Types of injury (8)
hypoxia microbial physical chemical oxygen/free readicals genetic immune nutritional
hypoxia
not enough oxygen
anoxia
no oxygen
number one killer
hypoxia_..storkes, infarctions
decrease input_..global hypoxia (as opposed to foca/local hypoxia)
restriction of all oxygen-whole body deprevation
examples of global hypoxia (9)
lack of air, inability to take in air, inability to transport O2 from the lungs to the blood, anemia, CO, cyanide, pump failure, dec blood volume, inc vascular space
lack of air
drowning,
gasses that displace o2 (like evaporating liquid nitrogen)
inability to take in air
external suffocation (cut of O2 only_takes longer), strangulation (cuts off O2 and carotids), plugged pipes (blocked trachea)
anemia
low hemoglobin/rbc
CO
irreversibly binds heme and shifts o2 binding curve_.person will be cherry red, the venous blood will be red like arterial blood
cyanide
uncouples oxidative phosphorylation - blocks cytochrome c oxidase
pump failure
can’t move blood around - heart is not pumping enough blood - cardiogenic shock
increased vascular space
but the same volume remains so this results in spetic shock - decrease pressure
decreased blood volume
bleeding out
most common cause of local hypoxia
ischemia (dec blood flow) ex. Coronary artery gets ischemic causing heart not to get enough blood
ischemia is worse than hypoxia bc
not only less o2 delivery but also don’t get metabolites needed for glycolysis and waste is not carried away like lactic acid
hypoxia is low o2 so there is a switch to_.
glycolysis
lactate pH and ATP, ADP in ischemia
lactate inc,
pH dc,
ATP dec,
ADP inc
Causes of ischemia
arterial occlusion, venous occlusion,
arterial occlusion (4)
artherosclerosis,
thrombosis,
embolization,
external pressure
venous occlusion
thrombosis–usually anastomotic channels are able to overcom this but in the kidney there is only one renal vein so thrombosis can cause blood to stop coming out, flow goes to zero, infac
how do you tell if venous or arterial occlusion
arterial - pale when it dies,
venous - engorged with blood and hemorrhaged
Effects of hypoxia
dec mitocondrial oxidated phosphorylation, dec ATP, dec activity of ATP dependent fn, in clycolysis dec pH and dec glycogen, ribosome detachment so dec protein synthesis
Anaerobic glycolysis
glucose + 2 adp –> 2 lactate + 2 atp (only 2 atp)
Aerobic glycolysis
glucos + 6O2 (this is not used in glycolysis) + 36 adp —> 6 CO2 + 6 H2O + 36 ATP (glycolysis + oxidative phosphorylation)
aerobic organs
brain and heart
problem with aerobic atp production
free radicals due to the use of O2, but normally we have defenses for it
reperfusion injury
an area the is occluded has blood with O2 returned to it, but that O2 forms free radicals by endothelial cells and leukocytes from inflammation causing more damage
What is a free radical
an atom/molecule with an unpaired electron that makes it extremely reactive and reactions lead to creation of more free radicals (chain reaction)
importance of free radicals
react with and modify cellular constituents, initiate chain reactions when they react with adjacent atoms and molecules amplifying their effect
how are free radicals made
additions of electors to molecular oxygen (reduction in ETC), cytochrom p450 metabolism
important oxygen radicals
superoxide aniion, hydrogen peroxide, hydroxyl radical (o2-, h2o2, oh’)
which ROI reacts w/ pretty much anything
Oh’
what is bad about superoxide
its ability to dismutate and frorm hydrogen peroxided that can then, with iron, from the hydrocxyl radical; it also reduces iron to the ferrous state
fenton rxn
O2 + e- –> O2- ,O2 - + Fe 3+ –> Fe 2+ + O2, 2 O2- –> H2O2, Fe 2+ + H2O2 –> Fe 3+ + OH ‘
what does vit C do
makes situation worse turning Fe3+ to Fe2+. This ferrous iron lying around can react w/ h2o2 to from the deadly OH’ radical
radical and cell death
when cells die these radicals leak out causing damage
Lipid peroxidation happens with
free radicals and unsaturated fatty acids_.very bad bc of chain reactions eating up membranes
4-hydroxylnanol (4- HNE)
highly toxic and damage cell resulting from chronic lipid oxidation
AA with sulfur are
cysteine and methionine
SH groups can be oxidized resultinging
S–S bond causing conformational changes, loss of enzyme activity, and protein crosslinking
SH group modification changes enzyme activity by
inhibiting ca atpases in membrane, ER/SR causing cytosolic ca to rise leading to death, and also causes cytoskeletal crosslinking
oxidant defenses
superoxide dismutase (cytoplasm, mitochondria, and plasma, catalase (peroxisomes), glutathione perosxidases (cytoplasm, plasma), glutathione reductase
problem with catalase
in peroxisome for fatty acid oxidation so cant protect from cytosol free radicals
glutathione peroxidase
2 red glut + h2o2 –> ox glut-glut + h2o req. selenium, lipid peroxides also substrate
glutathione reductase
ox glut-glut + nadph –> 2 red glut + nadp
reduced glutathione
directly scavenges radicals
vit E (alpha tocopherol)
scavenges radicals in cell membranes
ascorbic acid (vit C)
antioxidant in plasma (also reduced fe3+ to fe 2+)
uric acid (purine metabolite)
antioxidant in plasma
ferritin, transferrin, lactoferrin, and ceruloplasmin
bind fe 2 + and cu2+
hemochromatosis
genetic condition with lots of free iron (should normally be bound)
Physical injury (5)
electricity, radiation (free radicals), trauma, temperature, 357 magnum
chemical injury
corrosives, toxins and poisons (free radicals), carcinogens, sensitizers
direct cehmical injury
cyanide - direct inhibition of cyt C
indirect cehmical injury
ccl4 (in p450 sys makes CCl3’ radical) acetaminophen( in p450 sys decreases GSH)
Carbon tetrachloride
when reactive in liver forms lipid peroxidation
slide 74
do you know it yet?????
Microbial injury (6)
bacteria, viruses, fungi, parasites, richettsia, prions
Genetic injury
chormosomal abnormalites, mutations deletions, interaction with environment
Immune injury
allergy, anaphylaxis, autoimmune antiboides, antigen-antibody complexes, cell-mediated autoimmunity, transplant rejection
morphology associated with reversible injury
cell swelling, mitochondrial swelling, small dense bodies in mitochondria, membrane blebbing and swelling, intracellular accumulations
cell swelling
hydropic degeneration and cloudy swelling
why do cells swell during ischemia
lack of blood supply–>dec oxygen –>na/k atp pumps cant work –> sodium keeps comingin and water follows sodium –>swelling
tissue osmolality ___..due to catabolism within ischemic cells
increases
Lipid accumulation in hepatocytes due to
impaired lipoprotein synthesis (ethanol protein malnutrition),
decreased fatty acid oxidation (hypoxia),
increased liberation of fat from peripheral stores (starvation)
radiation can also cause
cataracts, esophageal stricture, pulomnary fibrosis, congenital malformations, sterility, nephritis, transversemyelitis, myocaridal fibrosis, constrictive pericarditis
why is tylenol bad
acetaminophen–>benzoquinone–>depletes GSH–>protien thiol oxidation–>crosslinking membrane proteins–>cell death