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69 Cards in this Set
- Front
- Back
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Q: What are the different causes of cell injury?
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-O2 deprivation, physical agents, chemicals/drugs, infectious agents, immunologic reactions, genetic and metabolic derangements, nutritional imbalances (lots of things can, not just trauma)
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Q: Describe oxygen deprivation as a means of cell injury.
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-This is also known as hypoxia. A complete lack of oxygen is anoxia. Hypoxia disrupts normal aerobic oxidative metabolism. A number of etiologies can occur. Drowning, carbon monoxide poisoning, cardiorespiratory failure, etc. All of these can result in cell injury or death. Ischemia, a loss of blood flow to an area, results in hypoxia and decrease of metabolic substrates such as glucose. A blood clot in an artery causes ischemia to the distal tissues. In contrast to hypoxia in which glycolytic energy production can continue, ischemia compromises the delivery of substrates for glycolysis. Anaerobic energy generation stops after glycolytic substrates are exhausted. For this reason, ischemia tends to injure tissues faster than hypoxia.
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Q: Describe physical agents as a means of cell injury.
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-Mechanical trauma such as auto accidents, bullet wounds, burns, electric shock, radiation, etc. In auto accidents there is “blunt force” trauma. Example is a car bumper breaking a leg. In bullet and knife wounds this is called penetrating trauma. Abrasions occur when someone falls off a motorcycle. One type of laceration occurs with knives but liver lacerations can occur from blunt force automobile trauma.
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Q: Describe chemical and drugs as a form of cell injury.
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-This is a huge category and would include poisons such as arsenic, various therapeutic medications, alcohol in drinks, cocaine, insecticides, etc. This may be called toxic injury because things like alcohol, insecticides, and arsenic are “toxins” to the body.
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Q: Describe infectious agents as a form of cell injury.
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-Another huge category including bacteria, viruses, fungi and parasites. Many of these organisms directly kill or injure cells. But some of these, such as viruses, may incite an immunologic response, which attacks the infected cell. Also, some bacteria elaborate toxins, which kill cells.
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Q: Describe immunologic reactions as a form of cell injury.
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-Severe allergic reactions such as food or chemicals and hornet stings. Autoimmune disease, “lupus”, occurs when there is an immune reaction against “self” antigens.
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Q: Describe genetic and metabolic derangements as a form of cell injury.
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-This is becoming a large category because of all of the mutations being discovered which lead to various neoplasms and diseases.
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Q: Describe nutrional imbalances as a form of cell injury.
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-Nutritional excesses, which result in obesity, can lead to atherosclerosis, diabetes, liver disease, etc. Nutritional deficiencies, such as lack of vitamin C can lead to scurvy.
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Q: What words are associated with cellular adaptation?
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-hyperplasia (INC in number), hypertrophy (INC in size), atrophy (DEC in size) and metaplasia (change in cell type)
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Q: What are some principles that are relevant to most forms of cell injury?
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-the cellular response to injurious stimuli depends on the type of injury, its duration and its severity (if it is not badly injured it quickly recovers, if it is badly injured then it may slowly recover and it is reversible, if the cell cannot recover then it dies)
-the consequences of cell injury depend on the type, state and adaptability of the injured cell -cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components |
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Q: What are different ways a cell can die?
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-Cell death caused by accidental injury is called necrosis. Another way a cell can die is by apoptosis. This is called programmed cell death because the cell, itself, programs specific pathways to undergo suicide. For example, milk producing cells in the female breast undergo apoptosis when a woman stops breast feeding.
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Q: How are cells able to adapt to a stress?
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-a stress on a cell can cause both INC functional demand and reversible cell injury, if the cell injury is severe it causes an irreversible cell injury and leads to coagulative necrosis, if the stress is persistent then cells adapt either by hypertrophy, hyperplasia, atrophy, metaplasia, dysplasia (precancer) or storage
-once the stress is removed then the cell becomes a normal cell |
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Q: What process/disease is causing hypertrophy?
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-growth factors are INC such as insulin growth factor-1 (IGF-1), this is followed by proteasomal degradation of proteins not needed for hypertrophy and leads to a loss of function, the cell also has a INC O2 demand, when the body is no longer able to compensate for INC O2 demand then cell degenerates
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Q: Describe atrophy.
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-is an adaptation to dimished need or resources, atrophy of muscles occur during immobilization (say in a cast), DEC workload, loss of innervation, diminished blood supply, inadequate nutration, loss of endocrine stimulation, aging, pressure
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Q: Describe hyperplasia.
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-INC # of cells from a persistent stress/stimulus
-there are different types of hyperplasia, endometrial hyperplasia is common from anovulatory cycles and uopposed estrogen, psoriasis is idiopathic but epidermal hyperplasia come froms chronic irritation -hyperplasia can be bad, say in chronic inflammation (irritation) in ulcerative colitis which can lead to cancer |
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Q: What are the biochemical mechanisms that are involved with cell injury and cell death?
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-ATP depletion, mitochondrial damage, free radicals, loss of Ca2+ homeostasis, defects in membrane permeability
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Q: Describe ATP depletion.
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-ATP is necessary for many important metabolic processes within the cell, it helps membranes maintain electrolyte gradients and is essential for the life of the cell, needed for protein synthesis
-ATP depletion and DEC ATP synthesis are frequiently associated with both hypoxic and chemical (toxic) injury |
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Q: How is ATP generated?
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-ATP is generated via oxidative phosphorylation and the glycolytic pathway
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Q: What effect does ATP depletion have on the sodium-potassium electroly pump?
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-The sodium-potassium electrolyte pump requires ATP. With ATP depletion, as occurs in cell injury, this pump cannot properly function. Sodium begins coming into the cell and potassium leaks out. This leads to high intracellular sodium and low intracellular potassium.
-also get an INC in the entrance of Ca2+ with the improper functioning of the Ca2+ ATPase -the net gain of solute (INC Na+, Ca++, lactic acid and inorganic PO4) is accompanied by isosmotic gain of water, causing cell swelling and dilation of the ER |
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Q: What other affects does ATP depletion have on the cell?
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-cellular energy metabolism is altered-get an INC in AMP which stimulates phosphofructokinase and phosphorylase activities, this causes INC in anaerobic glycolysis, this reduces intracellular pH resulting in DEC activity of many cellular enzymes
-failure of the Ca2+ pump leads to influx of Ca2+ -reduction of protein synthesis and unfolding of proteins |
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Q: Describe free radicals.
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-Free radicals (*), oxidative stress and antioxidants have become commonly used terms for disease mechanism. Free radicals are chemical species with a single unpaired electron in an outer orbit. Common ones in our bodies are superoxide (02*), hydroxyl (OH*) and hydrogen peroxide (H2O2). H2O2 is commonly called a free radical (it is not) because it reacts with iron and causes a Fenton reaction.
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Q: Describe oxidative stress.
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-“Oxidative stress” is the term now used to describe a disturbance in the balance between the production of reactive oxygen species (free radicals) and antioxidant defenses. Oxidative stress occurs when too many free radicals (usually oxygen type) are present.
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Q: How are free radicals formed?
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-Free radicals are formed by several different biochemical reactions including reduction of molecular oxygen during aerobic respiration which is oxidative phosphorylation. By-products in the oxidation of catecholamines, a by-product in hypoxanthine going to xanthine, phagocytosis of bacteria by neutrophils ischemia, and radiation. Because free radicals are formed as an unavoidable by-product in many biochemical processes, complex antioxidant defense mechanisms have evolved for protection. These defensive antioxidation mechanisms are normally in place and functioning.
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Q: Why are free radicals bad?
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-Free radicals are highly reactive and avidly react with proteins, nucleic acids and lipids to cause enzyme and receptor damage, DNA damage and membrane injury. Free radical membrane phospholipid damage is called lipid peroxidation and is one of the more, well studied free radical reactions.
-Free radicals can abstract a hydrogen atom (with one attached electron) from a methylene group (CH2) of fatty acids leaving behind an unpaired electron on the carbon (CH). The carbon-centered free radical rapidly rearranges to form a conjugated diene, which can react with oxygen forming a peroxyl radical (RO2). RO2 can extract another hydrogen atom (with an attached electron) to form a chain reaction. Lipid peroxidation can lead to cell membrane damage resulting in increased permeability and even membrane rupture. |
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Q: What mechanisms have cells developed to remove free radicals and minimize injury?
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-antioxidants (they either block the initiation of free radical formation or inactivate free radicals
-iron and copper can catalyze the formation of ROS, so minimizing their levels minimize ROS -enzymes that act as free radical-scavenging systems (catalse, superoxide dismutase, glutathione peroxidase) |
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Q: What are the basic reactions involved in the antioxidant defence mechanisms?
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-catalase-2H2O2 -> O2 + 2H2O
-SOD-2O2* free radicals + 2 H -> H2O2 + O2 -GSH-H2O2 + 2 glutathione peroxidase (GSH) -> GSSG + 2H2O -fenton reaction-H2O2 + Fe2 -> Fe3 + OH* + OH |
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Q: Why is overproduction of free radicals seen in a broad spectrum of diseases?
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-The reason that overproduction of free radicals is a feature of such a broad spectrum of diseases derives from the fact that oxidative metabolism is a necessary part of every cell’s metabolism. If that cell is sick or injured in any way that results in mitochondrial injury then increased production is likely to result.
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Q: Describe free radical formation using NO.
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-In ischemic events in the brain, and this includes strokes, nitric oxide is generated. One reason is that brain ischemia leads to increased nitric oxide synthase activity. After the NO (nitric oxide) is generated it combines with oxygen to form peroxynitrite. This latter compound then reacts with water to form reduced peroxynitrite and the hydroxyl free radical.
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Q: Give a summary of the role of ROS in cell injury.
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-O2 is converted to superoxide (O2-) by oxidative enzymes in the ER, mito, plasma membrane, peroxispomes and cytosol. O2- is converted to H2O2 by dismutation and thence to OH by the Cu2+/Fe2+-catalyzed fenton reaction. H2O2 is also derived directly from osidases in perosixomes. Resultant free radical damage to lipid (peroxidation), proteins and DNA leads to various forms of cell injury. Note that superoxide catalyzes the reduction of Fe3+ to Fe2+, thus enhancing OH generation by the Fenton reaction. The major antioxidant enzymes are SOD, catalase and glutathione peroxidase
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Q: What role do free radicals play in Alzheimer’s disease?
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-Alzheimer disease (AD) is a very common cause of dementia in older people. Usually AD begins with impairment of higher intellectual function and then there is progressive disorientation and memory loss. Microscopically, there is a progressive loss of neurons in certain areas of the brain. So, something is killing these neurons. Several findings suggest that oxidative stress plays an important role in this neuron destruction. Because of this two large recent studies were undertaken to determine if the intake of antioxidant nutrients would help in preventing AD. One study concluded that a high dietary intake of vitamin C and E may lower the risk of AD. The other study suggested that vitamin E from food may be associated with a reduced risk of AD.
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Q: Describe loss of Ca2+ homeostasis and its role in cell injury.
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-Usually cytosolic calcium is maintained at very low concentrations. The calcium concentration is 10,000 fold lower in the cytosol than in the extracellular fluid. Cell injury from hypoxia, ischemia, toxins, etc can lead to increased intracellular calcium. This increased calcium concentration activates enzymes such as phospholipases, which damage membranes. Proteases are activated which damage proteins in the membrane and cytoskeleton. Endonucleases are also activated which can damage DNA. All of this damage can lead to coagulative necrosis.
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Q: Describe defects in membrane permeability and its role in cell injury.
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-Almost all types of cell injury lead to some form of membrane damage/permeability. Loss of the calcium gradient is one problem. Loss of the sodium/potassium gradients is another problem occurring both from membrane damage and ATP depletion. When this happens sodium comes into the cell and potassium leaves the cell. Water follows the sodium so the cell begins filling up with water. This is called hydropic swelling and is a very common early sign of cell injury.
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Q: Describe mitochondrial damage and its role in cell injury.
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-When ATP depletion, free radical formation, loss of calcium homeostasis and defects in membrane permeability all occur the mitochondria are also affected. Depending upon the severity of injury, the mitochondria may or may not survive. If they die then the cell dies. As was described in loss of Ca2+ homestasis above, intracellular calcium increases during cell injury. Mitochondria avidly take up calcium and this poisons them resulting in mitochondrial damage.
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Q: Describe hydropic swelling.
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-intracellular edema of keratinocytes, often seen in viral infections, can also involve hepatocytes (get too much water in these cells and they become swollen), have damaged membrane and ion pumps
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Q: What happens with intracellular lipid accumulation?
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-accumulation is seen in a process called fatty change which refers to the accumulation of triglycerides in parenchymal cells, fatty infiltration refers to accumulation of fat in stromal cells, seen in fatty liver
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Q: What happens with intracellular cholesterol accumulation?
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-accumulation is seen in atherosclerosis and the hyperlipidemias
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Q: What happens with intracellular protein accumulation?
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-deposition is rare, but is seen in kidney tubules affected by glomerul-nephritis
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Q: What happens with intracellular glycogen accumulation?
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-accumulation is seen in diabetes mellitus and the glycogenoses
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Q: What happens with intracellular complex lipids and carb accumulation?
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-accumulate in the various storage disease
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Q: What happens with intracellular pigment accumulation?
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-conditions resulting from the deposition of exogenous pigmented compouds include anthracosis (C accumulation), siderosis (iron accumulation), silicosis (accumulation of silica tattoos which result form indiscretions of youth
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Q: Describe hemosiderin.
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-iron containing pigment
-the iron derived from red cell breakdown is held in the spleen, liver and marrow, combined with apoferritin, in the plasma it is transported by transferrin. the two mechanisms maintain an equilibrium between the iron contents in these three sites. when the amount of iron within the cells becomes excessive and overloads the ferritin system, it is deposited in a brown granular form (hemosiderin) |
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Q: What happens with too much iron?
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-too much iron causes oxidative stress in the liver
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Q: What are the two different forms of cell death?
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-necrosis-external stress leads to this unorganized cell death (ex: heart attach-cardiac myocytes undergo necrosis from ischemia)
-apoptosis-the cell programs its own death, organized process |
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Q: Case study: A 58-year-old female develops inflammation in one of her left leg veins (thrombophlebitis). Because of this, a blood clot (thrombus) forms in this vein. When she walks this thrombus dislodges from the vein wall and is carried through the blood stream, through the right heart and into the pulmonary artery. It lodges in a right lower lobe artery branch (pulmonary embolism). The blood supply to this portion of her lung is cut-off. She develops acute right chest pain and shortness of breath. What would the alveolar lining cells look like an hours after this occurs? What is this called?
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-If the blood flow is not restored the alveolar lining cells and all the cells dependent on this blood flow will die. This is called “coagulative” necrosis. Microscopically, the necrotic cells show nuclear pyknosis, which means the cell nucleus shrinks and becomes dark from chromatin clumping. Next, this pyknotic nucleus will break up into smaller fragments and this is called karyorrhexis.
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Q: In the above case study, is there oxygen exchange occurring in this necrotic lung? This is one reason for her shortness of breath. What would happen if a large thrombus occluded the main pulmonary branch to one lung?
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-Gangrene is a term used for ischemic coagulative necrosis, especially when the tissue begin turning black after some days. See figure 17-10 in your basic pathology textbook. Gas gangrene is from tissue necrosis from the bacteria Clostridium perfringens. Usually this infection follows penetrating wounds like in the Civil War.
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Q: What is hypertrophy?
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-refers to an INC in the size of cells, resulting in an INC in the size of the organ, there are no new cells, just larger cells, INC in size is due to synthesis of more structural components, hypertrophy is found in nondividing cells (skeletal and heart muscles) because they cannot adequately adapt to INC metabolic demands by mitotic division and production of more cells to share the work
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Q: Describe the different types of hypertrophy.
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-can be physiologic or pathologic caused by INC functional demand or by specific hormonal stimulation
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Q: What is the most common stimulus for hypertrophy of muscle?
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-INC workload, INC demand causes INC in size, the workload is shared by a greater mass of cellular components
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Q: What is atrophy?
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-shrinkage in the size of the cell by loss of cell substance is known as atrophy, a form of adaptive response and may culminate in cell death, can be physiologic or pathologic
-atrophic cells may have diminished function but they are not dead |
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Q: Describe physiologic atrophy.
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-common during early development, some embryonic structures such as the notochord and thyroglossal duct, undergo atrophy during fetal development, uterus DEC in size shortly after parturition and this is a form of physiologic atrophy
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Q: Describe pathologic atrophy.
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-depends on the underlying cause and can be local or generalized, in ischemic cell if the blood supply is inadequate even to maintain life of shrunken cells, injury and cell death may supervene
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Q: Describe the cellular changes associated with atrophy.
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-identical for whatever the stimulus, with different cells, get a DEC in organelles, by bringing into balance cell volume and lower levels of blood supply, nutrition or trophic stimulation a new equilibrium is achieved
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Q: What is hyperplasia?
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-an INC in the number of cells in an organ or tissue, usually resulting in INC volume of the organ or tissue, takes place if the cellular population is capable of synthesizing DNA, thus permitting mitotic divion, can be physiologic or pathologic
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Q: What is the mechanism of hyperplasia?
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-generally caused by INC local production of growth factors, INC levels of growth factor receptors on the responding cells or activation of particular intracellular signaling pathways
-these changes lead to production of transcription factors that tunr on many cellular genes |
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Q: Describe physiologic hyperplasia.
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-can be divided into hormonal (INC the functional capacity of a tissue when needed) and compensatory (INC tissue mass after damage or partial resection)
-example of hormonal is glandular epithelium proliferation of the female breast -example of compensatory hyperplasia is liver regeneration |
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Q: Describe pathologic hyperplasia.
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-most forms of pathologic hyperplais are caused by excessive hormonal stimulation or growth factors acting on target cells
-pathologic hyperplasia, however, constitutes a fertile soil in which cancerous proliferation may eventually arise |
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Q: What is endometrial glandular hyperplasia?
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-is abnormal hormone-induced hyperplasia, after a normal menstrual period, caused by abnormal balance between estrogen and progesterone resulting in absolute or relative INC in the amount of estrogen, with consequent hyperplasia of the endometrial glands
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Q: What is metaplasia?
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-a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type, it may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment
-the influences that predispose to metaplasia, if persistent, may induce malignant transformation in metaplastic epithelium |
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Q: What is the mechanism for metaplasia?
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-does not result froma change in the phenotype of a differentiated cell type, instead it is the result of a reprogramming of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue
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Q: What is neoplasia?
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-means the process of new growth and a new growth is called a neoplasm
-we know that the persistence of tumors, even after the inciting stimulus is gone, results from heritable genetic alterations that are passed down to the progreny of the tumor cells. these genetic changes allow excessive and unregulated proliferation that becomes autonomous (independent of physiologic growth stimuli) |
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Q: Describe fatty change.
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-describes abnormal accumulations of triglycerides within parenchymal cells, often seen in the liver because it is the major organ involved in fat metabolism, but can also occur in heart, muscle and kidney
-cause includes toxins, protein malnutrition, diabetes mellitus, obesity, and anoxia |
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Q: Describe reactive cellular changes.
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-This is a very common pathologic expression. You will hear this with Pap smear reports, on liver biopsies, etc. Reactive means that the cell is responding to some type of stress. Inflammation, viral attack, immune response, trauma can all cause reactive cellular changes. In infectious mononucleosis reactive lymphocytes are seen. Cells associated with Herpes virus infection show very reactive changes. Usually this is a reversible change and is benign. Of course, if the inflammation and stress continue on a chronic basis then metaplasia, dysplasia, etc. can occur.
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Q: Describe liquefactive necrosis.
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-characteristic of focal bacterial or fungal infections because microbes stimulate the accumulation of inflammatory cells, hypoxic death of cells within the CNS often evokes liquefactive necrosis, whatever the pathogenesis, liquefaction completely digests the dead cells, usually results in an abscess
-the end result is transformation of the tissue into a liquid viscous mass -if the process was initiated by acute inflammation the material is frequently creamy yellow because of dead white cells and is called pus |
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Q: Describe caseous necrosis.
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-distinctive form of coagulative necrosis, is encountered most often in foci of TB infection, the term caseous is derived from the cheesy, white gross appearance of the area of necrosis, on microscopic examination, the necrotic focus appears as amorphous granular debris seemingly composed of fragmented, coagulated cells and amorphous granular debris enclosed within a distinctive inflammatory border known as a granulomatous reaction, unlike coagulative necrosis, the tissue architecture is completely obliterated, usually forms an abscess like lesion
-inflammation is composed of lymphocytes and macrophages, also see macrophage giant cells microscopically (large macrophages with multiple nuclei |
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Q: Describe fat necrosis.
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-descriptive of focal areas of fat destruction, typically occurring as a result of release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity, occurs in calamitous abdominal emergency known as acute pancreatitis
-activated pancreatic enzymes escae from acinar cells, liquefy fat cell membranes and split triglyceride esters contained within fat cells, the released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification) -on histological exam, necrosis takes the form of foci of shadowy outlines of necrotic fat cells, with basophilic calcium deposits, surrounded by an inflammatory reaction |
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Q: Describe calcification.
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-When caseous necrosis and fat necrosis heal they frequently show what is termed calcification. This means there is deposition of calcium salts in this injured tissue. It causes the involved tissue to become hard or bone-like. Because it is bone-like and dense it can be seen by X-ray. Finding a focus of calcification in the lung by chest X-ray is a common finding with active or inactive T.B. Calcification is found in other diseases. Mammography is based on the detection of calcifications in breast cancers.
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Q: Describe how cells can undergo self-induced death.
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-Every day in our bodies “billions” of cells are eliminated or lost and “billions” more produced. Normally, most of these lost cells undergo apoptosis, which is a very normal way cells which are old, not needed, etc are eliminated. Every cell has a program using enzymes called caspases to undergo programmed cell death. For example, when a woman stops breast feeding her child the lactating ducts are no longer stimulated by the pituitary hormone prolactin. Her breast ducts undergo involution through apoptosis. So, this is a normal process. As opposed to necrosis, which elicits inflammation, apoptosis elicits no inflammation.
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Q: Describe apoptosis in some injurious processes.
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-When DNA is damaged due to ionizing radiation, free radicals, etc. this up regulates the expression of p53 which is a transcription factor that is involved in activating genes involved in the cell cycle and apoptosis. If the DNA damage is too severe then p53 induces the production of BAX, a protein which appears to damage mitochondria, and the cell undergoes apoptosis. Many cells express a Fas receptor on their cytoplasmic membrane surface. If these cells become virally infected or undergo malignant transformation, T lymphocytes will attack these cells. The cytotoxic, CD8T cells express a Fas ligand protein, which interacts with the Fas receptor. This causes activation of a pathway leading to caspase activation and apoptosis of the virally infected or malignant cell.
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Q: Describe the regulation of apoptosis.
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-As might be expected, the apoptotic pathways are heavily regulated by proteins, which induce apoptosis, and proteins that prevent apoptosis. One of the first anti-apoptotic proteins to be described was in a B cell lymphoma and is called Bcl-2. Good experimental evidence shows that in a neoplasm called a B cell follicular lymphoma, Bcl-2 is overexpressed and this probably is the reason that the lymphocytes, the malignant cells in this lymphoma, do not die and accumulate to form neoplastic masses of lymphocytes.
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