Equine Pathology Workbook

EQUINE MASSAGE THERAPY EQUINE PATHOLOGY

Chapters 1-42

EQUINE PATHOLOGY SECTION 1 CHAPTER 1-4: RESPONSE TO INJURY

CHAPTER ONE: TYPES OF CELLULAR INJURY

Definitions:

Pathogen – ___________________________________________________________________________

Pathogenesis – ________________________________________________________________________

Dysfunction – _________________________________________________________________________

Etiology – ____________________________________________________________________________

Idiopathic – ___________________________________________________________________________

Iatrogenic – ___________________________________________________________________________

Necrosis – ____________________________________________________________________________

Apoptosis – ___________________________________________________________________________

Ischemia – ____________________________________________________________________________

Hypoxia – ____________________________________________________________________________

Pyknosis – ____________________________________________________________________________

Karyorrhexis – _________________________________________________________________________

Karyolysis – ___________________________________________________________________________

Autolysis – ____________________________________________________________________________

Heterolysis – __________________________________________________________________________

Introduction to Pathology:

The body exists in an ever-changing environment. It therefore must be able to change and respond to external stimuli in order to survive. Just as the body has different levels of organization, from atoms to entire organs, our body’s response to its environment can be considered on many levels.

Response levels include:

1. Molecular

2. Cellular

3. Tissue

4. Organ

5. System

6. Body

In pathology response level is dependent on three factors:

1. The first is the of the pathogen. With a weak pathogen, response level tends to be lower while a strong pathogen elicits a higher response level.

2. Second, the of pathogen the body is exposed to has an effect on response level. With a small dose of pathogen lower response levels are usually sufficient while a large dose generally requires a higher response level.

3. The third factor governing response is the ability of the body’s to cope with a particular pathogen. Individuals in general good health, that have a balanced diet and are neither geriatric or very young have a stronger immune response than those who are already sick, undernourished, or are extremely old or young. Cellular Injury Healthy cells are dynamic and are constantly responding to stimuli in the external environment. This type of adaptation is a normal effort to maintain homeostasis. When a cells ability to adapt is exceeded, dysfunction and cellular injury occur. A stimulus that causes dysfunction is considered a . For example, a virus may take over the nucleus of a cell and alter the genetic material being replicated there, or the tearing of muscle fibres will prevent them from contracting.

The extent to which a particular pathogen can cause cell injury depends on the:

1. ________________________________________________________________________

2. ________________________________________________________________________

3. ________________________________________________________________________

4. ________________________________________________________________________

Some types of cell damage can be reversed once the insult is removed, while other types of cell injury are permanent. In cases where the pathogen is stronger than the cell, the damage to the cell may result in cell death.

Reversible & Irreversible Cell Damage

Initially, hypoxic injury is reversible. There is a decrease in respiration and ATP production is reduced. In order to attempt to maintain basic cell function some ATP production is sustained through . This inefficient process leads to a buildup of pyruvic acid inside the cell. Pyruvic acid is turned into acid, which continues to build up in the cytosol, causing the cytosol to become acidic. The low pH damages the membrane of the rough endoplasmic reticulum (RER), causing a decrease in protein synthesis. In low grade, sustained cases of hypoxia, amino acids are made into lipids and stored in cells capable of fat storage. The shortage of ATP also causes the sodium-potassium-ATPase to decrease its activity leading to an increase in intracellular sodium and a decrease in intracellular potassium. This disrupts the osmotic balance between the ECF and the ICF, and causes an influx of water seen as cellular . These changes are reversible. The time it takes for irreversible damage to occur will mainly depend on the cell type involved. If hypoxic conditions persist, the pH decreases to a point where enzymes are released into the cytosol. These enzymes attack the membranes of organelles such as the mitochondria as well as the entire cell membrane. Membrane damage is characterised as decreased phospholipids, cytoskeleton disruptions as well as free radical production all leading to a loss of membrane integrity. With loss of membrane integrity, we see an influx of ions into the cell. Calcium acts to further damage the mitochondria and the structural proteins of the cell. At this point the cell may continue to auto digest or heterolysis by a leukocyte may occur. In either case digestive enzymes may be spilled out into the ECF causing injury to the membranes of neighbouring cells. Cell death is called . Nuclear Changes during Cell Injury Cell injury often causes changes to the membrane and the contents of the nucleus. There are three patterns in nuclear injury that are seen associated with cellular injury.

______ - indicated by nuclear shrinkage and an increase in basophilia _– indicates fragmentation of the pyknotic (shrunken) nuclei – digestion of the nucleus by lysosomal enzymes

Types of Cellular Injury Some major types of cellular injury include hypoxic injury, chemical injury, viral injury and age- related injury.

Hypoxic injury is common and has many causes. For a cell to function normally it requires a constant input of oxygen and nutrients and the continuous removal of waste products. This occurs through the exchange of molecules between the extracellular fluid and the cytosol. For microscopic organisms this exchange can occur directly between the ECF and every cell of the organism. For complex organisms such as the horse, nutrient delivery is facilitated by the circulatory system. A fine meshwork of capillaries feed every cell in the body. Nutrients diffuse out of the blood into the ECF where the nutrients are available to the tissues. Reduced oxygen availability to a cell or tissue is called hypoxia. One cause of hypoxia is . Ischemia is the reduced perfusion of blood to an area or tissue. Without blood flow there is insufficient oxygen delivery to meet the tissue’s metabolic needs. Once this occurs injury to the cell begins. Chemical agents can contain molecules that interfere with membrane integrity or alter the function of membrane transport proteins, ultimately hampering the control of the content of the ICF, and thereby disrupting homeostasis. The body converts some of the chemicals into toxic metabolites such as , which need to be neutralized. If not, the cell can become overwhelmed. Viruses have two mechanisms by which they cause cellular injury. The first is . In this case the virus inserts its own genetic information into the nucleus of the host cell, thereby using the cell’s organelles to replicate viral components and produce more viruses. The second mechanism is . In this case the virus triggers the host cell to become cancerous and replicate rapidly and uncontrollably, spreading the virus as the tumour grows. Damage occurs to cells as they age. In normal cell function, metabolites known as free radicals are created. These molecules have a lone, unpaired in the valance shell of one of the atoms. This unpaired electron has an affinity for phospholipids and can disrupt the membrane of the cell and of organelles. Normally free radicals are neutralized by peroxisomes, but as the cell ages peroxisomes are reproduced more slowly and greater damage is done to the cell by free radicals. Cell Death There are two causes of cell death. Cases of extreme, irreversible cell injury leading to cell death is called necrosis, while genetically controlled cell death without cell injury is called . Necrosis is always pathological and is generally not restricted to single cells. Even if only one cell dies, the process will damage the cells neighbouring it. An inflammatory reaction always occurs with necrosis. Apoptosis is not always pathologic, meaning it is a part of the body’s normal physiological process. Apoptosis occurs without pre-existing cell damage and is generally limited to single cells, without bystander damage nor an inflammatory reaction.

Types of Necrosis

Coagulative Necrosis

Liquefactive Necrosis

Caseous Necrosis

Gangrenous Necrosis

Fibrinoid Necrosis

CHAPTER 1 REVIEW QUESTIONS

1. Define:

a. Pathogen __________________________________________________________

b. Etiology ___________________________________________________________

c. Idiopathic _________________________________________________________

d. Iatrogenic _________________________________________________________

e. Hypoxia ___________________________________________________________

f. Ischemia __________________________________________________________

g. Pyknosis __________________________________________________________

h. Karryorrhexis ______________________________________________________

i. Karyolysis _________________________________________________________

2. How the body responds to a pathogen is dependent on what 3 factors?

________________________________________________________________________

3. How does ischemia/hypoxia result in irreversible injury? __________________________

4. What are the 4 types of cell injury? ___________________________________________

5. Compare necrosis and apoptosis _____________________________________________

6. List and briefly describe the 5 types of necrosis _________________________________

________________________________________________________________________

CHAPTER TWO: CAUSES OF CELLULAR INJURY

Definitions

Disease – ______________________________________________________________________

Immunity – ____________________________________________________________________

Mutation– _____________________________________________________________________

Heritable – _____________________________________________________________________

Endotoxin – ____________________________________________________________________

Exotoxin – _____________________________________________________________________

Ectoparasite – __________________________________________________________________

Nematode – ___________________________________________________________________

Exogenous – ___________________________________________________________________

Endogenous – __________________________________________________________________

Introduction Cells respond to stress by

. If the cell’s ability to adapt is exceeded by external forces, changes take place in the cells that are unrelated to the normal function of the cell. Some changes are reversible once the external stress is removed while other cellular changes are irreversible, and ultimately lead to necrosis of the affected cell. A cell’s response to a pathogen is partially determined by the virulence, dose, intensity and duration of exposure to the pathogen, as well as by the state of the cell itself. Factors such as nutrition, blood supply, general health and genetics have an influence on the cell’s ability to adapt and resist disease. Generally, tissues that are in good health, that have access to a complete array of nutrients, and have an extensive blood supply resist disease better than tissues without these assets. The influence of genetics is less well defined, however certain individuals tend to be resistant to particular pathogens while other individuals are more susceptible. The relation between genetics and immunity is strengthened when we consider that certain diseases are more prevalent in particular species or breeds, while other species or breeds are resistant to that pathogen.

The way in which a cell responds to a pathogen is governed by the of pathogen involved as well as by the cell type. By understanding the mechanisms used by various types or classes of pathogens one can predict the responses that will be generated in the cell. Causes of Cellular Injury Some major types of cellular injury include hypoxic injury, chemical injury, physical injury, biological injury, immune-mediated responses, genetic mutations, age related injury & nutritional imbalances. 1. Hypoxia Hypoxia is the most common mechanism of cellular injury. Hypoxia is defined as a decrease in the oxygenation of tissues and has its most profound effect on aerobic cellular metabolism. The cells must rely on anaerobic energy production which results in decreased energy production, decreased protein synthesis, lipid deposition and an increasingly acidic environment.

There are three general causes for hypoxia:

The first is

. Ischemia is a reduction in tissue perfusion. Ischemia can be

caused by arterial constriction, venous congestion, or haemorrhage.

2. The second cause of hypoxia is decreased intake of oxygen from the . This occurs in cases where the environment has little or no oxygen, such as under water or at very high altitudes, or in cases of respiratory failure or disease. 3. The third scenario in which hypoxia occurs is instances where the blood has a decreased capacity to oxygen. Anemia is a reduction in the number of circulating red blood cells (RBC’s). The effect of anemia is that the blood cannot carry a normal amount of oxygen as haemoglobin molecules located inside RBC’s is the major carrier of oxygen in the blood. Anemia can be caused by genetic disease, hormonal imbalances, or insufficient dietary intake of iron. Another cause for a reduction in the carrying capacity of blood for oxygen is carbon monoxide poisoning. Haemoglobin has a greater affinity for carbon monoxide than it does for oxygen and therefore binds more readily to carbon monoxide molecules than to oxygen molecules. 2. Chemical Damage Chemical agents can contain molecules that interfere with membrane integrity or alter the function of membrane transport proteins, disrupt osmotic balance or enzyme/cofactor function ultimately hampering the control of the content of the ICF, and thereby disrupting homeostasis. Chemical damage can be caused by a wide variety of substances, many of which may not be normally considered “chemicals”. Substances such as poisons, venoms and drugs, and even molecules like glucose or vitamins if they are present in excess can affect homeostasis.

uses the particular effects of a drug to augment cell and tissue function in order to restore it to normal. In other cases, drugs, which are meant to be therapeutic, cause damage to another tissue or type of cell as a side effect. For example, barbiturates cause damage to liver cells as they are degraded into their metabolites, which cause free radical damage. High intracellular glucose levels result in elevated intracellular calcium ion levels. As we have seen in hypoxic injury, an influx in calcium damages mitochondria and ultimately leads to cell necrosis.

3. Physical Injury

is a leading cause of cell injury. Some cells are damaged as their structures such as the cell membranes and the cytoskeleton are mechanically torn apart by force. These cells are generally consumed by phagocytic white blood cells (WBC’s). Trauma in the form of pressure can cause local ischemia and may alter the membrane potential of certain cells. cause damage to cells by two mechanisms. Exposure to low temperatures causes vasoconstriction and may cause ischemia as well as reducing reaction rate and affecting the fluidity of membranes. Extreme low temperatures cause water in the cytosol to freeze and expand, rupturing the cell membrane and causing necrosis. High temperatures increase metabolic rate and cause acidosis due to a buildup of carbon dioxide in the blood. Low pH damages membranes and proteins. Exposure to extreme high temperatures causes dehydration and combustion, or burning, of the hydrocarbon chains associated with cell structures. Extreme can cause mechanical damage to cells in much the same manner mechanical pressure dose. Sudden changes in atmospheric pressure cause structures and fluids in the body to expand or compress, without giving the rigid structures in the body time to adjust. For example, the rapid expansion of a fluid can exceed the membrane integrity causing the cell to rupture. Atmospheric pressure also affects the relative partial pressures of gasses inside the body. At low atmospheric pressure, the partial pressure of oxygen in the environment is lower than the partial pressure of oxygen in venous blood. This prevents oxygen from diffusing from the lungs into the blood causing hypoxia. or radiant energy directly causes cell death at high intensities as it ionizes the cytoplasm and effectively disrupts all metabolic reactions. At lower intensities radiation disrupts the replication of genes and leads to mutations that may alter cell function. Sources of radiation include nuclear energy fromweapons or power plants, x-rays, and ultraviolet rays from the sun. energy generates heat and causes burn damage in the same way high temperature does. Electricity also disrupts the electromagnetic gradients formed by cells, causes the activation or inactivation of voltage-gated membrane channels, and affects the membrane potential of electrically conductive cells such as muscles and nerves.

4. Biological Agents Biological agents range in size from microscopic to large complex organisms. Biological agents include viruses, bacteria, protozoa, ectoparasites and nematodes. have two mechanisms by which they cause cellular injury. The first is cytologic. In this case the virus inserts its own genetic information into the nucleus of the host cell, thereby using the cell’s organelles to replicate viral components and produce more viruses. The second mechanism is oncogenic. In this case the virus triggers the host cell to become cancerous and replicate rapidly and uncontrollably, spreading the virus as the tumour grows. Some are harmful while others are beneficial to normal body function. For example, the flora of the gastrointestinal tract aid in the breakdown of food molecules, produce some vitamins and even help to protect the gastrointestinal tract from harmful agents. Other bacteria harm the body through the production of . Certain bacteria produce toxic molecules and either coat themselves in these molecules or else secrete these molecules into their environment. Toxins found on the surface of bacteria are called . Other bacteria only release their toxic molecules when they die and are broken down. These molecules are called . Both exotoxins and endotoxins usually have an effect on the cell by disrupting receptors on the cell membrane or interfering with the activity of mediator molecules. Occasionally there will be an explosion in the population of normal bacteria and bacterial colonies may spread to regions of the body that are not designed to support bacteria. In these cases, the bacteria damage cells and necrosis occurs. We see this as pus when the normal bacteria living on the outside of skin enters a wound. When there is a bacterial population in the blood we call this . Like bacteria, are unicellular organisms. Protozoa damage tissue as they consume organic materials as food. Some protozoa perform phagocytosis while others have pores that act like mouths. In horses the major impact protozoa have on tissues is when they enter a cyst phase and remain in tissues such as muscle and nerves. Protozoal cysts release chemicals that irritate the surrounding tissues and trigger an immune reaction. live on the skin surface and compete with the host organism for nutrients. For example, fleas bite the skin and compete with the host tissues for blood. Other ectoparasites inject venoms or chemicals into the host tissues that cause lysis of particular cells, or block certain receptors. are a class of internal parasites that are commonly called . Like ectoparasites, many nematodes compete with the host for nutritional resources. Other nematodes damage tissues as they consume them, or during migration. In the horse, blood vessels and even the heart are damaged by migrating nematodes. Still other nematodes produce toxic waste products that chemically interfere with normal cell function.

5. Immune Mechanisms In any immune response, cells are damaged through the phagocytic activity of . In cases where there is no pathogen present, the immune response itself is acting to damage normal cells. This type of reaction can be classified into two categories: exogenous and endogenous reactions. During an immune reaction, the body’s immune system attacks antigens in the body’s own cells. This is an reaction. Diseases such as haemolytic anemia and arthritis are autoimmune diseases. An immune reaction, there is an exaggerated response from the immune system to an external antigen that is not harmful to the body. are a common example of an exogenous immune reaction. 6. Genetic Mutation Changes, or mutations, in the genetic makeup of a cell can have three outcomes: If a single nucleotide is changed it is likely that there will be on the cell’s function. If a larger change occurs there may be an or decrease in the function of an enzyme or protein. In some cases, mutation is with survival and necrosis or apoptosis occurs. Any change in the genetic makeup of a cell is passed on to subsequent generations of cells. This means that mutation is heritable. Mutations can occur during the production of zygotes (sperm and eggs), during fertilization, or during the replication of adult cells (somatic mutation). 7. Age Related Injury Damage occurs to cells as they age. In normal cell function, metabolites known as free radicals are created. These molecules have a lone, unpaired electron in the valance shell of one of the atoms. This unpaired electron has an affinity for phospholipids and can disrupt the membrane of the cell and of organelles. Normally free radicals are neutralized by , but as the cell ages peroxisomes are reproduced more slowly and greater damage is done to the cell by free radicals. 8. Nutritional Imbalances Nutrition is essential for the normal function of cells. Certain deficiencies or imbalances can affect the ionic balance of cells, the ability to neutralize free radicals, the formation of coenzymes and cofactors and the ability to build cell structures. Essential nutrients are a group of nutrients that must come from the external environment in order for normal cell function. The essential nutrients include assorted vitamins and minerals as well as an energy source and water. . This is a deficiency in a vitamin or group of vitamins. In horses, there is little incidence of hypovitaminosis, however high-performance horses may not receive sufficient levels of vitamin E from their diets. One type of nutritional imbalance is hypovitaminosis or Hypervitaminosis is an excess of a particular vitamin. Severe hypervitaminosis can lead to vitamin . Again, in a natural diet there is little evidence of hypervitaminosis in horses, but over supplementation of vitamin A and vitamin D occurs.

imbalances have the most effect on tissues during fetal development and growth or during intense physical activity. In horses, mineral imbalances most often affect the musculoskeletal system and result in abnormal growth in the young and poor performance in mature animals. Performance is affected by imbalances or deficiencies. Minerals such as calcium, potassium, sodium, chlorine, selenium and cobalt impact functions such as nerve conduction, muscle contraction, ATP synthesis as well as acting as cofactors for enzymes, or having an interaction in the bioactivity of vitamins.

CHAPTER 2 REVIEW QUESTIONS

1. Define:

a. Disease ___________________________________________________________

b. Mutation __________________________________________________________

c. Heritable __________________________________________________________

2. What are the 3 outcomes of a cell responding to stress? __________________________

________________________________________________________________________

3. Give 3 causes/examples of hypoxia. __________________________________________

________________________________________________________________________

4. How does medicine become harmful? ________________________________________

5. What are some physical causes of cell damage? _________________________________

6. What are the 2 ways viruses cause cell injury? __________________________________

________________________________________________________________________

7. What is the difference between exotoxins and endotoxins?

________________________________________________________________________

8. What is the difference between endogenous & exogenous immune reactions?

________________________________________________________________________

9. What are the 3 effects of a genetic mutation? __________________________________

________________________________________________________________________

10. What are peroxisomes? ____________________________________________________

11. What are your 3 nutritional imbalances? ______________________________________

________________________________________________________________________

CHAPTER THREE: CELLULAR AND SUBCELLULAR RESPONSES TO INJURY

Definitions

Atrophy – ______________________________________________________________________

Hypertrophy – __________________________________________________________________

Hyperplasia – ___________________________________________________________________

Metaplasia – ___________________________________________________________________

Dysplasia – ____________________________________________________________________

Anaplasia – ____________________________________________________________________

Neoplasia – ____________________________________________________________________

Benign – _______________________________________________________________________

Malignant – ____________________________________________________________________

Metastasis - ____________________________________________________________________

Ossification – ___________________________________________________________________

Dystrophic Calcification – _________________________________________________________

Metastatic Calcification – _________________________________________________________

Subcellular Alterations To fully understand the effects of stress on a cell we must examine the alterations that occur in the organelles and in the membranes that surround the cell and the organelles. In exploring the causes of cellular injury, we have started to understand some of the changes that occur in different parts of the cell. A more in-depth exploration of these changes will help to clarify how cellular injury occurs. are some of the most susceptible areas of the cell to injury. Events such as hypoxia or toxicity have a direct effect on the integrity of membranes. Acidity in the cell and in the extracellular fluid (ECF) causes the of membrane proteins. As denaturation occurs, membrane proteins lose their function. Protein pores no longer regulate the passage of molecules into and out of the cell, protein receptors no longer are able to bind with chemical messengers and enzyme mediated reactions that govern the active transport of

molecules no longer function. Some chemicals act to disrupt the lipid bilayer of membranes. These chemicals break down the phospholipids that make up the bulk of the membrane, thereby allowing the free passage of molecules into the cell’s internal environment. of cells. For example, during the hypertrophy of tissues mitochondria increase in number in order to meet the increased metabolic demands of the larger cell. Similarly, with atrophy, a decrease in the number of mitochondria occurs. With certain pathological conditions, a change in the size of the mitochondria is seen. With alcoholism, an increase is seen in the size of mitochondria, while some nutritional deficiencies cause a decrease in the size of mitochondria. During some physiological process, there are changes seen in the Like cell membranes, the is susceptible to denaturation in acidic conditions. Once the integrity of the cytoskeleton is compromised many cells cannot carry out their normal function. WBC’s cannot perform cytoplasmic streaming to get to the site of injury or infection, cilia in the respiratory tract cannot function as part of the mucocilliary elevator and sperm lose their motility. are also damaged during cell injury. Once the membrane surrounding a lysosome loses integrity the digestive enzymes contained within the lysosome spill out into the cytosol and begin to digest cellular structures. This is the mechanism by which autophagy occurs. Cellular Adaptations Like there are patterns in inflammation there are patterns seen in the changes cells undergo in response to injury or stress. The type of change seen depends on the type of injury and the type of cell involved. Some changes are reversible while others are irreversible. Atrophy Atrophy is defined as a decrease in the size of a cell or tissue. Atrophy is not always a pathological change and it can be reversible. When a cell or tissue has a decrease in activity the cell breaks down some of its organelles, as there is a decrease in metabolic demand. For example, when an individual stops the metabolic demands of muscle tissue decreases and muscle cells loses mass as they reduce the number of contractile fibres and mitochondria found in each cell. Some cases of atrophy are associated with a pathological state. Any pathological condition that reduces the activity of a tissue will cause atrophy. For example, a requires that a bone or limb be stabilized by a cast, pin or splint. Forced immobility has the effect of decreasing metabolic demands in the muscle tissue of the area. In response to decreased metabolic demands the muscle cells decrease in mass. Some causes of atrophy include:

Hypertrophy Hypertrophy is the opposite of atrophy. Hypertrophy describes an increase in cell mass/size. Again, this process can be either physiological or pathological and can be reversible. A normal process such as exercise increases the metabolic demand on muscle tissue and causes a subsequent increase in tissue mass. Pathological conditions that increase the workload of a particular tissue or organ cause hypertrophy in that tissue in an attempt to for deficiencies in another area of the body. For example, the left ventricle of the heart becomes hypertrophic in an attempt to compensate for a leaky heart valve. Hyperplasia Hyperplasia is an increase in the number of cells in a tissue or organ. There is no change in the size or function of the cells that make up a hyperplasic tissue. Hyperplasia can be a normal physiological phenomenon when it is associated with normal growth or repair of an organism but can also be pathological when there is an uncontrolled increase in the number of cells in a tissue. Cell types that normally undergo , such as the epithelial cells of the skin, urinary track and gastrointestinal tract tend to become hyperplasic in response to stress or injury. The mechanism controlling hyperplasia involves over expression of the gene controlling proliferation. Hyperplasia may be reversible if the injurious agent is eliminated. Metaplasia Metaplasia describes a change from one type of cell to another. Often with a change in cell type there is some change in function. Chronic and inflammation is the most common cause of metaplasia. The irritated cells become a type of cell that can tolerate the irritation better. During a metaplastic change, the undifferentiated stem cells of the tissue undergo a shift that results in the differentiation of a cell type that is more able to withstand a particular stress. Metaplasia is reversible once the inflammation and irritation are removed. An example of metaplasia can be seen in the epithelial lining of the respiratory tract of smokers. In a non-smoker the airways are lined with ciliated columnar epithelium while the airways of smokers are made of non-ciliated squamous cells. Dysplasia Dysplasia refers to a loss of cell or tissue organization. In dysplastic tissue the cells are not uniform in morphology or function. Many of the cells in dysplastic tissue are immature cells while the number of functional, mature cells is decreased. Dysplasia is considered a precursor to , however when the causative pathogen is removed there is potential for the affected tissue to return to normal. Anaplasia Anaplasia is the loss of cell differentiation. Anaplastic cells have no discernable functional characteristics. The morphology of the cells in anaplastic tissue no longer resembles normal cells of any type. Anaplastic cells tend to have enormous nuclei with abnormally bunched chromatin. Anaplastic cells tend to undergo frequent mitosis with abnormalities in that process. Anaplasia is always considered as anaplasia is a cancerous change. Anaplasia is irreversible.

Neoplasia Neoplasia is the development of new, abnormal tissue. Neoplasia is the development of a cancerous tumor. It is characterized by the uncontrolled, progressive multiplication of cells and is irreversible. It is thought that the cells of a neoplasia are all descended from a single mutated cell and therefore all carry the same genetic mutation. Neoplasms, or cancer tumors, are divided into two categories; those that are and those that are . Benign tumors tend to be localized and slow growing. Usually benign tumors cause no dysfunction in a tissue and do not spread to other regions of the body. Benign tumors do not tend to reoccur once they are removed. Malignant tumors are fast growing, invasive growths that cause dysfunction in affected tissues. Malignant tumors tend to readily, meaning they easily spread to distant locations in the body. Even with aggressive and rapid treatment malignant neoplasia usually results in death. Common forms of neoplasia include:

Tissue Adaptations

Ossification Ossification describes the conversion of connective tissue into bone. Ossification can be a physiological process through which bone grows and repairs. Pathological ossification occurs in response to chronic irritation of connective tissue. Repeated trauma to joint capsules and ligaments causes a process called to occur at the periphery of the joint. Conditions such as ringbone and side bone are a result of pathologic ossification. Calcification Calcification describes the deposition of calcium, along with small amounts of other minerals, into soft tissue. Calcification is a pathological process and is usually quite painful. Calcium can be deposited into muscle, ligaments, tendons, the periosteum, and other soft tissues. There are two types of calcification. The first type is dystrophic calcification . In this process calcium is deposited into tissue. There are no anomalies in blood calcium levels associated with dystrophic calcification. The second type of calcification is metastatic calcification . Metastatic calcification involves the deposition of calcium into normal, healthy tissue as a result of . Hypercalcemia is a condition where the circulating levels of calcium ion are higher than normal. Common causes of hypercalcemia include renal failure and lymphoma.

CHAPTER 3 REVIEW QUESTIONS

1. Define:

a. Atrophy ___________________________________________________________

b. Hypertrophy _______________________________________________________

c. Hyperplasia ________________________________________________________

d. Metaplasia ________________________________________________________

e. Dysplasia _________________________________________________________

f. Anaplasia _________________________________________________________

g. Neoplasia _________________________________________________________

2. For the above conditions, state if they are reversible or not. _______________________

3. Define & explain:

a. Benign ___________________________________________________________

b. Malignant _________________________________________________________

c. Metastasis ________________________________________________________

d. Ossification _______________________________________________________

e. Calcification ______________________________________________________

4. What is the difference between dystrophic & metastatic calcification?

_______________________________________________________________________

CHAPTER FOUR: INTRACELLULAR ACCUMULATIONS

Effects of Intracellular Accumulations The presence of an intracellular accumulation may have no effect on cell function, or it may impair normal cellular operations and result in cell injury or death. Even in cases where an accumulation has no influence on cell function, we must treat the accumulation as significant. An intracellular accumulation is always of abnormal function somewhere in the body. The dysfunction associated with intracellular accumulation may be local or may be occurring in an unrelated system or tissue.

There are three general pathways for intracellular accumulation to occur:

1. The first scenario involves accumulation of an metabolite. This situation indicates that there is some dysfunction in the system that normally processes and removes that metabolite, or that there is excessive intake of a substance that has over saturated the systems that regularly process that substance. Metabolite accumulation is seen in individuals with diabetes . The mechanism for stimulating the uptake of glucose from the blood and for lipogenesis is reduced or not functioning. Over time this results in the accumulation of glycogen in cells that do not normally store glycogen if dietary sugar intake is not controlled for an extended period of time. , non-metabolizable substance is introduced into the body. For example, the injection of inorganic pigments into the cells of the skin results in the accumulation of those pigments in the epithelium, as in a tattoo . Today the pigments found in tattoo ink are tested to ensure that they have no impact on cell function, though in the past some pigments have contained toxic substances such as lead and arsenic. 2. The second situation in which intracellular accumulation occurs is when an 3. The third occasion in which intracellular accumulation occurs is when there is production of a normally occurring molecule. Over production is usually a result of a genetic mutation that disables the normal regulatory pathways for production of a particular molecule. For example, individuals with Addison’s disease exhibit an over production of the normally occurring skin pigment melanin. This results in areas of hyper pigmentation in the skin. Common Intracellular Accumulations There are a number of commonly seen intracellular accumulations, whose mechanisms are well understood. The presence of one or more of these accumulations can be indicative of disease and may be useful in the diagnosis of and the monitoring of disease. Glycogen Accumulation Glycogen accumulation is indicative of polysaccharide storage disorders . The most well-known of these in humans is . Diabetes involves the inability to produce the hormone insulin, either at all, or in sufficient quantities. There is little evidence of Diabetes

or of glycogen accumulation in equines; however Equine Metabolic Disease & Equine Polysaccharide Storage Myopathy are conditions that closely resembles the pre-Diabetic state seen in other mammals, though there is no evidence that there is a progression to Diabetes in horses. Lipid Accumulation Fatty change is described as an abnormal accumulation of lipids in parenchymal cells, where the intracellular lipid is stored in a central vacuole. Generally, this state is reversible once the instigating factor is removed. Most commonly fatty change is seen in cells of the as a response to stress. The liver is one of the areas in the body where beta-oxidation of free fatty acids (FFA’s) occurs. This makes the liver tissue sensitive to lipid imbalances in the diet.  In situations of starvation, the liver breaks down the lipids in fat stores and in cell structures to use as energy.  If there is an excess liberation of FFA’s, those not used for energy will be converted to triglycerides and stored in the parenchymal cells of the liver.  An excess of lipids in the diet can lead to , and excess lipids are similarly stored in the liver cells.  Liver failure may also cause fatty change as hepatic necrosis reduces the liver’s capacity to process FFA’s for storage in adipose tissue. Hyperlipemia may also cause lipid accumulation in the cardiovascular system. is deposited in the lumen of blood vessels as well as in the chambers of the heart causing increased resistance to blood flow, increased risk of thrombus formation, increased risk of aneurysm, and ultimately causing acute heart failure (a heart attack). A condition called is a result of hyperlipidemia. Xanthomas are masses formed by lipid accumulation in the macrophages’ residing in tendons and epithelial connective tissue. The central fat vacuole causes the macrophages to enlarge to a size that, if superficial, is palpable. Generally, a reduction in the intake of dietary lipids will halt the progression of a xanthoma, and over time the lipid deposition will reverse. Xanthomas can be formed as part of an autoimmune reaction or hypersensitivity reaction. in the synthesis and the degradation of structural proteins. An increase in protein synthesis without a corresponding increase in catabolism will result in the buildup of intracellular proteins. Dietary intake of protein seems to have no effect on the formation of protein accumulations. Most often protein accumulations are composed of the protein-polysaccharide complex amyloid, which has been linked to memory loss and Alzheimer’s disease in people. Protein accumulations of any kind are rare in horses; however, hypersensitivity reactions and autoimmune reactions involving structural proteins such as collagen may lead to an area of collagen deposition and granuloma formation. Protein Accumulation Generally, protein accumulation is caused by an

Pigment Accumulation Pigments produced inside the body are referred to as

pigments, while

those introduced into the body from the environment are referred to as

pigments.

Generally exogenous pigments are harmless, causing no change in cell function. involves the injection of a pigment into the dermis of the skin. The pigment, or ink, is chosen to be harmless and inorganic so that they are not broken down once inside the cells. Tattoos are used for identification purposes and are seen most commonly on the inside of the top lip in racehorses. Occasionally an accumulation of an exogenous pigment can be indicative of disease. When inhaled, carbon enters the epithelial cells of the respiratory tract giving the lungs a blue-black appearance. This is known as , as it was commonly seen in individuals and animals working in coalmines. A similar pigmentation is seen in the lungs of those who smoke cigarettes. The carbon irritates the respiratory epithelium, causing an inflammatory immune reaction. The epithelium reacts by the excessive production of secretions such as mucus and by the deposition of collagen. The excessive secretion causes a non-infective pneumonia, while the collagen results in hardening and fibrosis of the lungs. The result is compromised inflation of the lungs, and a reduction in the gas exchange between the alveoli and the pulmonary circulation. Conditions such as emphysema, pneumonia, and chronic bronchitis are linked to the presence of carbon in the lung tissue.

There are two categories of endogenous pigments.

1. Pigments that are of blood origin 2. Pigments that are not.

The , which is found inside RBC’s. We can most clearly see the haematogenous pigments when we consider the development and maturation of a hematoma (bruise). Initially the area of injury is red-blue due to the accumulation of blood from broken blood vessels. The damaged vessels form a clot leaving blood trapped in the intracellular space of the tissue. Phagocytes arrive at the site of injury and begin breaking down the trapped blood components. The metabolites of haemoglobin degradation are the pigments seen in a bruise as it ages. pigments are derived from the molecule First haemoglobin is broken down into biliverdin , then into bilirubin and finally haemosiderin . Each pigment has a distinctive colour. Biliverdin has a colour, while bilirubin is . Haemosiderin is a colour. Some diseases involving damage to the liver or extensive breakdown of RBC’s result in a condition called . This is when there is an excess of bilirubin in the blood causing the tissues to become stained a yellow brown. Bilirubin is normally broken down in the

liver and excreted in bile. When liver function is compromised, there is a reduction in the rate at which bilirubin is processed and it “backs-up” in the blood causing hyperbilirubinemia. Cases of massive RBC lysis may also show hyperbilirubinemia, as the liver cannot process haemoglobin as quickly as blood cells are being destroyed. In such cases of massive haemolysis, hyperbilirubinemia is also accompanied by the presence of the pigment in the blood and tissues. Hematin is produced in the liver from the metabolism of bilirubin and is also excreted in bile.

The non-haematogenous endogenous pigments are lipofuscin and melanin .

Lipofuscin is an insoluble yellow-brown pigment. Lipofuscin is made of the insoluble leftovers of the breakdown of cell components. Oxidative damage seems to be the instigating factor in the production of lipofuscin, leading us to associate the accumulation of lipofuscin in a tissue with . Lipofuscin is mostly seen in the cells of the liver and heart of geriatric individuals but may also be deposited in the skin. Other causes of lipofuscin accumulation are starvation, atrophy and an insufficient intake of dietary antioxidants. Melanin is a brown-black pigment made by melanocytes. Melanin is derived from the amino acid , and its production is catalyzed by the enzyme tyrosinase. Melanocytes are specialized epithelial cells that are capable of producing tyrosinase, and therefore melanin. Melanocytes are found in skin, hair follicles, the retina, the inner ear, the leptomeninges (the arachnoid matter and the pia matter covering the brain and spinal cord), the ovaries, the adrenal medulla and the substancia nigra (the area of the brain associated with Parkinson’s disease). is a hereditary condition in which there is hypopigmentation of the skin. This is due to a hereditary defect in the production of tyrosinase that prevents the synthesis of melanin. True albinism does not occur in horses, but a condition called leucism does. Leucism is a reduction in the presence of pigment producing cells, either throughout the body or in localized regions of the body. The localized form of this condition is responsible for coloration seen in paint horses and some appaloosas.

CHAPTER 4 REVIEW QUESTIONS

1. What are the 3 causes of intracellular accumulation?

________________________________________________________________________

2. Give brief explanations of glycogen, lipid & protein accumulation.

________________________________________________________________________

3. What is the difference between endogenous and exogenous pigments?

________________________________________________________________________

4. What are some exogenous pigments? _________________________________________

5. What are the 3 common endogenous pigments that are of blood origin & what colour

are they? ________________________________________________________________

________________________________________________________________________

6. What is hyperbilirubinemia & how does it occur? ________________________________

7. Describe lipofuscin and describe its origin. _____________________________________

________________________________________________________________________

8. What colour is melanin and what is its precursor molecule? _______________________

EQUINE PATHOLOGY SECTION 2 CHAPTER 5-8: INFLAMMATION & HEALING

CHAPTER FIVE: INFLAMMATION

Definitions

 Histamine _______________________________________________________________

 Kinin ___________________________________________________________________

 Transudate ______________________________________________________________

 Exudate _________________________________________________________________

 Haemostasis _____________________________________________________________

 Pyrexia __________________________________________________________________

 Leukocytosis _____________________________________________________________

 Phagocytosis _____________________________________________________________

Introduction to Inflammation

Inflammation is the body’s response to injury or disease. Inflammation is a non-specific, innate immune response that is meant to the body from pathogens. In many tissues, inflammation also plays a role in healing and is necessary to initiate the repair process. In some cases, inflammation is not beneficial. An excessive or inappropriate inflammatory response may cause damage to normal body tissue and may result in greater dysfunction. Horses are prone to excessive inflammation as seen in the development of in lower limb wounds. The main functions of inflammation are to destroy, neutralize or contain antigens that have entered the body. Inflammation utilizes non-specific mechanisms such as and to rid the body of potentially harmful invaders. Depending on the type of pathogen and the type of tissue being affected, inflammation can take on different forms and last for varying amounts of time. Several types of injury can trigger an inflammatory response. Practically any situation that involves cell necrosis will cause inflammation. In cases of infection (viral, bacterial, parasitic) inflammation is considered beneficial, while in most other cases inflammation itself is the cause of much of damage to normal tissue. It is important to remember that infection and inflammation are not analogous. is defined as the presence of a foreign biological agent that causes dysfunction or disease, while inflammation is defined as a localized tissue reaction characterized by pain, redness, loss of function, swelling and heat. Inflammation always

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