Cell Injury 1 Basics Flashcards
Basic Objectives for Cell Injury I Lectures.
Define: Etiology
the cause of disease
Define: Pathogenesis
the mechanisms of development of disease
Define: Morphologic Change
the gross and microscopic patters that occur as a consequence of changes at the molecular and cellular level
Define: Pathology
study of (logos) suffering (pathos). Study of structural and functional changes in cells and tissues that underlie disease.
What are the seven major causes of cell stress and injury?
- hypoxia
- chemical and/or drug
- microbiologic agents (such as infection)
- immunologic events (such as immune reactions)
- genetic defects (such as abnormal chromosome leading to protien defects)
- nutritional
- aging
What are the four common subcellular targets of injury?
cell membranes, mitochondria, endoplasmic reticulum, and genetic apparatus
What are the three common biological events that are associated with most forms of injury?
loss of calcium homeostasis, ATP depletion, and generation of oxygen-derived free radicals
Define: Ischemia
loss of blood supply due to impeded arterial flow or reduced venous drainage. Ischemia is a common cause of hypoxia, but not the only cause.
Define: Hypoxia
lack of oxygen
Describe the major events of ischemic injury (I0 steps)
- When blood supply is lost, tissue oxygen levels fall and this slows the production of ATP by oxidative phosphorylation.
- Glycolytic pathways are up regulated, lowering intracellular pH due to accumulation of lactic acid.
- Loss of ATP reduces the activity of both Na+K+-ATPase and Ca++, Mg++-ATPase.
- Increased concentrations of intracellular sodium cause movement of water into the cytoplasm and the cell swells.
- Increased calcium activates damaging enzymes.
At this point, the cell is in acute cellular swelling, this is reversible. - Mitochondrial changes and damage ensues with swelling of the matrix and loss of cristae.
- Swelling continues, the rough endoplasmic reticulum becomes distended and ribosomes are shed with loss of protein synthesis.
- Calcium-induced proteases and phospholipase attack the cell proteins and lipids of the cell membrane and dissociate the cytoskeleton from the cell membrane resulting in membrane blebs and loss of microvilli.
- Cell junctions and other cell-to-cell contacts are damaged.
- Endonucleases attack the DNA of the nucleus and chromatin condenses with nuclei becoming pyknotic.
Define: Reperfusion
restoration of blood flow to a tissue or organ
Does reperfusion after a hypoxic event reverse any injury that may happened in the tissue or organ?
No, the sudden input of oxygen and white blood cells may promote free radical damage. The increase in oxygen in an area of injury promotes continued free radical formation with products of the initial injury. In addition, the WBCs will also produce free radicals in the process of their normal phagocytotic activity.
Describe the ultrastructural damage that can be observed in injured cell mitochondria.
Mitochondrial changes include swelling observed in hypoxic injury with loss of cristae seen in reversible injury due to loss of ATP and increased water content. Mitochondria may also fill with flocculent material or collect dense deposits of calcium or debris (matrix dense bodies). During calcification, they may become extremely dense or shrink. Calcification and mtrix dense bodies are more indicative of irreversible injury and cell death. Adaptive changes include increased numbers of mitochorndria in metabolically active states and sites and altered shape and size (giant mitochondria) are seen with exposure to some toxins (e.g. alcohol).
Describe the ultrastructural damage that can be observed in injured cells with membrane damage.
Loss of membrane polarity and membrane leakage can result from loss of membrane ion transport pumps as a result of loss of ATP and the presence of chemicals. Other abnormal membrane features include blebbing, bizarre microvilli shapes, and total loss of microvilli. Loss of normal, cell-to-cell contacts and tight junction integrity in the case of epithelial cells is also common.
Describe the ultrastructural damage that can be observed in injured cell lysosomes.
The lysosomal system is very active in injured cells and more secondary lysosomes will be seen. Autophagosomes may be more apparent as the cell attempts to digest damaged organelles. Certain memberane components cannot be completely digested and remain as residual bodies. Lysosomal storage disorders also result in greater numbers of lysosomes and the contents of lysosomes will reflect the position of the deficient enzyme in a metabolic pathway. (e.g. Tay Sachs reflects a deficiency in the enzyme for sphingolipid, therefore cells include secondary lysosomes with whorls of membrane debris.)
Describe the ultrastructural damage that can be observed in injured cell RER and SER.
Swelling occurs in both types of ER with influx of water. Loss of associated ribosomes occurs in RER. Exposure to certain drugs may cause an increase in the volume of SER.
Describe the ultrastructural damage that can be observed in injured cell cytoskeleton.
The cytoskeleton includes microfilaments, microtubules, and intermediate filaments. Proteases liberated by increased calcium may clearly dmage all of these proteins while certain drugs may be specific (e.g. Taxol is specific for microtubules). Defects in proteins of the microtubule system may result in decreased motility (sperm and respiratory cilia). Intermediate filaments may form inclusions in a variety of diseases (e.g. Alzheimer neurofilament bundles)
Describe the ultrastructural damage that can be observed in an injured cell nucleus.
Chromatin has a tendancy to condense in injured cells. Condensed chromatin is frequently observed near the periphery of the nucleus and the nucleus may become indented. With injury that is irreversible, one would observe a very small nucleus with condensed chromatin throughout the entire structure. This feature is called pyknosis. Another pattern of nuclear change may include an initial loss of density in the nuclease secondary to endonuclease activity and this is karyolysis. Karyorrhexis is the process where the nucleus fragments before disappearing in the dead cell. Each of these features: karyolysis, pyknosis, and karyorrhexis indicate irreversible cell injury and cell death.
Define: Pyknosis
A condensation and reduction in the size of a cell nucleus, usually associated with hyperchromatosis.
Define: Karyolysis
The dissolution of the nucleus of a cell by swelling or necrosis
Define: Karyorrhexis
A stage of cellular necrosis in which the fragments of the nucleus fragments and its chromatin are distributed irregularly throughout the cytoplasm.
Define: Hydropic Change
Accumulation of water in a cell.
What are the four general principles that guide our understanding of the mechanism of disease?
- Cell response to an injury depends on the type of injury, its duration, and dose.
- There are cell-specific responses to types of insults and these responses are variable.
- Injury most often affects these four cellular targets: cell membranes, mitochondria, ER, and nucleus.
- Cell injury nearly always involves the following biochemical events: loss of calcium homeostasis, ATP depletion, and generation of free radicals.
