Veterinary Medicine Notes > University Of Nottingham Veterinary Medicine Notes > Principles of Clinical Veterinary Science Notes
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1. Introduction Pathology investigates the essential nature of disease and is usually summarised as the functional and morphological changes (gross and microscopic) in tissues and fluids of the body during disease.
2. Cellular response to injury There are numerous causes of cell injury that can be classified in many different ways. Some causes, such as physical trauma, viruses and toxins are extrinsic causes, whereas others such as spontaneous genetic mutations are intrinsic. Other causes can have both extrinsic and intrinsic components, such as workload imbalance, nutritional abnormalities and immunologic dysfunctions. General mechanisms of injury include ATP depletion, membrane damage, disturbances of cellular metabolism and genetic damage.
2.1 Reversible cell injury Reversible cell injury is injury from which the cell can adapt or recover and return to normal function. It is also known as cell degeneration. Acute cell swelling is a type of reversible cell damage. Acute swelling causes an increase in size and volume of a cell resulting from an overload of water caused by the inability of a cell to maintain homeostasis. It is accompanied my modification and degeneration of organelles. In a normal cell, ATP sodium potassium pumps drive sodium out of the cell whilst moving potassium into the cell. For every potassium molecule moved into the cell, three sodium molecules are moved out of the cell. Water moves passively following the osmotic gradient created by the movement of sodium and potassium. The ATP sodium potassium pump therefore is the key mechanism in water regulation within the cell. The main mechanisms for failure of water regulation are hypoxia-induced failure of ATP synthesis and membrane damage. Hypoxia results from any defect in the transportation of oxygen from the lungs to its role as final acceptor of electrons molecule in oxidative phosphorylation. Ischemia is reduced blood flow to a region of the body, usually as a result of an obstruction in blood supply. A lack of oxygen supply inhibits oxidative phosphorylation, and cellular ATP levels become depleted. Anaerobic glycolysis can provide ATP for survival for a short time. Some cells, such as neurones, cannot respire anaerobically and so are prone to hypoxic injury. Ultimately a deficiency of ATP causes the sodium potassium ion pump to stop, resulting in a loss of cell volume control as the osmotic gradient is lost.
Damage to cell membranes destroys their selective permeability. Failure of the membrane is caused by chemical modification of the phospholipids by free radicals, covalent binding of toxic chemicals, interference with ion channels and insertion of transmembrane protein complexes. Acute cell swelling results in organ swelling and decreased specific gravity. The influx of water dilutes the cytoplasmic matrix of cells, giving them a pale, finely vacuolated appearance known as cloudy swelling. If oxygen supply is restored or the cell membrane injury repaired, the cell will return to its normal state. This must occur before the 'point of no return'. After this point the changes in the cell are no longer reversible. Fatty change or hepatic steatosis is a further reversible type of cell injury. Lipidosis is the accumulation of triglycerides and other lipid metabolites within parenchymal cells. Normally, free fatty acids are delivered to hepatocytes as chylomicrons. Fatty acids are then converted to triglycerides within the cell, and then to lipoproteins via a lipid acceptor protein molecule. The lipoproteins are then secreted. Hepatic lipidosis can occur as a result of:
Excessive delivery of free fatty acids Decreased beta oxidation of fatty acids to ketones due to mitochondrial injury. Impaired synthesis of apoprotein. Impaired combination of triglycerides and protein to form lipoprotein. Impaired secretion of lipoproteins.
Microscopically, hepatocytes with lipidosis are highly vacuolated. The nucleus may be displaced to the periphery.
2.2 Irreversible cell injury and cell death a) Necrosis Necrosis is defined as the specific morphological changes indicative of cell death in a living animal. Cell death can occur in many ways. Extremes of temperature or direct trauma can cause instantaneous cell death. Oncosis is cell death after irreversible cell injury by hypoxia, ischaemia and direct cell membrane injury. Acute swelling as a result of hypoxia can cause irreversible cell injury. If oxygen supply is not restored from hypoxia, the switch the anaerobic metabolism causes intracellular acidosis. This disrupts protein synthesis machinery, causes cell membrane defects and lysosome rupture releasing enzymes such RNAses, DNAses that break down the contents of the cell. Ultimately this leads to cell death (necrosis) and rupture. It is thought that there is a link between calcium influx to a cell and the 'point of no return' from reversible to irreversible cell injury.
Free radicals, such as free oxygen radicals, can damage cell membranes irreversibly. Oxygen free radicals are produced by phagocytic cells in inflammatory lesions and account for most of the damage to surrounding tissue. On post-mortem examination, it is important to distinguish necrotic tissue (cells that died before somatic death) from tissues that died with the rest of the animal (post-mortem autolysis). Autolysis is the self-degradation of cells and tissues by enzymes normally present in them. The morphological appearance of oncotic necrotic cells varies with the tissue involved. At the cellular level, pyknosis, karyorhexis and karyolysis may be present:
Pyknosis: the nucleus is shrunken, dark, homogenous and round due to irreversible condensation of chromatin. Karyorhexis: the nuclear envelope is ruptured, giving the nucleus a fragmented appearance. Karyolysis: the nucleus is pale due to the dissolution of chromatin.
Grossly, necrotic tissue tends to be pale, soft and friable, and well demarcated from viable tissue by an inflammatory border. An exception to this is when blood oozes into necrotic tissue from damaged blood vessels in adjacent viable tissue. This is common in renal infarcts. Necrotic lesions can be classified to allow better description. More than one type of necrosis may be seen in a tissue. The types of necrosis include:
Coagulative Liquefactive Suppuration Caseous Fat Gangrenous
Coagulative necrosis is characterised by preservation of the basic cell outlines of necrotic cells. Cytoplasm is homogenous and eosinophilic due to coagulation of proteins. This type of necrosis can occur anywhere except in brain tissue, but it is classically seen in muscle, kidney and liver tissue. Coagulative necrosis indicates cell death as a result of hypoxic cell injury as seen in local blood loss or shock, such as in an infarct. Liquefactive necrosis is usual kind of necrosis seen in the CNS, although the neuron bodies themselves initially show coagulative necrosis. The cystic areas are cleared by macrophages surrounded by abundant lipid, giving the macrophages a vacuolated appearance. These macrophages are known as Gitter cells. In other tissues, focal infection by pyogenic bacteria leads to release of enzymes from leukocytes. This forms a focal liquid collection of necrotic neutrophils and tissue debris. If the lesion persists, loss of fluid results in it becoming more caseous.
Suppurative necrosis is characterised by pus formation from dead and dying neutrophils. Caseous necrosis implies conversion of dead cells into a granular friable mass grossly resembling cottage cheese. Compared to coagulative necrosis, this is an older and more chronic lesion associated with poorly degradable lipids of bacterial origin. Fat necrosis can occur in three ways:
Enzymatic necrosis of fat (pancreatic necrosis of fat): destruction of fat in abdominal cavity adjacent to pancreas by pancreatic lipases in pancreatic fluid escaped from duct system. Traumatic necrosis of fat: where adipose tissue is crushed - can occur after dystocia or recumbancy in cattle. Necrosis of abdominal fat of cattle: large masses of necrotic fat in the mesentery, omentum and retro-peritoneum. The cause is unknown.
Gangrenous necrosis is divided into dry gangrene, moist gangrene and gas gangrene. The initial lesion is coagulative.
Moist gangrene is defined as an area of necrotic tissue which is further degraded by the liquefactive action of saprophytic bacteria that usually cause putrefaction. Areas of coagulative necrosis that can be contaminated by extrinsic bacteria (such a limbs, lungs and intestine) are affected. Tissue becomes soft, moist and reddish-brown to black. Foulsmelling gas may be produced by the bacteria. Dry gangrene is coagulation necrosis secondary to an infarction followed by mummification due to a depletion of water. It occurs at extremities and can be a result of ingesting toxins. The tissue is dry, shrivelled and brown to black in colour. Parts of the affected tissue may slough. Gas gangrene occurs when anaerobic bacteria proliferate in necrotic tissue at penetrating wounds. When necrosis of the tissue occurs, the bacteria can proliferate. Tissues are dark red to black with gas bubbles and a fluid exudate that may contain blood.
b) Apoptosis Apoptosis is programmed cell death. Apoptosis prevents inappropriate cell proliferation. Apoptosis can be divided into an initiation stage, where caspases become catalytically active, and an execution stage, where these enzymes act to cause cell death. The initiation phase can be via the extrinsic (death receptor initiated) pathway or the intrinsic (mitochondrial) pathway. Death receptors include TNFR1 and Fas.
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