Cell Injury and Death Flashcards
Cell Injury Tree Diagram
Sequence of Events in Cell Injury and Death
Hypoxia in Cell Injury
Hypoxia interferes with aerobic respiration and depletes ATP.
Hypoxia is different from ischemia, or loss of blood supply to a tissue, which compromises nutrient delivery and waste removal (making it more damaging than hypoxia). Ischemia is the most common cause of hypoxia, but oxygen deficiency can also result from inadequate oxygenation of the blood (pneumonia) or reduction in the O2 -carrying capacity of the blood (anemia or CO poisoning).
Chemical agents in cell injury
Chemical agents can injure either directly (e.g. HgCl2 binding to membrane -SH groups), or indirectly via their metabolites. Virtually any chemical can cause injury – even oxygen and water(!) are toxic if sufficiently concentrated. Drugs can also cause injury at high doses (every drug has a therapeutic index), or at therapeutic doses in sensitive patients.
Infectious Agents in Cell Injury
Each agent tends to have a defined spectrum of injury.
Viruses multiply intracellularly, appropriating host biosynthetic machinery, and cause cell lysis.
Bacteria can cause injury in the same way if intracellular; in addition, extracellular bacteria have toxic cell wall constituents (endotoxin), and can release exotoxins.
In addition to these direct mechanisms, infectious agents can also cause injury indirectly: immune-mediated injury may occur (innate immunity, killing of infected cells, septic shock), and some infectious agents can cause malignant transformation.
Immune Responses in Cell Injury
Although the immune system serves to defend the body against foreign materials, immune reactions – intended or incidental – can also result in cell and tissue injury. Examples include anaphylaxis and autoimmune disease.
Genetic Defects in cell injury
Inborn errors of metabolism due to congenital enzyme deficiencies are excellent examples of cell and tissue damage resulting from genetic mutations
Nutritional Imbalances in cell injury
Nutritional deficiencies (e.g. protein-calorie malnutrition) remain a major world-wide cause of cell injury, but specific vitamin deficiencies are common even in industrialized nations. Nutritional excesses also cause cell injury; obesity increases risk of diabetes mellitus, and diets rich in animal fat are associated with increased risk of atherosclerosis and other disorders (including cancer).
Physical Agents in cell injury
Trauma, extremes of temperatures, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells.
Healing and Aging in cell injury
Healing of injured tissues does not always result in a perfect restoration of structure or function. Repeated trauma can also lead to tissue degeneration even in the absence of outright cell death. Moreover, intrinsic cellular senescence (AKA: aging) leads to alterations in replicative and repair abilities of individual cells and tissues. All of these changes result in a diminished ability to respond to exogenous stimuli and injury, and eventually to the death of the organism.
Molecular mechanisms of cell injury
Cell membrane damage
Ischemia
Loss of calcium homeostasis
Calpains
Activated by increased cytoplasmic calcium. Intracellular cysteine proteases which break down cytoskeletal proteins, damage ion channels, and alter the activity of cell adhesion molecules and cell surface receptors.
Necrosis
Apoptosis
Mitochondrial permeability transition
Mitochondrial integrity is required for oxidative metabolism and, therefore, cell survival. Increases in cytosolic calcium, intracellular oxidative stress, and lipid breakdown products all culminate in formation of non-selective pores in the inner mitochondrial membrane, which dissipate the proton gradient across the mitochondrial membrane and prevent ATP generation. Cytochrome C also leaks into the cytosol and activates apoptosis.
_____ is the most common cause of cell injury in clinical medicine
Ischemia is the most common cause of cell injury in clinical medicine, typically occurring due to diminished blood flow in a particular tissue vascular bed.
Ischemia results in compromised nutrient delivery and waste removal in addition to hypoxia, making it categorically worse than hypoxia. In contrast to hypoxia, where glycolytic energy generation can continue, glycolysis will also cease in ischemic tissues after potential substrates are exhausted or glycolysis is inhibited by accumulation of metabolites that would normally be removed by blood flow.
Mechanisms in ischemic injury
ATP depletion causes reduced activity of the plasma membrane Na/K ATPase, with accumulation of intracellular sodium and diffusion of potassium out of the cell. The net gain of sodium causes osmotic gain of water, producing acute cellular swelling.
Anaerobic glycolysis increases. Activation of this pathway generates some ATP, but leads to rapid depletion of glycogen stores and causes accumulation of lactic acid and inorganic phosphates from hydrolysis of phosphate esters, lowering the intracellular pH.
Dropping pH and ATP levels cause ribosomes to detach from the rough endoplasmic reticulum (RER), with a resultant reduction in protein synthesis.
If hypoxia/ischemia is not relieved, worsening mitochondrial function and increasing membrane permeability cause further morphologic deterioration.
Ischemia/reperfusion injury
Under certain circumstances, restoration of blood flow to ischemic but otherwise viable tissues results in paradoxically exacerbated and accelerated injury.
- Restoration of blood flow bathes cells in high concentrations of calcium. Increased intracellular calcium activates pathways causing loss of cellular integrity
- Restoration of blood flow into an area that is already irreversibly injured results in local augmentation of inflammatory cell recruitment. These cells release high levels of ROS that promote additional membrane damage as well as the mitochondrial permeability transition.
- Damaged mitochondria produce increased free radicals. In addition, ischemically-injured cells have compromised anti-oxidant defense mechanisms
Free radical-induced injury
Vulnerable targets:
Double bonds in membrane lipids
Thymidine in DNA
Thiols in proteins (produce non-physiological disulfide bridging and sulfur oxidation)
Cellular free-radical defusion mechanisms
Superoxide dismutases (2O2 •+ 2H+ —> H2O2 + O2)
Glutathione + glutathione peroxidase
Catalase
Endogenous or exogenous antioxidants
Metal storage and/or transport proteins (sequester ionized iron and copper, minimizing their potential for damage)
Atrophy
Shrinkage in the size of a cell or organ by loss of cell substance. Atrophic cells are not dead, although they do have diminished function. Cell loss can also lead to organ atrophy.
Causes of atrophy include decreased workload (e.g. immobilization or disuse of a limb), denervation, ischemia, inadequate nutrition, loss of hormone stimulation, and aging.
Atrophy represents a reduction in the structural components of the cell
Lipofuscin
A byproduct of “wear and tear” formed from crosslinked proteins and lipids. May accumulate with age. There is no metabolic mechanism to degrade it or method to transport it outside of the cell.
Coagulative necrosis
When denaturation is the primary pattern, coagulative necrosis develops. Coagulative necrosis implies preservation of the structural outline of the cell or tissue.
Coagulative necrosis, with preservation of the general tissue architecture, is characteristic of hypoxic death of cells in all tissues except the brain.
Liquefactive necrosis
Observed in the instance of dominant enzyme digestion. Liquefactive necrosis is characteristic of microbial (bacterial or sometimes fungal) infections, since these provide powerful stimuli for the accumulation of white cells. For unclear reasons, hypoxic death of cells within the central nervous system also results in liquefactive necrosis. Liquefaction completely digests the dead cells.
Gangrenous necrosis
Not actually a distinctive pattern of cell death, but refers to ischemic coagulative necrosis of an extremity. The term is still commonly used in surgical practice.
When there is superimposed infection with a liquefactive component, the lesion is called “wet gangrene.“
Caseous necrosis
Caseous necrosis is a distinctive form of necrosis encountered most often in foci of tuberculosis infection. The term “caseous” is derived from the cheesy, white gross appearance of the central necrotic area.
Microscopically, the necrotic focus is composed of amorphous granular debris enclosed within a distinctive ring of granulomatous inflammation. Unlike coagulative necrosis, the tissue architecture is completely effaced (unrecognizable).
Fat necrosis
Describes focal areas of fat destruction resulting from pathologic release of activated lipases
This occurs, for example, in the disastrous abdominal emergency known as acute pancreatitis; activated pancreatic lipases escape from acinar cells and ducts, liquefying fat cell membranes and hydrolyzing the triglycerides contained within them. The released fatty acids combine with calcium to produce visible chalky white areas (fat saponification).
Apoptosis
single cells, or clusters of cells, that appear as round or oval masses with intensely eosinophilic cytoplasm
The nuclear chromatin is condensed and aggregates peripherally, under the nuclear membrane, into well-defined aggregates of various shapes and sizes. Ultimately, DNA is chopped into nucleosome-sized pieces, presumably through the activation of endonucleases. The cells shrink, form cytoplasmic buds, and fragment into apoptotic bodies composed of membrane-bound vesicles of cytosol and organelles which are phagocytosed or degraded.
Necrosis vs Apoptosis Table
Additionally, necrosis usually involves regions while apoptosis usually involves individual cells.
Molecular features of apoptosis
