Chapter 1. Cell Injury - Tissue Hypoxia Flashcards
what are clinical findings of hypoxia?
cyanosis, confusion, cognitive impairment, lethargy
what are causes of tissue hypoxia?
- ischemia
- hypoxemia
- Hb-related abnormalities
describe ischemia
- what are examples?
- what are consequences?
decreased arterial blood flow or venous outflow of blood
- ex: coronary artery atherosclerosis, decreased CO, thrombosis of splenic vein
- causes atrophy, infarction, and organ dysfunction
why does a pulse oximeter sometives calculate falsely high SaO2?
it cannot identify dyshemoglobins like metHb and carboxyHb when they are present, thus causing a falsely high SaO2
what is the definition of hypoxemia?
decrease in PaO2 (<40 mmHg)
what is the definition of PaO2, contributing factors, and its significance?
pressure keeping O2 dissolved in plasma of arterial blood
- % of O2 in inspired air, atomospheric pressure, normal O2 exchange in lungs, driving force for movement of O2 from capillaries into tissue by diffusion
- reduced in hypoxemia
what is the definition of SaO2, contributing factors, and its significance?
average percentage of O2 bound to Hb
- PaO2 and valence of heme ion in each of 4 heme groups (Fe2+ binds to O2, Fe3+ doesn’t)
- SaO2 < 80% produces cyanosis of skin and mucus membranes
what is the definition of O2 content, contributing factors, and its significance?
total amount of O2 carried in blood
- Hb concentration in RBCs (most important; determines total amount of O2 delivered to tissue), PaO2, SaO2
- Hb is most important carrier of O2
what are causes of hypoxemia?
- decreased inspired PO2
- respiratory acidosis (hypoventilation)
- ventilation defect
- perfusion defect
- diffusion defect
if there is an increase in alveolar PCO2, there is a corresponding DECREASE in…
alveolar PO2 (PaO2), and SaO2
explain ventilation defects
-what’s an example?
impaired O2 delivery to alveoli, as in RDS
-no O2 exchange in lungs that are perfused but NOT ventilated (intrapulmonary shunt)
explain respiratory distress syndrome
ventilation defect with collapse of distal airways due to lack of surfactant
-pulmonary capillary blood has same PO2 and PCO2 as venous blood returning from tissue (much of pulmonary blood flow not arterialized) –> intrapulmonary shunting of blood
explain perfusion defects
absence of blood flow to aveoli (pulmonary embolus)
-no O2 exchange in lungs that are ventilated, but NOT perfused (increased dead space)
explain diffusion defects and examples
decreased O2 diffusion through alveolar-capillary interface
-interstitial fibrosis, pulmonary edema
what do ventilation, perfusion, and diffusion defects all affect?
increase difference in O2 concentration between alveolar PO2 (PAO2) and arterial PO2 (PaO2), AKA the alveolar-arterial gradient
what are 3 hemoglobin-related abnormalities?
- anemia
- methemoglobinemia
- CO poisoning
what is the definition of anemia and the causes?
decreased Hb concentration (<7 g/dL) but normal PaO2 and SaO2
- decreased Hb production (Fe deficiency)
- decreased production of RBC (aplastic anemia)
- increased destruction of RBCs (hereditary spherocytosis)
- increased sequestration of RBCs (splenomegaly)
what is methemoglobinemia, causes, pathogenesis, and treatment?
heme Fe3+, decreased SaO2 (but normal PaO2)
- caused by oxidant stress and congenital deficiency of cytochrome b5 reductase
- Fe3+ can’t bind O2
- ferric heme groups impair unloading of O2 by oxygenated ferrous heme causing left-shifted o2 binding curve
- causes chocolate-colored blood (increased [deoxyHb]) and cyanosis
- -skin color doesn’t return to normal after administration of O2
- treat with IV methylene blue (artificial e- carrier in pentose phosphate shunt)
what is methemoglobin (metHb)? how is it reduced?
Hb with oxidized heme groups (Fe3+)
-converted to ferous state by reduced NADH reductase system in glycolytic pathway
CO poisoning
- pathogenesis
- clinical findings
- treatment
leading cause of death due to poisoning
- CO competes with O2 for binding sites on Hb, which then inhibits cytochrome oxidase in ETC, causing left-shifted O2 binding curve
- decreases CaO2 WITHOUT affecting PaO2
- cherry red skin/blood, headache, dyspnea/dizziness, seizures/coma, lactic acidosis due to hypoxia
- treat w/ O2 via nonbreather mask or endotracheal tube (100% O2)
what factors cause left-shifted O2-binding curve?
- decreased 2,3-bisphosphoglycerate (BPG)
- CO, alkalosis, metHb, fetalHb, hypothermia
all increase affinity of Hb for O2 with less release of o2 to tissue
what happens at high altitudes?
atmospheric pressure is decreased, but percentage of O2 in atmosphere is the same
- hypoxemia stimulates peripheral chemoreceptors causing respiratory alkalosis, which shifts the O2 binding curve to the left
- alkalosis activates phosphofructokinase, increasing 1,3-BPG, which is converted to 2,3-BPG, shifting OBC to right, causing increased release of O2 to tissue
what are mitochondrial causes of ATP depletion?
enzyme inhibition of oxidative phosphorylation or uncoupling of oxidative phsophorylation
what are the causes of enzyme inhibition of oxidative phosphorylation? go into more detail about one of the culprits
- ATP synthesis decreases
- CO and cyanide inhibit cytochrome oxidase in ETC
- CN poisoning from drugs, combustion of polyurethane products, producing initial CNS and CV stimulation followed by CNS depression and death, producing lactic acidosis from hypoxia and increased venous PO2 and saturation
- -requires treatment with amyl nitrite (makes metHb that combines with CN to make cyanmetHb) then thiosulfate (CN converted to thiocynanate)
what does uncoupling of oxidative phosphorylation do?
uncoupling proteins carry H+ in intermembranous space through IMM into matrix without damaging membrane
- bypass of ATP syntahse causes decreased ATP synthesis
- ex: thermogenin and dinitrophenol
- heat normally used to make ATP raises core body temp
what are thermogenin and dinitrophenol used for?
both are uncouplers of oxidative phosphorylation
- thermogenin: natural uncoupler in brown fat, useful in stabilizing body temps
- dinitrophenol: used in making nitroglycerin, but danger of developing hyperthermia
what are examples of mitochondrial toxins? what is their mechanism?
alcohol and salicylates
- damage IMM causing H+ to move into matrix
- hyperthermia is common complication
what tissues are susceptible to hypoxia?
- watershed areas between terminal branches of major arterial blood supplies
- subendocardial tissue
- renal cortex (esp. straight portion of PT) and medulla (esp. Na-K-Cl cotransport channel in TAL)
- neurons in CNS (most adversely affected)
- hepatocytes in central vein (esp. zone III)
what does decreasing coronary artery blood flow cause?
- subendocardial ischemia (angina and ST-segment depression)
- left ventricle hypertrophy in presence of increased myocardial demand for O2 can also cause subendocardial ischemia
what are consequences of hypoxic cell injury?
- decreased ATP synthesis
- anaerobic glycolysis used for ATP (net gain of 2 ATP, lactic acidosis, impaired Na/K-ATPase pump)
- decreased PRO synthesis due to detachment of ribosomes (potentially reversible)
- irreversible cell changes (mostly caused by impaired Ca-ATPase pump causing increased cytosolic Ca++)
why does increased cytosolic Ca++ have lethal effects?
- enzyme activation
- phospholipase increases membrane permeability
- proteases damage cytoskeleton
- endonucleases cause fading of nuclear chromatin (karyolysis) - reentry of Ca++ into mitochondria
- increases mitochondrial membrane permeability
- release of cyt c into cytosol activates apoptosis
