology
risk factors and distribution in populations
(i.e. age, ethnicity, socioeconomic status, geographic location and incidence and prevalence of the disease)
incidence
number of new cases occurring in a given population within a given time period
(Down syndrome in US is 1 in 690 births (1/690x 100=0.14%)
prevalence
number of cases existing in both old and new
(Down Syndrome in US is 400,000 for a population of about 314 million=0.13% (400,000/314,000,000x100=0.13%)
pathogenesis
disease mechanisms, sequence of events that occurs between the stimulus events and the manifestations of the disease
(i.e pharyngeal infection- it involves what occurred physiologically and pathologically between the time that the patient encountered the infecting organism an appearance of clinical manifestations)
clinical manifestations
signs, symptoms, and diagnostic criteria
-physical signs/findings are usually related to the outcome of a physical examination or assessment
-symptoms or subjective
outcomes
cure, remissions, chronicity or death
-primary: directed towards preventing the initial occurrence of a disorder
-secondary/tertiary: seek to arrest or retard the existing disease and its effects through early detection and appropriate tx/reduce the occurrence of relapse and establishment of chronic conditions
(i.e. rehab)
causes of cell adaptation
-may be physiologic (disappears when the stressors removed) or pathologic (remain when stressor is removed)
-cell may be neither injured or killed by stressors, rather they adapt to changes, they change size, number and characteristics
-Atrophy
-Physiologic
-Pathologic
what happens in the cell during atrophy
decrease or shrinkage in cell size, the whole organ can shrink if enough of the cell do
an example of cell atrophy d/t physiologic change
with early development, like the thymus gland atrophies during childhood
cell atrophy during pathologic change
-occurs as a result of decreased workload, use, pressure, blood supply, nutrition, hormonal/nervous stimulation: immobilized people with skeletal muscle disuse atrophy
what are the mechanisms of atrophy
decreased protein synthesis/increased protein degradation, or both
what happens to muscles if you dont use it
it atrophies: less ER mitochondria, myofilaments
what happens in nerve loss
decrease o2 and AA uptake
what is cell hypertrophy?
increase in size of cells that consequently increases size of affected organ
what causes physiologic change during cell hypertrophy and give an example
- Physiologic: caused by increased demand in stimulated by hormones and growth factors, in skeletal muscles response to heavy work
i.e. Pregnancy and hormone induced uterine enlargement
Example of pathologic change that causes cell hypertrophy
- chronic hemodynamic overload (HTN/heart valve dysfunction)
what causes the left ventricle of the heart to hypertrophy?
increase blood pressure
what does cardiac hypertrophy trigger?
-mechanical signals (like stretch) and trophic signals (like growth factors and vasoactive agents)
o Stretch: triggered from increased workload- can increase production of growth factors and vasoactive factors (eg. angiotensin)
o Membrane sensors activate pathways and trigger transcription factors to increase synthesis of muscle proteins
o Initial enlargement: dilation but is short lived -> increased muscle proteins for muscle fibers to do more work
o Nucleus increases DNA synthesis: cell size associated with cellular component increase not cell fluid
o Eventually, cardiac hypertrophy = increased growth of adult myocytes
what can prolonged hypertrophy cause to the heart
contractile dysfunction, decompensation and then heart failure
what is cell hyperplasia
-an increase in the number of cells in an organ or tissue that is still capable of mitotic division.
Response to severe and prolonged injury
Production of growth factors stimulate remaining cells to make new components and divide, also can be from increased output of new cells from tissue stem cells
physiologic cause of cell hyperplasia (2)
- compensatory hyperplasia and hormonal hyperplasia
o Compensatory: adaptive mechanism that enables certain organs to regenerate (liver renews self by duplicating differentiated cells, callus forming on skin, inflammatory response)
o Hormonal hyperplasia: mostly in estrogen dependent organs like uterus and breast (uterus enlarges during pregnancy
pathologic cause of cell hyperplasia
- abnormal proliferation of normal cells and can be in response to excessive hormone stimulation or growth factors on target cells
o Hyperplastic cells are identified by pronounced enlargement of the nucleus, clumping of chromatin, and the presence of one or more enlarged nucleoli (endometrium hyperplasia d/t imbalance of estrogen and progesterone and causes excessive menstrual bleeding, BPH)
what is metaplasia
- reversible replacement of one mature cell type by another less differentiated cell type
- Associated with tissue damage, repair, and regeneration
- Replacement cell might be more suitable for change in conditions
(i.e.GERD damages squamous epithelium and are replaced by glandular epithelium to better tolerate the acid or smoker trachea epithelial cells replaced by stratified squamous- do not secrete mucus or have cilia (worse))
what is dysplasia
- abnormal changes in size, shape, and organization of mature cells
o maladaptation; deranged cell growth and differentiation within a specific tissue; results in cells that vary in size shape, and appearance and is a precursor of cancer
o Not considered a true adaptive process
o Related to hyperplasia and often called atypical hyperplasia
o Mostly in epithelia
o Dysplasia: NOT cancer and doesn’t lead to cancer
o Can be reversible if does not involve entire epithelial thickness and stimulus is removed
how does cell injury occur?
if the cell is stressed or unable to maintain homeostasis, can recover or die
what does cell injury and cell death result from? (4)
- from toxic chemicals, infections, physical trauma, and hypoxia
Ex. of cell injury are (1) ischemic and hypoxic injury, (2) ischemia-reperfusion injury, (3) oxidative stress or accumulation of oxygen-derived free radicals–induced injury, and (4) chemical injury.
what is the basis for most disease today?
impaired ATP production
what happens to cells with impaired ATP production? give example
cell cannot produce adequate energy in the form of ATP to fuel normal activities of that particular cell type - Example: hypoxia- insufficient oxygen the aerobic phase cannot progress and ATP production declines and hypoglycemia- the anaerobic portion of ATP relies on the adequate glucose from glycolysis, if glucose is m issing ATP production stalls
list examples of direct cell membrane damage (5)
- free radicals (reactive oxygen species)
- activation of the complement system
- lysis by enzymes
-lysis by viruses - physical/ chemical stressors
what are free radicals
unstable compounds with an unpaired electron in its outer ring, this makes free radicals anxious to mate with other substances and they have a particular affinity for lipid substances (which is what cell membranes are made of)
what happens during activation of the complement system
during acute inflammation activated complement proteins can cause destruction of the normal cell membrane
what happens during lysis by enzymes?
allowing organisms to dissolve surrounding tissue and allows them to move deeper into the tissues, blood and lymphatics
what happens during lysis by virus
certain viruses once they have infected a cell will cause membrane rupture as newly produced viral particles leave the host
- example would be a HIV or Hep B)
what are genetic alteration? (2)
- inherited in the germ cell line of an individual
- acquired (exposure to some mutagenic/carcinogenic environmental factors)
the four anatomic and pathophysiologic occurrences that characterizes all cell injury and death
- ATP depletion
- Oxygen and Oxygen derived free radicals
- Intracellular calcium and loss of calcium steady state
- Defects in membrane permeability
pathophysiologic cell characteristic of: ATP depletion
Loss of mitochondrial ATP and decreased ATP synthesis → cell swelling, decreased protein synthesis, decreased membrane transport and lipogenesis, → all contribute to the loss of integrity of the plasma membrane
pathophysiologic cell characteristic of: Oxygen and Oxygen derived free radicals
Reduced blood supply like in ischemia; activated oxygen species (free radicals, H202, O2, NO) cause destruction of cell membranes/structure
pathophysiologic cell characteristic of: Intracellular calcium and loss of calcium steady state
Normally intracellular Ca concentrations are low, ischemia and certain chemicals cause an increase in cytosolic Ca concentration ; sustained high levels of Ca cause damage to plasma membrane, Ca causes intracellular damage by activating many enzymes
pathophysiologic cell characteristic of: Defects in membrane permeability
Early loss of selective membrane permeability found in all forms of cell injury
what are the deleterious effects of free radical on cells?
- are unstable compounds with an unpaired electron on its outer ring, this makes them anxious to “mate” with other substances they have a particular affinity for lipids (like the phospholipid bilayer around cells and organelles)
The effect that free radical causes when it combines with a cell or organelle membrane
- it is called lipid peroxidation
- it is the binding which results in dissolution of the membrane
- Free radical are said to “drill a hole” in the membrane or said to have a phosphokinase-like effect ( an effect like enzymes that normally break down phospholipids)
examples of common diseases/conditions linked to oxygen-derived free radicals
- Atherosclerosis, Radiation injury, Cancer, Diabetes
- AIDS associated dementia, cancer, DM, sleep apnea, reperfusion injury
how does the body handle free radicals to prevent tissues injury
- Antioxidants-
o endogenous or exogenous; block synthesis or inactivates free radicals– Vitamins E & C, cysteine, glutathione, albumin, ceruloplasmin, transferrin - Enzymes-
o superoxide dismutase, converts superoxide to H2O2; catalase decomposes H2O2, glutathione peroxidase decomposes OH and H202 ( these enzymes modulate the cellular destructive effects of free radicals and are released in inflammation)
what are normal cellular substances that can cause accumulations? (4)
- water
- protein
- lipid
- carb excesses
what are abnormal substances that can cause cell accumulations?
usually results from mutated genes; accumulates d/t defects in protein folding, transport, or degradation
Endogenous:
- products or abnormal metabolism or synthesis
- (normal or abnormal) not catabolized- usually d/t lack of lysosomal enzyme called “storage diseases”
Exogenous:
-infectious agents or a mineral
-heavy metals, mineral dusts, microorganisms
what does reperfusion injury result from?
the generation of highly reactive oxygen intermediates including hydroxyl radical (OH), superoxide, and hydrogen peroxide (H2O2)
where does bilirubin become conjugated?
in the liver
describe hyperbilirubinemia
- Results from hemolytic anemia or after birth
- Too much unconjugated bilirubin is going to the liver at a rate that the liver cannot handle→ accumulates in the blood bc it is lipid soluble and becomes jaundice causing a yellowing of the skin
describe Hepatocellular jaundice
when the liver cells are sick and cannot conjugate bilirubin
what is obstructive jaundice? Stool and urine color?
obstruction to the flow of bile in the hepatic or common bile duct, conjugated bilirubin accumulates in the liver cell and more diffuses into the blood than normal; stools will be clay colored, urine will be very dark
what causes fatty liver? (6)
- ETOH, DM, protein malnutrition, toxins, anoxia, obesity
**lipids fill the cells and vacuolation pushes nucleus and organelles aside and the liver looks yellow and greasy
cell injury from fat accumulations leads to:
o increased movement of free fatty acids into liver
o increased synthesis of triglycerides from fatty acids
o decreased creation of apoproteins (lipid acceptor proteins)
o failure of lipids to bind with apoproteins to form lipoproteins
o failure of mechanisms that transport lipoproteins out of cell
o damage to ER by free radicals released by ETOH effects
what protein binds to unconjugated bilirubins?
albumins
what removes calcium from the cytosol?
ATP-dependent calcium pumps
describe what happens with calcium in normal cells
in normal cells, calcium is bound to buffering proteins, such as calbindin or paralbumin, and is contained in the ER and the mitochondria
what causes calcium levels to increase in the cytosol? (3)
- abnormal permeability of calcium ion channels
- direct damage to membranes
-or depletion of ATP (i.e. hypoxic injury)
what happens if free calcium cannot be buffered or pumped out of cells
- uncontrolled enzyme activation takes place, causing further damage
- uncontrolled entry of calcium into the cytosol is an important final pathway in many causes of cell death
karyolysis
nuclear dissolution and lysis of chromatin from the action of hydrolytic enzymes
pyknosis
o the nucleus shrinks and becomes a small, dense mass of genetic material
“clumping of nuclear material”
o the dense mass eventually dissolves (by karyolysis) as a result of the action of hydrolytic lysosomal enzymes on DNA
karyorrhexis
o part of the nucleus fragmentation process between karyolysis and pyknosis
o fragmentation of the nuclear material
coagulative necrosis
o occurs mostly in kidneys, heart, adrenal glands
o Usually from ischemia or hypoxia by chemical injury (especially mercuric chloride)
o Caused by protein denaturation- albumin changes from gelatinous, transparent state to a firm opaque state (like a cooked egg white)
o Tissues appear firm and swollen
o Area of coagulative necrosis is called infarct
liquefactive necrosis
o usually from ischemic injury to neurons and glial cells in brain
o Brain cells have a lot of digestive hydrolytic enzymes and lipids with little connective tissue
o As cells are digested the tissue becomes soft, liquefies, and is walled doff from healthy tissue, forming cysts
o Can be from bacterial infection which accumulates pus
caseous necrosis
o usually from tuberculosis pulmonary infection
o Combo of coagulative and liquefactive necrosis
o Dead cells disintegrate but debris is not digested completely
o Tissues soft and granular like clumped cheese surrounded by wall
fat necrosis
o usually in breast, pancreas, and abdominal structures
o Caused by lipases which break down triglycerides, release free fatty acids and create soaps by combining with Ca, Mag, and Na ions
o Tissue looks opaque and chalk white
gangrenous necrosis
-death of tissue
- from severe hypoxic injury usually from atherosclerosis and bacterial invasion, usually in the lower legs
dry gangrene
usually coagulative necrosis
Skin becomes dry and shrinks, color goes to dark brown or black
wet gangrene
when neutrophils invade the site causing liquefactive necrosis
Usually in internal organs
Site becomes cold, swollen, and black with foul odor
gas gangrene
caused by infxn of injured tissue by clostridium
Bacteria destroys connective tissue and cell membranes and cause bubbles of gas to form in muscle cells
Can be fatal d/t shock
Treated with antitoxins and O2 in hyperbaric chamber
what are the systemic manifestations of cellular injury? 5)
- Fever: release of endogenous pyrogens from bacteria or macrophages, acute inflammatory response
- Increased heart rate: increase in oxidative metabolic processes resulting from fever
- Increase in leukocytes: increase in total number WBCs bc of infection
- Pain: various mechanisms, release of bradykinins, obstruction, pressure
- Release of enzymes such as LDH, CK, AST, ALT, ALP, amylase, aldolase, troponins
What tissue cells releases the enzyme: LDH (4)
-RBCs
-liver
-kidney
-skeletal muscles
What tissue cells releases the enzyme: CK (3)
-skeletal muscle
-brain
-heart
What tissue cells releases the enzyme: AST (5)
-heart
-liver
-skeletal muscle
-kidney
-pancreas
What tissue cells releases the enzyme: ALT (3)
-liver
-kidney
-heart
What tissue cells releases the enzyme: ALP (2)
-liver
-bone
What tissue cells releases the enzyme: amylase
pancreas
What tissue cells releases the enzyme: aldolase (2)
-skeletal muscle
-heart
What tissue cells releases the enzyme: troponin
heart
what is apoptosis initiated by?
activation of caspase enzymes
what is the duration of apoptosis
12-24 hrs
cell characteristics of apoptosis
shrinkage of the cell, condensation of cytoplasm, detachment of cell from ECM, membrane budding (separate membrane forms around detached cellular material), phagocytosis by neighboring cells nuclear DNA fragmentation, activation of caspases and DNAses
what is necrosis initiated by? (3)
-ischemia
-toxins
-physical stimuli
durations of necrosis
20-30 minutes
cell characteristics of necrosis
cell swelling, rupture of cell membrane, clumping of nuclear chromatin, swelling of organelles, electrolyte overload, Ca overload
describe the mechanisms involved in the process of apoptosis
o Normal cell→ condensation of chromatin → cellular fragmentation → phagocytosis of apoptotic cells and fragments
The relationship of apoptosis to: cancer
autophagy suppresses tumor development but also can facilitate it
o Suppress induction of p53 tumor suppressor protein and maintain mitochondrial function
o Failure to clear ROS producing mitochondria lead to nuclear DNA mutations and cancer
The relationship of apoptosis to: rejection of organ transplantation
is from apoptosis against host tissue or the transplanted organ
