2) Cellular injury.pdf

Cellular Injury Dr. Inas Almazari, PhD Zarqa University School of Pharmacy  Introduction Pathology is divided into: – General pathology: which focuses on the cellular and tissue alterations caused by pathologic stimuli in most tissues – Systemic pathology: whic...

Cellular Injury Dr. Inas Almazari, PhD Zarqa University School of Pharmacy  Introduction Pathology is divided into: – General pathology: which focuses on the cellular and tissue alterations caused by pathologic stimuli in most tissues – Systemic pathology: which examines the reactions and abnormalities of different specialized organs.  Introduction In the study of pathophysiology, point considered: The causes of disease The changes to normal anatomy and physiology (pathophysiology) The signs and symptoms (clinical manifestations) of the disease Diagnostic tests and treatments available Cellular Injury and Adaptation  Cell injury Cellular injury can occur as a result of trauma, infection, ischemia, and exposure to toxins. Many disease processes begin with cellular injury. The environment around cells is dynamic and constantly changing. Cells are exposed to numerous stimuli and stresses, some of which may be injurious. In order for cells to survive, they must have the ability to adapt to variable conditions. Adaptation can involve changes in cellular size, cell number or cell type. Adaptive changes may be physiologic and benefit the individual or be pathologic and detrimental to the individual.  Cellular responses to stress and toxic substances In general, cells have specific function and morphology Nevertheless, they are able to handle physiologic demands, maintaining a steady state called homeostasis Adaptations are reversible functional and structural responses to more severe physiologic stresses and some pathologic stimuli. Adaptation is considered to be a new steady state. Cell injury (reversible) follows if the limits of adaptive responses are exceeded or if cells are exposed to injurious agents or stress. Irreversible cell injury and ultimately cell death (necrosis/apoptosis) occurs if the stimulus persists or is severe enough from the beginning  Factors affect cells response (Cellular response) 1) Nature of stress 2) Severity of stress 3) the involved cell itself (mechanism of cell tolerance) 4) Basal cellular metabolism 5) Blood and nutrient supply An adaptation to stress can progress to functionally significant cell injury if the stress is not relieved.  Cellular adaptation To survive, cells must have the ability to adapt to variable conditions. This process of adaptation can involve changes in cellular size, number or type. many things may be changed around the cell: PH, temperature, sugar level, chemical and physical stimulus, electrolytes level etc. Adaptive changes in cells  Cellular adaptation 1. Atrophy: Atrophy is characterized by a decrease in size of a cell or tissue Causes of atrophy may include prolonged bed rest, disuse of limbs or tissue, poor tissue nutrition and ischemia Decreased size results in decreased oxygen consumption and metabolic needs of the cells and may increase the overall efficiency of cell function Atrophy is generally a reversible process, except for atrophy caused by loss of nervous innervation to a tissue  Atrophy of the brain in an 82-year-old man with atherosclerotic disease. Atrophy of the brain is due to aging and reduced blood supply.  2. Hypertrophy: Hypertrophy is characterized by an increase in cell size and tissue mass but not cell number Often occurs when a cell or tissue is exposed to an increased workload Occurs in tissues that cannot increase cell number as an adaptive response ❑ Hypertrophy may be: Normal physiologic response: to increased workload, such as the increase in muscle mass that is seen with exercise. Pathologic: as in the case of the cardiac hypertrophy that is seen with prolonged hypertension. Such pathologic hypertrophy is often irreversible. Compensatory process: When one kidney is removed, the remaining kidney hypertrophies to increase its functional capacity  3. Hyperplasia: Hyperplasia is characterized by an increase in the number of cells in an organ or tissue Hyperplasia can only occur in cells capable of mitosis (therefore not in muscle or nerve cells)  Hyperplasia may be: Normal process, as in the breast and uterine hyperplasia that occurs during pregnancy, Pathologic: such as gingival hyperplasia (overgrowth of gum tissues) that may be seen in certain patients receiving the drug phenytoin. Compensatory mechanism: For example, when a portion of the liver is surgically removed, the remaining hepatocytes (liver cells) increase in number to preserve functional capacity of the liver  4. Metaplasia: Metaplasia is characterized by the conversion of one cell type to another that might have a better chance of survival under certain circumstances Metaplasia often occurs in response to chronic irritation or inflammation An example of metaplasia can be observed in the respiratory passages of chronic cigarette smokers.  4. Metaplasia: Following years of exposure to irritating cigarette smoke, the ciliated columnar epithelium lining the respiratory passages gradually converts to stratified squamous epithelium. Although the stratified squamous cells may be better able to survive the constant irritation of cigarette smoke, they lack the cilia of the columnar epithelial cells that are necessary for clearing particulates from the surfaces of the respiratory passages  5. Dysplasia: Dysplasia is characterized by a derangement of cell growth that leads to tissues with cells of varying size, shape and appearance. It is not a true adaptive change but more so a pathologic change Dysplasia generally occurs in response to chronic irritation and inflammation. Dysplastic changes may be a precursor to cancer in certain instances such as in the cervix, GI or respiratory tract  Mechanisms of cell injury Cell injury can occur in a number of different ways. The extent of injury that cells experience is often related to the intensity and duration of exposure to the injurious event or substance. Cellular injury may a reversible process, in which case the cells can recover their normal function, or irreversible and lead to cell death. Although the causes of cellular injury are many, the underlying mechanisms of cellular injury usually fall into one of two categories, free radical injury or hypoxic injury. Causes of cellular injury  Mechanisms of cell injury 1. Free Radical Injury: Free radicals are highly reactive chemical species that have one or more unpaired electrons in their outer shell. Examples of free radicals include: – superoxide (O2–) – hydroxyl radicals (OH) – hydrogen peroxide (H2O2) Free radicals are generated as by-products of normal cell metabolism and are inactivated by free radical scavenging enzymes within the body such as catalase and glutathione peroxidase. When excess free radicals are formed from exogenous sources or the free radical protective mechanisms fail, injury to cells can occur  1. Free Radical Injury: Free radicals are highly reactive and can injure cells through: – Peroxidation of membrane lipids – Damage of cellular proteins – Mutation of cellular DNA Exogenous sources of free radicals include tobacco smoke, organic solvents, pollutants, radiation, and pesticides Free radical injury has been implicated as playing a key role in the normal aging process as well as in a number of disease states such as diabetes mellitus, cancer, atherosclerosis, Alzheimer’s disease, and rheumatoid arthritis Can free radicals be a protective mechanism in the body???:  2. Hypoxic Cell Injury: Hypoxia is a lack of oxygen in cells and tissues that may result from ischemia, or poor oxygenation of blood During periods of hypoxia, aerobic metabolism begins to fail → dramatic decreases in ATP production → Hypoxic cells begin to swell as energy-driven processes (ATP-driven ion pumps) begin to fail. The pH of the extracellular environment begins to decrease as waste products such as lactic acid, begin to accumulate. The cellular injury process may be: – reversible, if oxygen is quickly restored; – or irreversible, and lead to cell death. ATP depletion –(HYPOXIA/ISCHAEMIA)  2. Hypoxic Cell Injury: Certain tissues such as the brain are particularly sensitive to hypoxic injury. Death of brain tissues can occur only 4–6 minutes after hypoxia begins The loss of ionic balance in hypoxic cells can also lead to the accumulation of intracellular calcium, which is normally closely regulated within cells. There are a number of calcium-dependent protease enzymes present within cells that become activated in the presence of excess calcium and begin to digest important cellular constituents.  Manifestations of cellular injury 1. Cellular Swelling: Caused by an accumulation of water due to the failure of ATP-driven ion pumps. Breakdown of cell membrane integrity and accumulation of cellular electrolytes may also occur Cellular swelling is considered to be a reversible change  Manifestations of cellular injury 2. Cellular Accumulations: In addition to water, injured cells can accumulate a number of different substances as metabolic and transport processes begin to fail. Substances that can be accumulated in injured cells may include fats, proteins, glycogen, calcium, uric acid and certain pigments such as melanin These accumulations are generally reversible but can indicate a greater degree of cellular injury. Accumulation of these substances can be so marked that enlargement of a tissue or organ may occur. An example of this is the fatty accumulation (steatosis) that can develop in the liver of an alcoholic as the liver becomes injured and its function impaired  Cells death falls into two main categories: 1- Apoptosis: -Physiological or pathological. 2- Necrotic cell death: -Always pathological. -Many cells are involved; so it affects tissues.  1. Apoptosis Apoptosis is a controlled, genetically “preprogrammed” cell death that occurs with aging and normal wear and tear of the cell. Apoptosis may be a mechanism to eliminate worn out or genetically damaged cells. Certain viral infections (e.g., Epstein- Barr virus) may activate apoptosis within an infected cell, thus killing both host cell and infecting virus Apoptosis may involve the activation of “suicide genes” and lead to cell lysis and destruction through the activation of cellular enzymes called caspases It has been theorized that cancer may arise as a failure of normal apoptosis in damaged or mutated cells A physiologic example of normal apoptosis would be the sloughing of the endometrium during the menstrual cycle  2. Necrotic Cell Death: Involves the unregulated, enzymatic digestion (“autolysis”) of a cell and its components Occurs as a result of irreversible cellular injury Different types of tissues tend to undergo different types of necrosis. Three main types of necrosis have been identified  3. Gangrene: Gangrene is the clinical term used when a large area of tissue undergoes necrosis. Gangrene may be classified as being “dry gangrene” or “wet gangrene.” ❖“dry gangrene”: – the skin surrounding the affected area shrinks, wrinkles and turns black. There is generally a clear line of demarcation between living and dead tissue ❖“wet gangrene.”: – presents with an area that is cold, wet from tissue exudates and swollen. Wet gangrene often occurs when venous return from the affected tissue is lacking and a clear line of demarcation is generally not evident between living and dead tissue. ❖A gas gangrene: – may also occur if the area of necrosis becomes infected with bacteria (often Clostridium) that produce hydrogen sulfide gas as a by-product  Apoptosis Necrosis Summary Apoptosis Necrosis is the premature death of (programmed cell cells and living tissue. Though death) is a form of cell necrosis is being researched as a death that is generally possible form of programmed cell triggered by normal, death, it is considered an "un- healthy processes in programmed" cell death process at the body. this time Natural Yes Caused by factors external to the cell or tissue, such as infection, toxins, or trauma. Effects Usually beneficial. Always detrimental and can be Only abnormal when fatal. cellular processes that keep the body balance cause too many cell deaths or too few.  Apoptosis Necrosis Process Membrane blebbing, Membrane disruption, shrinkage of cell, nuclear respiratory poisons and collapse (nuclear hypoxia which cause ATP fragmentation, chromatin depletion, metabolic condensation, chromosomal collapse, cell swelling and DNA fragmentation), rupture leading to apoptotic body formation. inflammation. Then, engulf by white blood cells. Symptoms Usually not noticeable Inflammation, decreasing symptoms related to the blood flow at affected site, process. tissue death (gangrene). Medical Very rarely needs treatment. Always requires medical treatment treatment. Untreated necrosis is dangerous and can lead to death/could be Apoptosis Vs Necrosis  Tissue repair Injured or damaged tissues can be repaired by: – regeneration – connective tissue replacement. The mechanism used for repair will depend upon the type of cells that were injured. Certain cells in the body are fully or partially capable of regenerating after an injury, whereas other cells types are not and can only be replaced with connective (scar) tissue.  1. Repair by Regeneration With regeneration, the injured tissue is repaired with the same tissue that was lost. A full return of function occurs and afterwards there is little or no evidence of the injury. Repair by regeneration can only occur in: labile cells (cells that continue to divide throughout life) – Examples of labile cells include those of the skin, oral cavity and bone marrow. stable cells (cells that have stopped dividing but can be induced to regenerate under appropriate conditions of injury). – Examples of stable cells include hepatocytes of the liver. Certain cell such as nerve cells and cardiac muscle cells are fixed cells and cannot undergo regeneration under any circumstances. These cell types are only capable of repairing injuries through connective tissue replacement.  2. Repair by Connective Tissue Replacement Involves the replacement of functional tissue with nonfunctional connective tissue (collagen). Full function does not return to the injured tissue. Scar tissue remains as evidence of the injury.  Steps in tissue (wound) repair Clean, neat wounds such as surgical incisions are said to heal by primary intention because they tend to heal quickly and evenly with a minimum of tissue loss. Sutures are used to bring the edges of wounds together to facilitate the process of healing by primary intention. Larger, open types of wounds may take considerably longer to heal and are said to heal by secondary intention. In secondary intention, the edges of the wound are not able to come into contact with one another and, as a result, the gap must be filled by granulation tissue. These larger wounds often require a significant amount of tissue replacement, take longer to heal and tend to be associated with more obvious scar formation. In general, tissue repair involves three stages, the inflammatory stage, the proliferative stage, and the maturational/remodeling stage  1. Inflammatory Stage Starts with the formation of a fibrin blood clot to stem bleeding from the injury. Infiltration of phagocytic white blood cells occurs. Neutrophils tend to arrive first followed by larger macrophages. The arriving macrophages produce growth factors that stimulate growth of epithelial cells around the wound as well as angiogenesis (the formation of new blood vessels).  2. Proliferative Stage Over the first 1–3 days after the initial injury, fibroblasts in and around the injured tissue proliferate in response to growth factors such as fibroblast-activating factor produced by infiltrating macrophages. These activated fibroblasts produce the collagen that will repair the bulk of the wound. Epithelial cells at the margins of the wound also proliferate in response to macrophage-produced growth factors. Angiogenesis is likewise occurring at this point. The soft, pink tissue that forms during this phase of wound healing is referred to as granulation tissue.  2. Proliferative Stage Over time, the collagen that is laid down adds mechanical strength to the repaired area. Contraction of the wound occurs over the course of 1–2 weeks as the edges of the wound grow closer to one another. Suturing a wound can facilitate healing by primary intention and minimize scar tissue formation by bringing the margins of the wound into close contact with one another.  3. Maturation and Remodeling Over the course of one to several months following the injury, there is continued synthesis of collagen in conjunction with removal of old collagen by collagenase enzymes. This remodeling of the collagen is designed to maximize strength of the repair. Capillaries that were present in the repaired area begin to disappear, leaving an avascular scar. The maturation and remodeling phase of the healed wound may continue for a number of years; however, for larger wounds, the final healed scar will never have the full tensile strength that the original tissue had prior to the injury. A number of factor can impair the wound healing process Factors that impair wound healing  KELOID SCARS Large, raised scars that result from oversynthesis of collagen and decreased collagen breakdown. Keloid scars are often unsightly and may extend beyond the original boundaries of the wounds. A familial tendency for keloid scar formation has been observed with a greater occurrence in blacks than whites.