Chapter 2: Cell Injury, Cell Death, and Adaptations Flashcards
What is the field of pathology is devoted to?
Understanding the causes of disease and the changes in cells, tissues, and organs that are associated with disease and give rise to the presenting signs and symptoms in patients
What does etiology refer to?
Etiology refers to the underlying causes and modifying factors that are responsible for the initiation and progression of disease.
What does pathogenesis refer to?
Pathogenesis refers to the mechanisms of development and progression of disease, which account for the cellular and molecular changes that give rise to the specific functional and structural abnormalities that characterize any particular disease.
The steps in the evolution of disease go as follows:
Etiology (cause of disease) -> pathogenesis (mechanisms of disease -> molecular, functional and morphologic abnormalities in cells and tissues -> clinical manifestations: signs and symptoms of disease.
What are possible causes of disease (don’t learn this by heart)?
Toxins, infections, immunologic abnormalities, genetic abnormalities (inherited and acquired), nutritional imbalances and trauma
The steps in the evolution of disease go as follows:
Etiology (cause of disease) -> pathogenesis (mechanisms of disease -> molecular, functional and morphologic abnormalities in cells and tissues -> clinical manifestations: signs and symptoms of disease.
Wat are the possible changes in the pathogenesis of a disease?
Biochemical and structural changes
Cells can encounter physiologic stress or potentially injurious conditions and can thus undergo a certain state/phase. What is this called?
Adaptation, this is a new steady state that preserves viability and function
What are the categories for possible causes of cell injury?
Hypoxia (oxygen deficiency) and ischemia (reduced blood), toxins, infectious agents, immunologic reactions, genetic abnormalities, nutritional imbalances, physical agens (e.g. trauma, temperature, radiation) and ageing
What is reversible injury?
Reversible injury is the stage of cell injury at which the deranged function and morphology of the injured cells can return to normal if the damaging stimulus is removed
What are cellular changes that morphologically correlates to reversible injury?
Cellular swelling and fatty change.
But also esosinophilic (become redder), plasma membrane alterations, mitochondrial changes, dilation of ER and nuclear alterations
What causes that an injury becomes irreversible?
If the stress is severe, persistent, or rapid in onset
What happens when an injury is irreversible
Cell death
Three phenomena are considered the ‘turning point’ for a cell, that eventually results in cell death. What are these cellular disfunctions/abnormalities?
(1) the inability to restore mitochondrial function (oxidative phosphorylation and adenosine triphosphate [ATP] generation) even after resolution of the original injury; (2) the loss of structure and functions of the plasma membrane and intracellular membranes; and (3) the loss of DNA and chromatin structural integrity
What is the difference between etiology and pathology?
Etiology refers to why a disease arises and pathogenesis describes how a disease develops
In some situations, potentially injurious insults induce specific alterations in cellular organelles, what is this organelle?
The smooth endoplasmic reticulum, because smooth ER is involved in the metabolism of certain chemicals.
What is ‘accidental cell death’?
When severe disturbances, such as loss of oxygen and nutrient supply and the actions of toxins, cause a rapid and uncontrollable form of death
What is the morphological manifestation of accidental cell death called?
Necrosis
Name some examples where necrosis occurs (don’t learn this by heart, it’s just for illustration)
Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma.
What is ‘regulated cell death’?
In contrast, when the injury is less severe, or cells need to be eliminated during normal processes, they activate a precise set of molecular pathways that culminate in death. It earns its name because this kind of cell death can be manipulated by therapeutic agents or genetic mutation
What is the morphologic appearance of most types of regulated cell death called?
Apoptosis
In some instances, regulated cell death shows features of both necrosis and apoptosis. How is this called?
Necroptosis, this is initiated by e.g. TNF-receptors and RIP-kinases
Fill in: Apoptosis/Necrosis is a process that eliminates cells with a variety of intrinsic abnormalities and promotes clearance of the fragments of the dead cells without eliciting an inflammatory reaction.
Apoptosis
Fill in: Unlike apoptosis/necrosis, which is always an indication of a pathologic process, apoptosis/necrosis also occurs in healthy tissues.
Necrosis, apoptosis (respectively)
What is a synonym for physiologic cell death?
Programmed cell death
It is important to point out that cellular function may be lost long before cell death occurs, and that the morphologic changes of cell injury (or death) lay far behind loss of function and viability. Name an example of this.
For example, myocardial cells become noncontractile after 1 to 2 minutes of ischemia, but may not die until 20 to 30 minutes of ischemia have elapsed.
What is a form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell?
Necrosis
Is inflammation a characteristic of necrosis or apoptosis?
Necrosis, (it is induced by substances released from dead cells and which serves to eliminate the debris and start the subsequent repair process)
The biochemical mechanisms of necrosis vary with different injurious stimuli. What are these different mechanisms? (don’t learn by heart, for illustration)
Failure of energy generation in the form of ATP because of reduced oxygen supply or mitochondrial damage; damage to cellular membranes, including the plasma membrane and lysosomal membranes, which results in leakage of cellular contents including enzymes; irreversible damage to cellular lipids, proteins, and nucleic acids, which may be caused by reactive oxygen species (ROS); and others.
Most of the types of necrosis described here have distinctive gross appearances. What are the six different types of necrosis?
- Coagulative necrosis
- Liquefactive necrosis
- Gangrenous necrosis
- Caseous necrosis
- Fat necrosis
- Fibrinoid necrosis
What is coagulative necrosis?
Coagulative necrosis is a type of accidental cell death typically caused by ischemia or infarction. In coagulative necrosis, the architectures of dead tissue are preserved for at least a couple of days.
What is Liquefactive necrosis?
Liquefactive necrosis is a type of necrosis which results in a transformation of the tissue into a liquid viscous mass. Often it is associated with focal bacterial or fungal infections, and can also manifest as one of the symptoms of an internal chemical burn. In liquefactive necrosis, the affected cell is completely digested by hydrolytic enzymes, resulting in a soft, circumscribed lesion consisting of pus and the fluid remains of necrotic tissue. Dead leukocytes will remain as a creamy yellow pus. After the removal of cell debris by white blood cells, a fluid filled space is left. It is generally associated with abscess formation and is commonly found in the central nervous system.
What is gangrenous necrosis
Although gangrenous necrosis is not a distinctive pattern of cell death, the term is still commonly used in clinical practice. It usually refers to the condition of a limb (generally the lower leg) that has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers. When bacterial infection is superimposed, the morphologic appearance changes to liquefactive necrosis because of the destructive contents of the bacteria and the attracted leukocytes (resulting in so-called “wet gangrene”).
What is caseous necrosis?
Caseous necrosis is most often encountered in foci of tuberculous infection. Caseous means “cheeselike,” referring to the friable yellow-white appearance of the area of necrosis on gross examination (Fig. 2.8). On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in H&E- stained tissue sections. Unlike coagulative necrosis, the tissue architecture is completely obliterated and cellular outlines cannot be discerned. Caseous necrosis is often surrounded by a collection of macrophages and other inflammatory cells; this appearance is characteristic of a nodular inflammatory lesion called a granuloma (Chapter 3).
What is fat necrosis?
Fat necrosis refers to focal areas of fat destruction, typically resulting from the release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity. This occurs in the calamitous abdominal emergency known as acute pancreatitis (Chapter 17). In this disorder, pancreatic enzymes that have leaked out of acinar cells and ducts liquefy the mem- branes of fat cells in the peritoneum, and lipases split the tri- glyceride esters contained within fat cells. The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions (Fig. 2.9). On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells surrounded by basophilic calcium deposits and an inflammatory reaction.
What is fibrinoid necrosis?
Fibrinoid necrosis is a special form of necrosis. It usually occurs in immune reactions in which complexes of antigens and antibodies are deposited in the walls of blood vessels, but it also may occur in severe hypertension. Deposited immune complexes and plasma proteins that leak into the wall of damaged vessels produce a bright pink, amorphous appearance on H&E preparations called fibrinoid (fibrinlike) by pathologists.
How can the tissue-specific necrosis be detected?
By using blood- or serum samples (leakage of intracellular proteins)
What is a pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins?
Apoptosis
What makes apoptosis different from necrosis?
The plasma membrane stays intact, so the cellular elements do not leak and therefore there is no inflammation.
There are physiologic and pathologic conditions associated with apoptosis. What are different physiologic conditions for apoptosis?
(so this is normal)
- during embryogenis (loss of growh factor signaling)
- turnover of proliferative tisseus (e.g. intestinal epithelium, lymphocytes, thymus)
- Involution of hormone dependent tissues (e.g. endometrium)
- Decline of leukocyte numbers at the end of immune- and inflammatory respons
- Elimination of potentially harmful self-reactive lymphocytes
There are physiologic and pathologic conditions associated with apoptosis. What are different pathologic conditions for apoptosis?
(this is semi-normal)
- DNA damage
- Accumulation of misfolded proteins
- Infections, expecially viral
Apoptosis is regulated by biochemical pathways that control the balance of death- and survival-inducing signals and ultimately the activation of enzymes. What are these enzymes called?
Caspases
What are the different pathways for apoptosis?
- The mitochondrial (intrinsic) pathway (for physiologic and pathologic situations)
- The death receptor (extrinsic) pathway of apoptosis (TNF factor on surface)
- Clearance of apoptotic cells (sending ‘eat me’ signals)
For a visual representation of the different pathways of apoptosis, see fig 2.12 in the book pls
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Next to apoptosis, necrosis and necroptosis, there is another pathway of cell death. What is other pathway?
Pyroptosis
What is pyroptosis?
This form of cell death is associated with activation of a cytosolic danger-sensing protein complex called the inflammasome. (The name pyroptosis stems from the asso- ciation of apoptosis with fever (Greek, pyro = fire)). It is thought to be one mechanism by which some infectious microbes cause the death of infected cells.
What is autophagy?
Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own components
Why is autophagy a survival mechanism?
It is a survival mechanism in times of nutrient deprivation, so that the starved cell can live by eating its own contents and recycling these contents to provide nutrients and energy.
Where is extensive autophagy seen?
In ischemic injury and some types of myopathies
Before discussing individual mechanisms of cell injury and death, some general principles should be emphasized. What are the general principles?
(sorry did not know a specific question for this one.. :()
- The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity.
- The consequences of an injurious stimulus also depend on the type, status, adaptability, and genetic makeup of the injured cell.
- Cell injury usually results from functional and biochemical abnormalities in one or more of a limited number of essential cellular components.
Next, we will discuss some mechanisms / pathways of cell injury. It is important to understand that unique mechanisms will be discussed, but this is not the reality. Why?
Any initiating trigger may activate one/more of these mechanisms, and several mechanisms may be active simultaneously
Deficiency of oxygen leads to failure of many energy- dependent metabolic pathways, and ultimately to death of cells by… (apoptosis/necrosis)?
Necrosis
What is hypoxia?
Low oxygen in your tissues (due to hypoxemia (low oxygen in your blood))
What is Ischemia?
Blood flow (and thus oxygen) is restricted or reduced in a part of the body
What is the difference between hypoxia and ischemia?
Hypoxia is when oxygen saturation is low, while ischemia is when blood flow is restricted/reduced
What do cells subjected to the stress of hypoxia that do not immediately die activate?
Compensatory mechanisms that are induced by transcription factors of the hypoxia- inducible factor 1 (HIF-1) family
What does the factor HIF-1 do?
HIF-1 simulates the synthesis of several proteins that help the cell to survive in the face of low oxygen.
Such as vascular endothelial growth factor (VEGF) is stimulated by HIF-1. What does this protein do?
It stimulate the growth of new vessels and thus attempt to increase blood flow and the supply of oxygen
What are other mechanisms (besides VEGF) induced by HIF-1 that help the cell survive during hypoxia?
Other proteins induced by HIF-1 cause adaptive changes in cellular metabolism by stimulating the uptake of glucose and glycolysis and dampening mitochondrial oxidative phosphorylation. Anaerobic glycolysis can generate ATP in the absence of oxygen using glucose derived either from the circulation or from the hydrolysis of intracellular glycogen.
Normal tissues with a greater glycolytic capacity because of the presence of glycogen are more likely to survive hypoxia and decreased oxidative phosphorylation than tissues with limited glucose stores. Name examples of these two different types of tissues
Great glycotic capacity: e.g., the liver and striated muscle
Limited glucose stores: e.g., the brain
Persistent or severe hypoxia and ischemia ultimately lead to failure of ATP generation and depletion of ATP in cells. What cellular effects are seen as a result of this?
(please don’t learn by heart, understand the concepts/process)
(LOOK AT FIG 2.16 in the book pls)
- Reduced activity of plasma membrane ATP-dependent sodium pumps, resulting in intracellular accumulation of sodium and efflux of potassium. The net gain of solute is accompanied by isoosmotic gain of water, causing cell swelling and dilation of the ER.
- The compensatory increase in anaerobic glycolysis leads to lactic acid accumulation, decreased intracellular pH, and decreased activity of many cellular enzymes.
- Prolonged or worsening depletion of ATP causes structural disruption of the protein synthetic apparatus, manifested as detachment of ribosomes from the rough ER (RER) and dissociation of polysomes into monosomes, with a consequent reduction in protein synthesis.
- It also has been suggested that hypoxia per se increases the accumulation of ROS. Whether this is true is a matter of debate; however, there is ample evidence that hypoxia predisposes cells to ROS-mediated damage if blood flow (and oxygen delivery) is reestablished, a phenomenon called reperfusion injury (described later).
- Ultimately, there is irreversible damage to mitochondrial and lysosomal membranes, and the cell undergoes necrosis. Membrane damage is a late event in cell injury caused by diverse mechanisms, and is discussed later. Although necrosis is the principal form of cell death caused by hypoxia, apoptosis by the mitochondrial pathway is also thought to contribute.
What is Ischemia-Reperfusion Injury?
Paradoxically, the restoration of blood flow to ischemic but viable tissues results in increased cell injury.
In what tissues does ischemia-reperfusion injury especially occur?
Myocardial and cerebal
Explain the several mechanisms that may account for the ischemia-reperfusion injury?
- New damage may be initiated during reoxygenation by increased generation of ROS. Some of the ROS may be generated by injured cells with damaged mitochondria that cannot carry out the complete reduction of oxygen, and at the same time cellular anti-oxidant defense mechanisms may be com- promised by ischemia, exacerbating the situation. ROS generated by infiltrating leukocytes also may contribute to the damage of vulnerable injured cells.
- The inflammation that is induced by ischemic injury may increase with reperfusion because it enhances the influx of leukocytes and plasma proteins. The products of activated leukocytes may cause additional tissue injury. Activation of the complement system also may contribute to ischemia-reperfusion injury. Complement proteins may bind to the injured tissues, or to antibodies that are deposited in the tissues, and subsequent complement activation generates byproducts that exacerbate the cell injury and inflammation.
What is oxidative stress?
Cellular abnormalities that are induced by ROS, which belong to a group of molecules known as free radicals
In what type of circumstances is free radical-mediated call injury seen? (for illustration)
Chemical and radiation injury, hypoxia, cellular aging, tissue injury caused by inflammatory cells, and ischemia-reperfusion injury
What type of cell death occurs because of oxidative stress?
Necrosis, apoptosis, or the mixed pattern of necroptosis.
The accumulation of ROS is determined by their rates of production and removal. ROS are produced by two major pathways. What are these?
- ROS are produced normally in small amounts in all cells during the reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy generation.
- ROS (as well as NO) are produced in phagocytic leukocytes, mainly neutrophils and macrophages as a weapon for destroying ingested microbes and other substances during inflammation and host defense
How can the generation of free radicals be increased?
- The absorption of radiant energy (e.g., ultraviolet (UV) light, x-rays). Ionizing radiation can hydrolyze water into hydroxyl (•OH) and hydrogen (H•) free radicals.
- The enzymatic metabolism of exogenous chemicals
- Inflammation, in which free radicals are produced by leukocytes
- Reperfusion of ischemic tissues
Cells have developed mechanisms to remove free radicals and thereby minimize their injurious effects. What are these?
- The rate of decay of superoxide is significantly increased by the action of superoxide dismutase (SOD).
- Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from oxidative damage. The most abundant member of this family, GSH peroxidase 1, is found in the cytoplasm of all cells. It catalyzes the breakdown of H2O2 by the reaction 2GSH + H2O2 → GS-SG + 2H2O. The intracellular ratio of oxidized GSH to reduced GSH is a reflection of this enzyme’s activity and thus of the cell’s ability to catabolize free radicals.
- Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen peroxide (2H2O2 → O2 + 2H2O). It is one of the most active enzymes known, capable of degrading millions of molecules of H2O2 per second.
- Endogenous or exogenous anti-oxidants (e.g., vitamins E, A, and C and β-carotene) may either block the formation of free radicals or scavenge them after they have formed
ROS causes cell injury by damaging multiple components of cells. What are these?
- Lipid peroxidation of membranes
- Crosslinking and other changes in proteins
- DNA damage
