Rr 01 Cell Injury Part 1

Front 1

Describe hypoxia

Back 1

-Refers to inadequate oxygenation of tissue
-Inadequate oxygen decreases synthesis of ATP
-Several types of hypoxia produce O2-related changes reported with arteriole blood gas measurements

Front 2

Describe how lack of oxygen decreases ATP synthesis

Back 2

1. ATP synthesis occurs in the inner mitochondrial membrane by the process of oxidative phosphorylation
2. O2 is an electron acceptor located at the end of the elctron transport chain in the oxidative pathway
3. A lack of O2 or a defect in oxidative phosphorylation culminates in a decrease in ATP synthesis

Front 3

Describe the clinical findings of hypoxia

Back 3

-Cyanosis
-Confusion
-Cognitive impairment
-Lathargy

Front 4

Define ischemia

Back 4

Decreases arterial blood flow or venous outflow of blood

Front 5

Describe the consequences of ischemia

Back 5

1. Atrophy (reduction in cell/tissue mass)
2. Infarction of tissue (localized area of tissue necrosis)
3. Organ dysfunction (eg, heart failure)

Front 6

Define hypoxia

Back 6

Decrease in PaO2 (<40mmhg)

Front 7

Describe Respiratory acidosis

Back 7

-Hypoventilation
-CO2 retention in the lungs always produces a corresponding decrease in PaO2
-Depression of medullary respiratory center (eg barbiturates), paralysis of the diaphragm, chronic bronchitis

Front 8

Define PaO2

Back 8

Pressure keeping O2 dissolved in the plasma of arterial blood (0.003*PaO2)

Front 9

Describe the contributing factors and significance of PaO2

Back 9

Contributing Factors:
-Percentage of O2 inspired air, atmospheric pressure, normal O2 exchange in the lungs
-Driving force for movement of O2 from capillaries into tissue by diffusion

Significance:
Reduced in hypoxemia

Front 10

Define SaO2

Back 10

Average percentage of O2 bound to Hb

Front 11

Describe the contributing factors and significance of SaO2

Back 11

Contributing Factors:
-PaO2 and valence of heme iron in each of the four heme groups
-Fe2+ binds O2, Fe3+ does not

Significance:
SaO2<80% produces cyanosis of skin and mucous membranes

Front 12

Define O2 content

Back 12

total amount of O2 carried in blood

Front 13

Describe the contributing factors and significance of O2 content

Back 13

Contributing Factors:
-Hb concentration in RBCs (most important), PaO2, SaO2
-Hb concentration determines total amount of O2 delivered to tissue

Significance:
Hb is the most important carrier or O2

Front 14

Describe ventilation defects

Back 14

1. Impaired O2 delivery to alveoli
-Example: respiratory distress syndrome with collapse of the distal airways due to lack of surfactant
2. No O2 exchange in lungs that are perfused by not ventilated
3. Diffuse disease (RBS) produces intrapulmonary shunting of blood
-Pulmonary capillary blood has the same PO2 and PCO2 as venous blood returning from tissue
4. Inspired %O2 from 0.24% to 0.28% or greater does not significantly increase PaO2
-This only applies to a diffuse ventilation defect involving both lungs; smaller defects are compensated for in normally ventilated lungs

Front 15

Describe perfusion defects

Back 15

1. Absence of blood flow to alveoli
2. No O2 exchange in lungs that are ventilated by not perfused
3. Produces an increase in dead space
-Exchange of O2 and CO2 does not occur
4. Inspired %O2 from 0.25% to 0.28% or greater increases the PaO2
-Other parts of ventilated and perfused lungs have normal gas exchange

Front 16

Describe the causes of hypoxemia

Back 16

1. Decreased inspired O2
2. Respiratory acidosis
3. Ventilation defect
4. Perfusion defect
5. Diffusion defect

Front 17

Describe diffusion defects

Back 17

1. Decreased O2 diffusion through the alveolar capillary interface
2. Examples: Interstitial fibrosis, pulmonary edema

Front 18

Describe the A-a gradient

Back 18

Ventilation, perfusion, adn diffusion defects increase the differnece in O2 concentration between alveolar PO2 (PAO2) and arterial O2 (PaO2)
-This difference is called the alveolar-arterial (A-a) gradient

Front 19

Describe the causes of tissue hypoxia

Back 19

1. Ischemia
2. Hypoxemia
3. Hemaglobin-related abnormalities

Front 20

Describe anemia

Back 20

-Decreased Hb concentration (<7g/dL)
-Normal PaO2 and SaO2

Front 21

Describe the causes of anemia

Back 21

1. Decreased production of Hb (eg, iron deficiency)
2. Increased destruction of RBCs (eg hereditary spherocytosis)
3. Decreased production of RBCs (eg aplastic anemia)
4. Increased sequestration of RBCs (eg splenomegaly)

Front 22

Describe methemoglobinemia

Back 22

Hb with oxidized heme groups (Fe3+)

Front 23

Describe methemoglobin

Back 23

-Converted to a ferrous stage (Fe2+) by the reduced nicotinamide adenine dinucleotide (NADH) reductase system located off the glycolytic pathway in RBCs
-Electrons from NADH are transferred to cytochrome b5 and then to metHB by cytochrome b5 reductase to produce ferrous Hb
-Newborns are particularly at risk fro developing methemoglobinemia after oxidant stresses owing to decreased levels of cytochrome b5 reductase until at least 4 months of age

Front 24

Describe the causes of methemoglobinemia

Back 24

1. Oxidant stresses
-Examples: Nitrite- and sulfur-containing drugs, sepsis, local anesthetics (eg benzocaine)
2. Congenital deficiency of cytochrome b5 reductase

Front 25

Describe the pathogenesis of methemoglobinemia

Back 25

1. Fe3+ cannot bind O2
-Normal PaO2, decreased SaO2
2. Ferric heme groups impair unloading of O2 by oxygenated ferrous heme
-This causes a left-shifted O2 binding curve

Front 26

Describe the clinical signs of methemoglobinemia

Back 26

-Patients have chocolate-colored blood from increased concentration of deoxyhemeglobin
-Cyanosis occurs at metHb levels >1.5g/dL
-Skin color does not return to normal after administration of O2

Front 27

Describe the treatment of methemoglobinemia

Back 27

IV methylene blue which acts as an artificial electron carrier in the reduced NADPH metHB reductase system located in the pentose phosphate shunt

Front 28

Describe CO poisoning

Back 28

1. Leading cause of death due to poisoning
2. Produced by incomplete combustion of carbon-containing compounds
3. Causes include automobile exhaust, smoke inhalation, wood stoves, methylene chloride (paint thinner)

Front 29

Describe the pathogenesis of hypoxia from CO poisoning

Back 29

1. CO competes with O2 for bindings sites on Hb
-Decreases SaO2 without affecting PaO2
2. CO inhibits cytochrome oxidase in the electron transport chain
3. CO causes left-shifted O2-binding curve

Front 30

Describe the clinical features of CO poisoning

Back 30

1. Cherry--red discoloration of skin and blood
2. Headache (first symptom at levels of 10-20%)
3. Dyspnea, dizziness (levels f 20-30%)
4. Seizures, coma (levels of 50-60%)
5. Lactic acidosis due to hypoxia

Front 31

Describe the treatment for CO poisoning

Back 31

O2 via nonbreather mask or endotrachial tube (100% O2)

Front 32

Describe the factors causing a left-shifted oxygen binding curve

Back 32

1. Decreased 2,3-bisphosphoglycerate (BPG)
-Intermediate of glycolysis via converstion of 1,3-BPG to 2,3-BPG
2. CO, alkalosis, metHb, fetal Hb, hypothermia
3. These factors increase affinity of Hb for O2 with less release of O2 to tissue

Front 33

Describe the factors causing a right-shifted oxygen binding curve

Back 33

-Acidosis
-Increased BPG, Temp, Altitude

Front 34

Describe how high altitudes leads to a right-shifted oxygen binding curve

Back 34

-Atmospheric pressure is decreased, but O2% is still 25
-Hypoxemia stimulates peripheral chemoreceptors causing respiratory alkalosis, which shifts the OBC to the left
-Alkalosis activates phosphofrutokinase causing increased production of 1,3-BPG which is converted to 2,3-BPG
-This eventually shifts the OBC to the right, leading to increased release of O2 to tissue

Front 35

Describe the oxidative part of the oxidative phosphorylation pathway

Back 35

-Occurs in the inner mitochondrial membrane-Donated electons are transfered from NADH and FADH2 derived from the energy cycles down the electron transport chain to O2
-Oxygen is a strong e acceptor located at the end of the chain on complex IV
-Transfer of electors in coupled with the transport of protons supplied by NADH and FAHD2 across the inner mitochondrial membrane into the intermembranous space, which established both a proton and pH gradient

Front 36

Describe the phosphorylation part of the oxidative phosphorylation pathway

Back 36

-The synthesis of ATP
-ATP synthesis occurs when the protons on the cytosolic side of the inner membrane enter small channels (proton pores) within the ATP synthase molecule (complex V) and reenter the mitochondrial matrix, where ATP is synthesized
-The inner mitochondrial membrane is normally impermeable to protons except through the channel in the ATP synthase molecule
-This relationship is critical to the maintenance of the proton gradient
-If enzymatic reactions in the e transport are inhibited, the formation of protons and the proton gradient are disrupted as well, leading to a decrease in ATP synthesis

Front 37

Describe enzyme inhibition of oxidative phosphorylation

Back 37

1. Synthesis of ATP is decreased
2. CO and cyanide inhibit cytochrome oxidase in the ETC

Front 38

Describe cyanide poisoning

Back 38

1. May result from drugs (eg nitroprusside) and combustion of polyurethane products in house fires
2. Produces an initial CNS and CV stimulation followed by CNS depression and death
3. Produces lactic acidosis due to hypoxia
4. Produces increased venous PO2 and saturation
-Tissue cannot extract O2

Front 39

Describe the treatment for cyanide poisoning

Back 39

-Involves 2 stages:
-Amyl nitrite (produces metHb which combines with CN to form cyanmetHb)
-Followed by thiosulfate (CN converted to thiocyanate)

Front 40

Describe uncoupling from oxidative phosphorylation as a cause for ATP depletion

Back 40

1. Uncoupling proteins carry protons in the intermembranous space through the inner mitochondrial membrane into the mitochondrial matrix without damaging the membrane
a. Bypass of ATP synthase causes decreased synthesis of ATP
b. Examples: thermogenin (natural uncoupler in broth fat in newborns), dinitrophenol used in synthesizing nitroglycerine

2. Heat normally used to synthesize ATP raises the core body temperature
a. There is a danger of developing hyperthemia with dinitrophenol
b. Thermogenin is useful in stabilizing body temperature in newborns.

Front 41

Describe mitochondrial toxins

Back 41

-Alcohol and salicylates
-They damage the inner mitochondrial membrane, causing protons to move into the mitochondrial matrix
-As with dinitrophenol, hyperthermia is a common complication in alcohol and salicylate poisoning

Front 42

What tissues are susceptible to hypoxia?

Back 42

1. Watershed areas between terminal branches of major arterial blood supplies
2. Subendocardial tissue
3. Renal cortex and medulla
4. Neurons in the CNS
5. Hepatocytes located around the central vein

Front 43

Describe watershed areas between terminal branches of major arterial blood supplies

Back 43

1. Susceptible to hypoxia
2. The blood supply from the two vessels does not overlap
3. Examples:
i. Areas between the distribution of the anterior and middle cerebral arteries
ii. Area between the distribution of the superior and inferior mesenteric arteries (ie, splenic fixture)

Front 44

Describe subendocardial tissue

Back 44

1. Susceptible to hypoxia
2. Coronary vessel penetrate the epicardial surface
3. Subendocardial tissue receives the least amount of O2

Front 45

Describe factors decreasing coronary artery blood flow

Back 45

-Produce subendocardial ischemia
-Manifests as chest pain (angina), ST segment depression in the ECG
-Increased thickness of the LV in the presence of increased myocardial demand for O2 can also produce subendocardial ischemia

Front 46

Describe hypoxia of the renal cortex and medulla

Back 46

1. Susceptible to hypoxia
2. In the cortex, the straight portion of the proximal tubule is most susceptible to hypoxia
-Primary site for reclaiming bicarbonate and reabsorbing Na
3. In the medulla the NaK2Cl cotransport channel int eh thick ascending limb is most susceptible to hypoxia
-Primary site for regenerating free water, which is necessary for normal dilution and concentration of urine

Front 47

Describe hypoxia in neurons of the CNS

Back 47

1. Susceptible to hypoxia
2. Examples: Purkinje cells in the cerebellum, neurons in layers 3, 5, and 6 of the cerebral cortex
3. Irreversible damage occurs ~5min after global hypoxia

Front 48

Describe the portal triads

Back 48

-Hepatic artery tributaries carrying oxygenated blood and portal vein tributaries carrying unoxygenated blood empty their blood into the liver sinusoids
-These drain blood into the central veins
The central veins become the hepatic vein which empties into the inferior vena cava

Front 49

Describe hepatocyes around the portal triads

Back 49

1. Zone 1: Hepatocytes closest to the portal triads receive the most oxygen and nutrients
2. Zone 2: In the middle
3. Zone 3: Those farthest from the portal triads, around the central vein, receive the least amount of oxygen and nutrients
4. Production of free radicals, tissue hypoxia (shock, CO poisoning), and alcohol related fatty change of the liver initially damage zone III hepatocytes

Front 50

Describe the consequences of hypoxic cell injury

Back 50

1. Decreased synthesis of ATP
2. Anaerobic glycolysis is used for ATP syntheses and is accompanied by several changes
3. Decreased protein synthesis
4. Irreversible cell changes
5. Reentry of Ca2+ into mitochondria

Front 51

Describe the changes that accompany the switch to anaerobic glycolysis for ATP synthesis

Back 51

1. Activation of phosphofructokinase
-Causes by low citrate levels and increased AMP
2. Net gain of 2 ATP
3. Decreased in intracellupar pH caused by an excess of lactate
a. Also accumulates in blood producing lactic acidosis
b. Denatures structural and enzymatic proteins
4. Impaired Na/K ATPase pump
a. Diffusion of Na and H2O into cell causes cellular swelling
b. Potentially reversible with restoration of O2

Front 52

Describe the decreased protein synthesis as a result of hypoxic cell injury

Back 52

From the detachment of ribosomes (potentially reversible)

Front 53

Describe the irreversible cell changes that are a consequence of hypoxic cell injury

Back 53

1. Impaired Ca ATPase pump
-Normal function of the pump is to keep Ca out of the cytosol
2. Increased cytosolic Ca has two lethal effects
a. Enzyme activation
i. Phospholipase increases cell and organelle membrane permeability
ii. Proteases damage the cytoskeleton
iii. Endonucleases cause fading of nucelar chromatic (karyolysis)
b. Reentry of Ca into mitochondria
i. Increases mitochondrial membrane permeability
ii. release of cytochrome c into cytosol activates apoptosis

Front 54

Describe cell death

Back 54

Cell death occurs when cells or tissues are unable to adapt to injury