Lecture 1: Altered Cellular Biology JG~MM Flashcards
Normal Homeostasis
Normal internal equilibrium
Stress (Insult)
Stimulus which upsets normal homeostasis
Compensation
The body’s attempt to maintain normal homeostasis under stress
Cell Injury
Result of a stimulus in excess of a cell’s immediate adaptive response
Reversible Cell Injury
Injury which does not kill the cell (anything that doesn’t kill me makes me stronger)
Works at the cellular level but NOT at the tissue level
Irreversible Cell Injury/Cell Death
Injury that results in cell death
Apoptosis
Clean controlled cell death
Necrosis
Messy uncontrolled cell death
Cell Adaptation
Adaptation (compensation) that occurs at cellular level
Atrophy
● ↓ in the size of cells
● “a”- without, “trophy”- feast (now statuette)
● No feast: looks like cells are starving
Hypertrophy
● ↑ the size of the cells ● Lots of feasting, much bigger ● Fat cells (adipocytes) ● Skeletal muscle cells ● Cardiac → hypertrophy
Hyperplasia
● ↑ in number of cells
● “Plasia” (e.g. plastic) = form
● Hyperplasia: most everything else
○ I.e. benign prostatic hyperplasia
Metaplasia
● Change from one cell type to another cell type
○ Can be normal or abnormal
● I.e. columnar → stratified squamous → in bronchioles of smokers
○ Result of a stressor
○ GERD: esophageal lining is stratified squamous
then turns to columnar
○ Smoking: ciliated pseudostratified → stratified
squamous
■ If quit smoking goes back to what should be?
● Metaplastic tissue can become dysplastic
*chronic injury or irritation
Dysplasia
● Abnormal cells that are not necessarily cancer
● “dys” = bad/painful + form
● Cells that are not a legitimate cell type
● NOT necessarily cancerous, but precancerous (could progress to cancer)
○ In reality almost ANY cell in body can progress
to cancer
○ But dysplastic cells are well on the way to
becoming cancer
● NOTE: cancer cells will almost always be dysplastic
*Persistent severe injury or irritation
Neoplasia
● Abnormal disorganized new growth, sometimes referred to tumor (swelling that is abnormal)
● Not all neoplasia is cancer, but all cancer results in neoplasia
○ I.e. Warts: not cancer but neoplasia. (Warts are also dysplasia)
Hypertrophy in Cardiac Muscle
● Caused mainly by hypertension, aortic stenosis (valve doesn’t open all the way)
○ No rest for the heart during these conditions as compared to exercise
● Power athletes (i.e. cyclists, rowers, sprinters) usually show cardiac (left ventricular) hypertrophy but not as much as pathological hypertrophy
○ Left ventricular hypertrophy in an athlete is not usually a problem
● Stressor that injures a cell but doesn’t kill it
○ Moving heavy boxes, injures cells & they start adapting, but sore next day (DOMS)
○ When you move again within a week you don’t feel so bad
○ Heart attack: if cells don’t die they prepare for future heart attack
○ Dead cardiomyocytes however are not replaced by new myocytes
Myocardial cells ONLY undergo hyperplasia or hypertrophy?
hypertrophy
What do skeletal muscle, cardiac muscle, and neurons all have in common?
Do not undergo hyperplasia.
ATP depletion
● O2 deficiency greatly ↓ ATP production
● Blood flow ↓ → don’t get enough O2 → without O2 don’t get enough ATP production
● Lack of ATP prevents Na+/K+ ATPase
○ Na+ flows in → H2O follows in → cell swells
Free Radicals & Reactive O2 Species (ROS)
● Cause oxidation of membranes & other structures
○ I.e. hydrogen peroxide on skin: bubbles & skin bleached & burn
● Particularly problematic with reperfusion
○ Restoring blood flow to area can cause oxidative damage (unpaired electron)
*see slide 8 drawn graph for athlete vs non-athlete
↑ Intracellular Ca2+
● Low ATP & Na+ gradient prevent removal of Ca2+
● Release of Ca2+ from mitochondria & ER
● Ca2+ activates many enzymes & apoptosis
● Very high levels Ca2+ signals apoptosis
● A lot of Ca2+ causes cell death
Defects in Plasma Membrane
● Loss of Na+ gradient, activation of proteases & phospholipases
● Permeable plasma membrane prevents normal cell function
● Lose normal cell function
Ischemia (slides 9 & 10)
● Tissue not getting new O2 → becoming hypoxic → with ↓ in ATP production (from 34 ATP → to 2 ATP)
● Glycolysis ↑ to get as much ATP as possible
○ This also creates H+ & cells & tissue become acidic (acidosis)
● Lactate is pyruvate that has H+ added; lactate buffers H+
● Tissue becomes acidic, pH falls, nucleus begins clumping (not irreversible) but can’t access DNA
○ No O2 to neutralize the H+ in tissue
● ↓ in pumping Na+ out, lose gradient, H2O follows, ↑ extracellular K+ (from K+ leak channels) d/t no ATP
○ Lose electrical gradient
○ Resting membrane potential begins to go up & start depolarizing cells
● Ca2+ continues to come into cell & is unable to be pumped out
○ Needs contraction but unable to d/t no ATP
● Acute swelling of cell d/t H2O coming in
● Dilation of Rough ER
○ Ribosomes begin to detach, ↓ in protein synthesis (to save ATP), lose ability to maintain cytoskeleton (not making actin d/t ↓ in protein synthesis)
● Now membrane damage begins to take place
● Loss of membrane allows things to leak out:
○ Lactate dehydrogenase (LDH), creatine-kinase (CK): indicators that cells somewhere in body are dying
● Lysosomes swell
○ When they rupture, lysosomes release digestive enzymes that begin breaking the cell down (autolysis)
● Irreversible Injury
○ Defects in the membrane
○ Karyolysis
■ DNA is chopped up & game over (not able to reproduce)
Karyolysis
dissolution of a cell nucleus
Hypoxia
● Low tissue O2 level
● Caused by hypoxemia, or hemoglobin problems such as anemia (i.e. w/o hypoxemia)
Anemia
● Not enough RBCs in body, 100% O2 saturation
● Less hemoglobin to carry O2, less O2 in blood d/t overall less blood cells
● Will NOT cause hypoxemia but WILL cause hypoxia
● Will have normal O2 saturation
Anoxia
● Very low tissue O2 level, extreme form of hypoxia
● No O2
Hypoxemia
● Low blood O2 tension (pressure) (↓ O2 saturation)
● Low O2 pressure/tension in blood
● Caused by: poor air exchange, difficulty breathing, (hold your breath for long enough), suffocation, heart failure
● ↓ O2 saturation
● % of hemoglobin binding sites that are actually occupied with O2
● Normally about 100%
● Deoxygenated hemoglobin is blue
● One of the causes of hypoxia
- Polycythemia can cause hypoxemia w/o resulting hypoxia!
Ischemia
● Insufficient blood supply to tissue or organ
● Restriction/constriction blood flow to tissue/organ
● Reversible
○ I.e. when you measure someone’s BP you cause temporary ischemia
Causes of ischemia
Thrombus:
● Fixed in one place & blocks artery; blood supply cut d/t size
● Get rid of thrombus & restore blood flow
● When we restore blood we damage some tissue with free radicals
Causes of ischemia
Embolism:
● Moving; breaks off & gets stuck somewhere; blood supply cut
○ I.e. Pulmonary embolism (P.E.)
● When restore blood supply you cause harm with ROS (Reactive Oxygen Species)
Infarction
● Ischemia with necrosis (irreversible)
● Most common: myocardial infarctions (heart attacks)
Reperfusion
● Restoration of blood supply that had been cut off
● Reperfusion injury (O2 returning to damaged tissue causes additional damage)
○ Produces lots of reactive O2 species (ROS)
Free radical
● Molecule with an unpaired electron written with little dot
Reactive O2 species (ROS)
● Highly reactive molecule that contains oxygen
● Some overlap between free radicals & ROSs
● Extremely reactive with anything it comes in contact with
● Endogenous antioxidant system to take care of this
Major (3) Antioxidants Include (slide 13):
Superoxide dismutase (SOD)
Catalase
Glutathione
Superoxide dismutase (SOD) (slide 13)
● Takes care of superoxide ion (O2-.) → converts to hydrogen peroxide (H2O2)
Catalase (slide 13)
● Convert H2O2 in our cells → to H2O
Glutathione (slide 13)
● Will happily take free radical
● Converts H2O2 → to OH. → then back to H2O & then we restore glutathione to rid of another H2O2
Hydrogen peroxide (H2O2)
● NOT a free radical; but a reactive oxygen species (ROS)
● Pour on cut, bleaches skin & kills everything that is there because its is extremely reactive
● Oxidizes everything it comes in contact with
● Normally just use 1% hydrogen peroxide
● Beneficial when we want to kill bacteria
● Don’t want H2O2 in our cell, use catalase to convert it to H2O
Hydroxyl radical (OH.)
● Produced in miscellaneous metabolism & need to get rid of
How Reperfusion Injury Occurs
● When restore blood supply O2 comes in & thus get ↑ in free radical species & ROS created, thus further damaging cells
● Problem when restoring blood supply during heart attack
● Get influx of Ca2+ which also causes more harm
Cell can die 1 of 2 ways…..
Necrosis or Apoptosis
Necrosis
● Irreversible damage
● Contents spill out d/t membrane damage
● Signals inflammatory response
Apoptosis
● Controlled cell death
● Eaten by phagocytes, contents of dying cell never exposed to the outside
○ Contents contained by apoptotic body
● Does not produce any kind of inflammatory response
Coagulative Necrosis
● Tissue left maintains normal architecture after death (most places in body except brain)
● Usual result of infarction
● Infarctions in brain don’t give coagulative necrosis
Liquefactive Necrosis
● Tissue is dissolved by digestive enzymes, loses normal appearance
● Ex. Brain infarction: brain will have holes & tissue replaced by fluid
● Seen in abscesses (e.g. picture of fungal abscess)
Caseous necrosis:
● Yellow-white & cheesy (queso)
● Happens specifically with tuberculosis
Fat necrosis
● Typically seen in pancreas
○ Produces pancreatic enzymes that digest things
■ I.e. lipases that break down fat
● If leak out (pancreatitis), digest fat in the area, Ca2+ reacts & get fatty Ca2+ deposits
○ Ex. Breasts; Ca2+ deposits in breasts d/t fatty necrosis
● Completely benign but show up on mammograms
● Hypocalcemia in patients with pancreatitis
Dry gangrene
● Occurs in dry tissue
○ I.e. feet of diabetic
● Often involves clostridium infections that are exposed to air
Wet gangrene
● Occurs in moist tissue
○ I.e. internal organs & bedsores
● Numerous bacteria involved, but C. perfringens most common
Gas gangrene
● Similar to wet gangrene with addition of gas production
● Really bad & out of control at this point
● Medical emergency
○ Can spread quickly resulting in sepsis & death
Cellular Aging: Telomeres
slide 18
● DNA cap at ends of chromosomes
● Doesn’t code for anything
● Every time cell replicates we don’t copy the end completely, we lose a little bit of telomere at the end
Cellular Aging: Telomeres
(slide 18)
● Replicative senescence
○ When we have lost enough of telomeres the cell does not replicate anymore
Cellular Aging: Telomeres
(slide 18)
● Replication
● Cells can replicate 60-70 times
● Lead to theory of aging
● Why do we have this mechanism?
○ Puts a stop to cancerous cells who can’t replicate further than this
○ Effective in protecting against cancer unless activate telomerase (ACTIVATES lengthening of caps)
○ Also need to turn on telomerase for germ cells
