Cellular Response to Injury, Reversible/Irreversible Cell Injury, Necrosis, Apoptosis The stimulus of non-lethal injuries will lead to this cellular response:

A protein to be degraded is flagged for destruction by ubiquitin. If that protein is still chosen for degredation, it is sent to a Proteasome for degradation. If not, the protein is ubiquitylated.

What are some examples of diseases in which defective Ubiquitination is seen?

Parkinsons, Neoplasms such as Human Cervical Cancer where P54 is inactivated by mutated ubiquitins

What is Hypertrophy?

It is an increase in cell size and functional capacity resulting from increased production of cellular proteins. This occurs in organs containing terminally differentiated cells. This can be physiological or pathological.

What is the mechanism of Hypertrophy?

Cellular Remodeling in which increased proteasomal degradation occurs of selected macromolecular constituents. There is an increase in protein degredation as with atrophy, but there is also an increase in quick protein translation. There is an increase and up regulation of certain gene expressions and an increase in "Survival" or the inhibition of apoptosis.

What is the key difference in the direct causes of Physiological vs Pathological Hypertrophy?

Physiological Hypertrophy is directly due to mechanical stress which can be due to a multitude of reasons leading to an increase in work load. Pathological Hypertrophy is due to agonistic response and growth factors coming from a multitude of reasons.

What is particularly distinguishing in Cardiac Hypertrophy?

There is the presence of Box Car Nuclei that are long with blunted ends.

What happens in subcellular hypertrophy?

This is a hypertrophy of the smooth ER. In this, barbiturates stimulate an increase in cytochrome p450 mixed function oxidases. This is seen in drug adaptations.

What is hyperplasia? What elicits hyperplasia?

This is an increase in the number of cells resulting from physiological or pathological stimuli. This may occur with or without hypertrophy. The ultimate mechanism is stimulating resting cells (G0) to enter the cell cycle(G1) and multiply. It is elicited by Hormonal Stimuli, Increased Functional Demand, and Chronic Injury.

What is Atrophy?

The reduction size of organ or tissue because of a decrease in cell size and number. There is physiological (developmental, uterus) or pathological (local or generalized)

What are the mechanisms of change in Atrophy?

Protein synthesis decreases, and protein degredation increases. The Ubiquitin-related degradation pathways are activated. The NFkB inhibitors are eliminated and FFA is not used as an energy source.

What is metaplasia?

It is the conversion of one differentiated cell type to another. Examples are Barrett Esophagus.

What is Sequelae?

These are problems that occur from a major problem. An example is "Chronic Liver Disease is a Sequelae of Diabetes"

What are the Sequelae of Metaplasia?

It can become preneoplastic if not fixed.

What are the mechanisms behind metaplasia?

There is a re-programming of stem cells that exist in normal tissues or of undifferentiated mesenchymal cells in CT.

What is Dysplasia?

Disordered growth and maturation of cellular components of a tissue in epithelium. Epithelial cells generally exhibit uniformity of size and shape; with dysplasia there is a variation in size and shape, nuclear enlargement, hyperchromatism, and disarray in arrangement.

Where is Dysplasia mostly seen?

In Hyperplastic squamous epithelium.

What is the pathogenesis of Dysplasia?

It is a response to persistent stimulus such as smoking, and can regress if the stimulus is removed. It is the result of sequential mutations in proliferating cellular populations. It is the morphologic expression of the disturbance in growth regulation.

What is the difference between Dysplasia and Neoplasia?

Dysplastic cells are not entirely autonomous.

Explain how Mitochondrial Damage can lead to further cell injury"

Mitochondrial Injury results in the formation of channels in the membrane called MPTP. This leads to loss of mitochondrial membrane potential. That leads to the loss of oxidative phosphorylation leading to a loss of ATP. The loss of ATP can lead to Necrosis. Remember that Apoptotic Proteins are sequestered between inner and outer membranes, so those come out.

Explain the role of Calcium during Cellular Injury:

ECF Calcium floods into the cell causing an increase in ICF Calcium. This causes ATPase, Phospholipase, Protease, and Endonuclease activity to increase. That yields less ATP, less phospholipids, disruption in the membrane and cytoskeleton, and nucleus chromatin damage.

What is Hydropic Swelling?

A form of reversible cell injury that leads to a large pale cytoplasm and a normally located nucleus. It reflects an increase in water content. It is an acute, reversible injury from a variety of insults such as toxins, ischemia, and excessive hot/cold.

What is the pathogenesis of Hydropic Swelling?

It leads to the impairment of cellular volume regulation. Thus the regulation of sodium is disrupted. The Supply of ATP is interrupted due to the increasing permeability to sodium by exceeding pump capacity. Also, the Sodium Pumps can be damaged directly.

What are the two types of cell death?

Physiological and Pathological. Physiological Cell death is Apoptosis while Pathological is Necrosis.

What are the types of Necrosis?

Coagulative, Liquefactive, Caseous, Fat, Fibrinoid. CCLFF

What is Coagulative Necrosis?

Light Microscopic changes in dead or dying cell whereby cellular outlines are still recognizable in early stages. This is most often associated with ischemia and early stages are similar to reversible injury.

What are the three non-sequential changes that occur to the nucleus during coagulative necrosis?

Pyknosis in which the nucleus and shrunken and more basophilic. Karyorrhexis in which the nucleus becomes fragmented. Karyolysis in which the nucleus is extruded from the cell or it loses chromatin staining.

What is the most common example of Coagulative Necrosis?

Gangrene

What are the two forms of Gangrene?

Wet form which is associated with bacterial infiltration. The Dry form which has no bacteria and is characterized by mummification.

What is Liquefactive Necrosis?

It is the rapid dissolution of cells most often due to release of neutrophil hydrolytic enzymes. The area becomes a cavity surrounded by fibrous connective tissue after liquid is drained or reabsorbed.

What happens in the brain regarding Liquefactive Necrosis?

In the brain, coagulation necrosis liquifies very rapidly and forms cavities that are long lasting.

What is an abscess?

It is a loclized collection of dead and dying neutrophils plus or minus necrotic debris.

What is Caseous Necrosis?

Necrotic Cells fail to retain cellular outlines but do not liquefy. Dead cells persist as amorphous, coarsely granular, eosinophillic debris. It resembles clumpy cheese.

What are the common causes of Caseous Necrosis?

Usually caused by Tuberculosis, but it is lso caused by some fungi and bacteria. It is generally seen with Granulamatous Inflammation.

What is Fat Necrosis? Describe the detailed mechanism:

Digestive enzymes from the pancreatic duct or small intestine are released from cells and activated. These attack membranes of adipocytes and triglycerides are released. Pancreatic Lipase hydrolyzes triglycerides producing fatty acids. These will bind with Calcium forming soaps which appear as amorphous, basophilic deposits a the edges of necrotic adipocytes. These will appear chalky.

What is Fibroid Necrosis?

Generally seen in immune reactions associated with blood vessels, the immune complexes and fibrin are seen in vessel walls.

What are the two main sources of Superoxide?

Leaks in mitochondrial ETC lead to electrns being transferred to Oxygen, creating the Superoxide. Second, it is part of the phagocytic inflammatory response.

What are the two main sources of Hydrogen Peroxide?

Catabolism of Superoxide by Superoxide Dismutase. It is also produced directly in Peroxisomes by oxidases.

What is the function of the Fenton Reaction?

Hydrogen Peroxide stimulates the uptake of iron, enhancing the Fenton Reaction which enhances the formation of OH radical.

What do the Fenton and Haber-Weiss Reactions have in common

They both utilize Hydrogen Peroxide to yield an OH radical. The difference is that Fenton uses Iron and H202 while Haber Weiss uses O2- and H+ with H202.

Where does the most reactive ROS, the -OH radical Hydroxyl, come from? What is its mechanism of action?

It comes from the Fenton Reaction, the Haber-Weiss Reaction, and Radiolysis. Its mechansim of action is Lipid Peroxidation which results in the loss of membrane integrity. These also attack Sulfur-Containing Amino Acids which cause the fragmentation of certain proteins as well as breaking DNA strands.

What does Peroxynitrite do? What is its source?

It attacks lipids, proteins, and DNA. Its source is NO- andO2- combining to make ONOO-.

What are the 3 major ways in which Free Radicals are removed?

1. Antioxidants block initiation or inactivate free radicals. 2. Iron and Copper Catalyze Formation of ROS, if they bind to storage proteins, they slow down. 3. Scavenging Enzymes such as catalase, superoxide dismutase, and glutathione peroxidase.

What can happen in Mitochondrial membrane damage?

Permeability leads to decreased ATP and the release of pro-apoptotic proteins.

What can happen in Plasma membrane damage?

Loss of ionic balance and influx of extracellular ions and fluid as well as loss of cellular contents.

What can happen in lysosomal membrane damage?

Lysosomal Enzyme leakage and the activation of acid hydrolases can lead to enzymatic digestion of cellular constituents.

What is an α1-Antitrypsin Deficiency?

It is a mutation in the coding gene leading to insoluble protein that is not easily transported from hepatocytes. It leads to emphysema and liver cirrhosis.

What are Prion Diseases?

Accumulations of abnormally folded proteins that give rise to neurodegenerative disorders. Conversion of α-helical structure to β-pleated sheet proteins due to inherited mutation or exposure to aberrant form of the protein.

What are Lewy Bodies?

α-Synuclein. This is observed in neurons of substantia nigra in Parkinson's Disease

What are Neurofibrillary Tangles?

"Tau Protein" these characterize cortical neurons in Alzheimer's Disease.

What are Mallory Bodies?

"Intermediate Filaments" that are present in hepatocellular inclusions in alcoholic liver injury.

Why does ischemic injury lead to cellular damage?

Deprivation of oxygen leads to a switch from aerobic to anaerobic metabolism which means less ATP production. With less ATP, cellular energy for metabolism including maintenance of the gradient between external and internal compartments will be unstable.

Is Ischemic Injury reversible or irreversible?

Both, its irrersvisble if it is a long duration.

What is reperfusion injury?

It is tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. Restoration of circulation results in inflammation and oxidative damage through the induction of oxidative stress rather than restoration of normal function. ROS increase due to the initial cellular damage and neutrophil recruitment.

What is Xanthine Oxidase?

Created from Xanthine dehydrogenase by proteolysis during Ischemic Event

How can ionizing radiation cause cell death?

1. Radiolysis of H20 can cause Oxidative Stress on Proliferating Cells. These cells can have major DNA damage that can lead to apoptosis. 2. The energy transfer to macromolecules can cause all cells to go into necrosis.

Explain the two types of viral cytotoxicity:

1. Direct in which there is a subversion of cellular enzymes or depleting nutrients. In addition there is a manipultion of apoptosis in which Viruses upregulate anti-apoptotic proteins to inhibit apoptosis. 2. Immunologically Mediated Cytotoxicity- both humoral and cellular arms of the immune system protect against harmful effects of viruses.