Chapter 1.2 Cellular Injury

Question 1

When does cellular injury occur? What determines whether the cell will adapt or be injured? Give a clinical example.

Answer 1

injury occurs when stress exceeds cell’s ability to adapt

stress could be so severe that it exceeds the cell’s ability to adapt …rather than growth adaption, cell becomes injured

Adapt or injured?
-depends on type of stress, severity, and type of cell affected (neurons are v susceptible to hypoxia, can only withstand 3-5 minutes, skeletal muscle can withstand hypoxia for long periods)

(if slowly cut blood supply to kidney, kidney will atrophy due to decreased nutrients; ex: athrosclerosis of renal artery or fibromuscular dysplasia of renal artery…so kidney shrinks in size)

(if thrombus in left heart and that thrombus lodges and embolized and lodged in renal artery, could block supply to such extent would result in infarction or death of kidney parenchyma)

Question 2

What are some common causes of injury?

Answer 2

inflammation
nutritional deficiency or excess
hypoxia
trauma
genetic mutations (when proteins not formed or not formed properly)

Question 3

Describe hypoxia and explain the mechanism by which it can lead to damage.

Answer 3

Hypoxia= low oxygen delivery to tissue

Oxygen is final electron acceptor in the ETC, that accepting of electrons by oxygen allows for generation of ATP and so low oxygen impairs oxidative phosphorylation, low ATP, injury

(low oxygen, low ATP, low ATP- cellular injury)

Question 4

What are the 3 major causes of hypoxia?

Answer 4

ischemia
hypoxemia
decreased O2 carrying capacity of the blood

Question 5

Define ischemia.Describe the mechanisms by which ischemia can occur. Provide a clinical example for each cause.

Answer 5

decreased blood flow through an organ:

1. artery feeding organ
2. vein draining the organ
3. shock (decreased generalized perfusion of vital organs)

ischemia =decreased blood flow through an organ

can occur if there is a block in arterial flow into the organ (if block like athrosclerosis, decreased blood flow through organ..ischemia)
athrosclerosis of coronary artery results in angina or chest pain

-decrease flow through the vein, if vein blocked, then flow of fresh blood across bed is blocked, and decrease amount of oxygen in organ, results in ischemia, ex: Budd-Chiari Syndrome =thrombosis of hepatic vein, blood can’t flow through liver, and infarction in liver parenchyma

Question 6

Describe the mechanism of Budd-Chiari Syndrome. What type of cellular injury occurs? Describe two causes; which is most common?

Answer 6

Budd-Chiari Syndrome =thrombosis of hepatic vein, blood can’t flow through liver, and infarction in liver parenchyma (ex of ischemia being cause of hypoxia)

most common cause: polycythemiavera (disorder in which patients have high RBC count due to over production of RBC, increased viscosity and thickness of blood, leads to clotting, thrombosis occurs in hepatic vein.

patient with Lupus who has Lupus anti-coagulant which creates hypercoagulable state in that patient.

Question 7

Define hypoxemia. Describe the pathway of oxygen from atmosphere to RBC.

Answer 7

Low partial pressure of O2 in the blood (PaO2 is less than 60 mmHg, SaO2 less than 90%)

certain concentration of oxygen present in atmosphere (FiO2) goal of lungs is to bring FiO2 and bring it into alveolar air sacs– PAO2 -will squeeze oxygen across interstitium and into capillaries creating PaO2 (partial pressure of oxygen in arterioles) PaO2 goal is to squeeze oxygen across RBC membrane to load O2 onto Hb to create SaO2

(anytime PaO2 goes down, SaO2 will also go down)

Question 8

If patient is at high altitude how do FiO2, PAO2, PaO2 and SaO2 change?

Answer 8

FiO2 is decreased which will decrease PAO2, PaO2, and SaO2 resulting in hypoxemia

Question 9

If PACO2 increases how is PAO2 affected?

What are clinical examples of CO2 building up in lung?

Answer 9

it must go down bc certain pressure can exist and it is a balance between O2, CO2 and nitrogen (nitrogen is a constant)

anytime CO2 building up in lung, PACO2 must go down

(CO2 builds up in hypoventilation, COPD = air gets trapped in lungs and so that will decrease PAO2…PaO2 will then go down, hypoxemia)

if thicken alveolar air sac so interstitial fibrosis of lung, oxygen diffusion barrier increases or thickens so oxygen not squeezed well into blood from PAO2 to PaO2

Question 10

What could lead to decreased oxygen carrying capacity within blood?

Answer 10

dissolved oxygen in blood enters RBC and binds Hb …Hb has role of carrying O2 to tissues and unloading it at level of tissues

(if knock out RBC or RBC ability to carry oxygen, will result in hypoxia in tissue)

ex: anemia (decrease in RBC mass)

CO poisoning (CO binds Hb more avidly than O2, PaO2 normal, SaO2 decreased

Question 11

When there is a decrease in RBC mass, anemia, how are PaO2 and SaO2 affected?

Answer 11

decrease amount of oxygen carried in blood, less oxygen to tissues - hypoxia

PaO2 normal, SaO2 normal (SaO2 just looks at what percentage of Hb is bound by O2)

FiO2–PAO2–PaO2–SaO2

Question 12

How are FiO2, PAO2, PaO2 and SaO2 affected in CO poisoning?

What are common exposures that lead to CO poisoning?

Answer 12

SaO2 decreased bc CO binds Hb more avidly than O2

(FiO2, PAO2, PaO2 are normal)

exposures include smoke from fires and exhaust from cars or gas heaters

Question 13

What is classic finding of patient with CO poisoning? Describe mechanism why.

What are early signs of exposure? (Significant exposure?)

Answer 13

cherry red appearance of skin (Hb so tightly bound, reflects red light and creates red appearance of skin..deceptive bc patient is hypoxic bc not carrying oxygen to tissues)

early sign of exposure is headache; significant exposure can lead to coma and death

Question 14

How does methemoglobinemia lead to hypoxia?

How are FiO2, PAO2, PaO2 and SaO2 affected?

Answer 14

decreased oxygen carrying capacity of blood

heme in Hb contains iron, that iron normally in Fe2+ state. that Fe2+ binds O2

if Fe2+ becomes oxidized and goes into 3+ state, cannot bind O2

PaO2 normal, SaO2 decreased

seen with oxidant stress (sulfa and nitrate drugs) or in newborns

Question 15

In what clinical context would we see methemoglobinemia?

Answer 15

seen with oxidant stress (can oxidize the iron) (sulfa and nitrate drugs) or in newborns

always oxidizing iron within Hb, blood carries O2, oxidant stress always present in blood, we have enzymes to create mediators necessary to reduce iron back to 2+ state, newborns machinery to do this is immature so they are more susceptible to development of methemoglobinemia

Question 16

What is the classical clinical finding of patients with methemoglobinemia?

How is it treated?

Answer 16

classic finding is cyanosis with chocolate-colored blood

Treatment is IV methylene blue (generates necessary mediators to reduce iron back to 2+ state)
-helps reduce Fe3+ to Fe2+ state

Question 17

Ischemia, hypoxemia, decreased O2 carrying capacity cause hypoxia. What is consequence?

Answer 17

impairs oxidative phosphorylation

decreases ATP

Question 18

Hypoxia leads to impaired oxidative phosphorylation and decreased ATP. What are the implications of low ATP on a cellular level?

Answer 18

Low ATP disrupts key cellular functions

Na/K pump
Ca pump
aerobic glycolysis

Question 19

What will happen if Na/K pump fails due to a lack of ATP?

Answer 19

goal of Na/K pump is to pump Na outside of the cell

if pump fails due to lack of ATP then Na builds up in cell, water will follow and when water follows the cell will swell, swelling of cell is sign of damage to cell

Question 20

What will happen if Ca pump fails due to a lack of ATP?

Answer 20

goal of cell is to maintain super low concentration of Ca in cytosol (Ca can get pushed into blood, hidden in SR or in mitochondria) if low ATP the Ca pump can fail and result in high cytosolic Ca which is dangerous bc could activate enzymes that you wouldnt want to activate in the cell.

Question 21

Describe the implications low cellular ATP in regards to glycolysis.

Answer 21

switch from aerobic glycolysis to anaerobic glycolysis which then results in poor production of ATP and byproduct of lactic acid (lower pH in cell and cause precipitation of both DNA and proteins)

Question 22

Initial phase of injury is reversible. What are the hallmark signs of this stage?

Answer 22

hallmark is cellular swelling

leads to loss of microvilli, membrane blebbing, swelling of RER

(if Na/K pump fails, Na builds up in cell, water follows, swelling of actual cell…swelling can cause loss of microvilli present in PT of kidney or small bowel)

cell contains cytoskeleton to maintain size and shape of cell and integrity of membrane, if excess water coming in little blebs can form

cellular swelling - RER swells, ribosomes are attached loosely and so RER swells and ribosomes pop off, protein can then no longer be synthesized properly, so another sign of reversible injury is decreased protein synthesis

Question 23

What are the implications for RER swelling and is this reversible damage?

Answer 23

cellular swelling - RER swells, ribosomes are attached loosely and so RER swells and ribosomes pop off, protein can then no longer be synthesized properly, so another sign of reversible injury is decreased protein synthesis

Question 24

What is the hallmark of irreversible damage?

Answer 24

membrane damage

3 membranes of cell that get damaged
1. plasma membrane (borders entire cell) when irreversible damage, plasma membrane will be damaged and lost, then whatever is present inside cell will leak out of cell and into blood -sign of membrane damage … Ca now that was present outside the cell can rush in, intracellular Ca levels will increase further

2. mitochondrial membrane (inner mitochondrial membrane is ETC, within mitochondria is cytochrome C which is carefully guarded, if cytochrome c leaks out into cytoplasm it can activate apoptosis (mechanism of cell death)
3. lysosome (recycling factory of the cell, contains lytic enzymes that can trash molecules into basic building blocks, if those enzymes leak out they will digest the cell itself, and Ca has already come into cell which is enzyme activator, so presence of lytic enzymes and Ca in cytosol is dangerous

Question 25

A patient comes into ER complaining of chest pain, you’re worried about MI, you test for blood, what are you looking for?

Answer 25

stick needle in vein, take blood, send to lab, test for cardiac enzymes like troponin

was there irreversible damage? MI means irreversibly killed off myocytes, have enzymes gone from in the cell to the blood? then there has been MI which is irreversible damage

Question 26

Where is the ETC?

Answer 26

the inner mitochondrial membrane

if membrane damage to inner mitochondrial membrane that is irreversible…

Question 27

What are the 3 membranes of cell that get damaged in irreversible cell injury?

Describe the mechanisms and consequences of damage to these membranes.

Answer 27

plasma membrane, mitochondria, lysosome

1. plasma membrane (borders entire cell) when irreversible damage, plasma membrane will be damaged and lost, then whatever is present inside cell will leak out of cell and into blood -sign of membrane damage … Ca now that was present outside the cell can rush in, intracellular Ca levels will increase further
2. mitochondrial membrane (inner mitochondrial membrane is ETC, within mitochondria is cytochrome C which is carefully guarded, if cytochrome c leaks out into cytoplasm it can activate apoptosis (mechanism of cell death)
3. lysosome (recycling factory of the cell, contains lytic enzymes that can trash molecules into basic building blocks, if those enzymes leak out they will digest the cell itself, and Ca has already come into cell which is enzyme activator, so presence of lytic enzymes and Ca in cytosol is dangerous

Question 28

What is the end result of irreversible injury?

Answer 28

cell death