Cell Injury, Inflammation, & Tissue Healing (PDF)

CEDERA SEL, INFLAMASI, & PROSES PENYEMBUHAN JARINGAN MATA KULIAH PATOLOGI FISIOTERAPI RENA MAILANI, S.Ft., M.Biomed., AIFO PROGRAM STUDI FISIOTERAPI PROGRAM DIPLOMA TIGA Cell Injury The structural and functional changes produced by pathology start with injury to the cells that...

CEDERA SEL, INFLAMASI, & PROSES PENYEMBUHAN JARINGAN MATA KULIAH PATOLOGI FISIOTERAPI RENA MAILANI, S.Ft., M.Biomed., AIFO PROGRAM STUDI FISIOTERAPI PROGRAM DIPLOMA TIGA Cell Injury The structural and functional changes produced by pathology start with injury to the cells that make up the tissues Mild injury produced by stressors leads to sublethal alterations of the affected cells that may be reversible, whereas moderate or severe injury leads to lethal alterations that are likely irreversible, and can lead to cell death Cells may be damaged by a variety of factors Cell injury may be reversible or irreversible The injury is reversible is dependent on the cell’s ability to withstand the derangement of homeostatic mechanisms and its adaptability (i.e., ability to return to a state of homeostasis). Reversing the injury and achieving homeostasis are determined by a combination of factors including the mechanism of injury, length of time the injury is present without intervention, and the severity of the injury. Cellular Response Causes Ischemia (lack of blood supply) Infectious agents Immune reactions Genetic factors Nutritional factors Physical factors Chemical factors Ischemia At the tissue or organ level, ischemia occurs when the blood flow is insufficient to maintain cell homeostasis and metabolic function This can be due to a reduction in flow or an increase in metabolism of the tissue beyond the capability of the arterial vascular system. Insufficient blood flow results in a partial (hypoxia) or total (anoxia) reduction in oxygen supply; a decreased delivery of nutrients; and decreased removal of waste products from the tissue. The lack of oxygen leads to loss of aerobic metabolism The resulting reduction in adenosine triphosphate synthesis leads to accumulation of ions and fluid intracellularly The cells swell and their function is compromised. Hypoxia or anoxia may occur under many circumstances, including obstruction of the respiratory tree (e.g., suffocation secondary to drowning), inadequate transport of oxygen across the respiratory surfaces of the lung (e.g., pneumonia), inadequate transport of oxygen in the blood (e.g., anemia), or an inability of the cell to use oxygen for cellular respiration (e.g., carbon monoxide poisoning) Ischemia is usually the result of arterial lumen obstruction and narrowing caused by atherosclerosis and/or an intravascular clot called a thrombus. Ischemia, resulting in myocardial infarction (MI) and stroke (lack of blood flow to the heart or brain, respectively), can cause death of tissue (necrosis) and accounts for two of the three leading causes of mortality in industrialized nations Infectious Agents Infectious agents, such as bacteria, viruses, mycoplasmas, fungi, rickettsiae, protozoa, prions, and helminths may also cause cell injury or death Bacterial and viral agents are responsible for the vast majority of infections. Bacterial infections cause cell injury primarily by invading tissue and releasing exotoxins and endotoxins that can cause cell lysis and degradation of extracellular matrix and aid in the spread of the infection Injury can also result from the inflammatory/immunologic reactions induced by bacteria in the host. For example, exotoxins may be released by clostridial organisms that cause gas gangrene, tetanus, and botulism. Clostridium tetani, for example, releases an exotoxin that is preferentially absorbed by the alpha motor neurons and delivered into the central nervous system (CNS). Once inside the CNS, the exotoxin crosses the synapse of the anterior horn cell and interferes with release of inhibitory neurotransmitters. This disruption of homeostasis eventually causes the activation of motor neurons that in turn cause involuntary muscular contractions (tetanus) When microorganisms or their toxins are present in the blood, a condition called sepsis can occur Endotoxins released from gram-negative bacteria induce the synthesis of cytokines (extracts of normal leukocytes such as tumor necrosis factor [TNF] and interleukins [ILs]) that are responsible for many of the systemic manifestations of sepsis In sepsis, endothelial cell damage, loss of plasma volume, and maldistribution of blood flow result in hypovolemia. Cardiovascular collapse may ensue and lead to a condition called septic shock The detection of an infectious agent initiates an inflammatory reaction designed to contain and inactivate the pathogen, but the magnitude of this defensive response by the host may also cause cellular or tissue destruction in the infected area Infectious Agents Viruses kill cells by one of two mechanisms and are the consequence of complete redirection of the cell’s biosynthesis toward viral replication The first is a direct cytopathic effect usually found with ribonucleic (RNA) viruses. These viruses kill from within by disturbing various cellular processes or by disrupting the integrity of the nucleus and/or plasma membrane The second mechanism is an indirect cytopathic effect mediated by immune mechanisms. In this process, virally encoded proteins become inserted into the plasma membrane of the host cell (forming a channel) and alter the permeability of the cell membrane to ions. The resulting loss of the ionic barrier leads to cell swelling and death. DNA type viruses also kill cells through an indirect cytopathic effect by integrating themselves into the cellular genome. These viruses encode the production of foreign proteins, which are exposed on the cell surface and recognized by the body’s immune cells. Immunocompetent cells, such as the T lymphocyte, recognize these virally encoded proteins inserted into the plasma membrane of host cells and attack and destroy the infected cell When the immune system is compromised or if the number of invading microorganisms overwhelms the immune system, disease (and the symptoms of illness) occurs Inflammation A natural response on the part of the body to injury or infection In the inflammatory process the body attempts to isolate an affected area to prevent injury or infection from spreading to other locations The process of inflammation allows the body to repair damaged tissues and the immune response to heal the wound A protective response that attempts to eliminate initial causes of cell injury and necrotic cells and tissues that result from that injury  Most components of the inflammatory process are found in the circulatory system Most early mediators (facilitators) of inflammation increase the movement of plasma and blood cells from the circulation into the tissues surrounding an injury The collective term for such fluids is exudate These fluids defend the host against infection and facilitate tissue repair and healing. Mekanisme Fisiologis Inflamasi The body protects itself against injury in either specific or nonspecific ways, which include the skin, mucous membranes, body secretions, cellular activities, and immune defenses The first line of defense is the mechanical barrier created by the skin and mucous membranes, which block bacteria and harmful substances from entering the body tissues. Also, body secretions such as saliva and tears containing enzymes and other chemicals help to destroy foreign materials The second line of defense includes phagocytosis and inflammation. Phagocytosis involves neutrophils (one of the leukocytes) and macrophages, which engulf and destroy bacteria, cell debris, and foreign matter. Inflammation involves events that limit the effects of injury or foreign agents. Nonspecific agents that protect uninfected cells against viruses are known as interferons The third line of defense is the immune system, which stimulates production of unique antibodies or sensitized lymphocytes after exposure to specific foreign substances Classification of Inflammation Inflammation is the reaction of vascularized tissue to local injury. It is a normal body defense mechanism that localizes and removes agents that are harmful to the body Signs and symptoms of inflammation are actually warning signs of a problem in or on the body and should not be confused with infection. Inflammation can be caused by microorganisms that cause infection but also by cuts, allergic reactions, insect bites, sprains, ischemia, cell necrosis, infarction, caustic agents, splinters, dirt, and burns It is signified by redness, heat, swelling, pain, and, sometimes, loss of function. Swelling occurs because of the leakage of plasma from the dilated and more permeable vessels. This causes the volume of fluid in the inflamed tissue to increase Accute Inflammation Inflammation can develop immediately and last for a short time or have a delayed onset and last for a more severe, prolonged time. Tissue injury causes the damaged mast cells and platelets to release chemical mediators (histamine, serotonin, prostaglandins, leukotrienes, and others) into the interstitial fluid and blood It is nonspecific and may result from any injury. Chemical Mediators Mechanism Histamine and certain other chemical mediators are released immediately from granules in mast cells for immediate effect. Others must be synthesized from arachidonic in mast cells before release. Many anti- inflammatory drugs and antihistamines reduce these chemical mediators’ effects. The rapid release of chemical mediators results in local vasodilation, which causes hyperemia. Capillary membrane permeability increases to allow plasma proteins to shift into the interstitial spaces along with more fluid. This fluid dilutes toxic materials, whereas globulins act as antibodies, and fibrinogen forms a fibrin mesh to localize the harmful agent. Vasodilation and increased capillary permeability constitute the “vascular response” to injury. During the “cellular response” leukocytes are attracted via chemotaxis to the area of inflammation, acting like magnets for damaged cells. Neutrophils and then monocytes and macrophages collect along capillary walls to move through wider separations in the walls to the interstitial areas (diapedesis).  When excessive fluid and protein collects in the interstitial compartment, blood flow in the area decreases The fluid shifting out of the capillaries is reduced Naturally occurring defense or control mechanisms in the body inactivate chemical mediators to prevent spreading or prolonging of inflammation Redness and warmth are caused by increased blood flow to the damaged area Swelling (edema) is caused by the shift of protein and fluid into the interstitial space Pain is caused by the increased pressure of the fluid on the nerves as well as irritation by chemical mediators Loss of function is caused when the cells lack nutrients or the swelling interferes with an action (such as joint movement). Characteristics of exudate Fibrinous exudates: Thick, sticky, with high cell and fibrin contents; this type increases the risk of scar tissue in the area Hemorrhagic (bloody) exudates: Present if blood vessels have been damaged Purulent exudates: Thick, yellowish green in color, with higher amounts of leukocytes and cell debris along with microorganisms; indicate bacterial infection; commonly called “pus.” An abscess is a localized pocket of pus in a solid tissue (such as around a tooth) Serous (watery) exudates: Consist mostly of fluid and small amounts of protein and white blood cells; often caused by allergic reactions or burns. For example, after a severe burn of the skin, a blister may form.  General manifestations of inflammation may also include malaise, mild fever (pyrexia), fatigue, headache, and anorexia Fever can be severe if infection has caused the inflammation, depending on the causative microorganism. High fever may impair the growth and the reproduction of the pathogen. Fever is caused by the release of pyrogens from white blood cells or macrophages. Shivering may occur to allow the body to increase cell metabolism. Involuntary cutaneous vasoconstriction reduces heat loss, and if the patient “curls up” voluntarily, the body will conserve heat. These mechanisms continue until the body temperature is reset to its new, higher level by the hypothalamus. Once the cause of the fever is removed, body temperature is normalized by reversing these mechanisms.  Diagnostic tests used to determine the type of infection include those that check for leukocytosis, elevated serum C-reactive protein (CRP), elevated erythrocyte sedimentation rate, and increased plasma proteins and cell enzymes in the serum Although not indicating the cause or site of the inflammation, they help in the monitoring of the patient through the course of the infection A differential count (of the proportion of each type of white blood cell) may help in distinguishing a viral infection from a bacterial infection. Examining a peripheral blood smear may disclose abnormal cells in high numbers Increased circulating plasma proteins (fibrinogen, prothrombin, and alphaantitrypsin) may result from a liver response that increases protein synthesis. When there is severe inflammation and necrosis, tissue is destroyed to some extent and must be repaired. This results in cell enzymes and isoenzymes becoming elevated in the blood. This event helps these substances to locate the site of the necrotic cells that have released enzymes into the blood and tissue fluids. Certain enzymes are not specific to certain tissues.  The amount of tissue necrosis that occurs is related to the specific type of trauma and other factors related to the inflammatory response If necrosis is extensive, it may lead to ulcers, tissue erosion, or tissue death. Infection may develop in inflamed tissues because microorganisms can penetrate them more easily once they are damaged and blood supply is impaired Inflammatory exudate is an excellent medium for microorganisms to use for reproduction and colonization Deep ulcers that result from prolonged, severe inflammation may lead to complications such as perforation of the viscera or the development of scar tissue in large amounts Inflammation can also cause strong muscle contractions or skeletal muscle spasms, which can force joints out of alignment. Chronic Inflammation Chronic inflammation differs from acute inflammation in that it may last for weeks, months, or even years Acute inflammation is usually self-limited and of short duration. Chronic inflammation may develop as the result of a recurrent or progressive active inflammatory process. Rheumatoid arthritis involves chronic inflammation with acute exacerbatory periods. Chronic inflammation may develop from chronic irritation due to bacteria, long- term immune abnormalities, and smoking. Chronic inflammation causes less swelling and exudate than acute inflammation. However, it increases the amounts of lymphocytes, macrophages, and fibroblasts and usually causes more tissue destruction. Increased scar tissue may form because of higher amounts of collagen being produced. Sometimes a granuloma develops around a foreign object such as a splinter or as a result of an immune response. Treatment of Inflammation Inflammatory agents include such medications as acetylsalicylic acid (ASA), acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and prednisone. A mnemonic used to remember the treatment for inflammation is “RICE”: Rest, Ice, Compression, and Elevation. Application of ice packs constricts blood vessels and decreases edema and pain. Chronic rheumatoid arthritis responds well to application of heat, but heat should be avoided in acute exacerbations of the condition. Elevation usually improves fluid flow away from the damaged area. Compression garments help the muscle pump to reduce accumulation of fluid. Mild-to-moderate exercise is useful for many chronic inflammatory conditions to improve blood and fluid flow. Orthotics helps to prevent contractures and is often used along with rest, adequate nutrition, and good hydration. Healing & Tissue Repair Tissue repair overlaps the inflammatory process It is a response to tissue injury and represents an attempt to maintain normal body structure and function Tissue repair may take the form of regeneration of parenchymal cells, in which injured cells are replaced with cells of the same type. Sometimes there is no residual trace of previous injury, although it may take the form of replacement by connective tissue, leaving a permanent scar. Several methods of wound healing Resolution: Occurs after minimal tissue damage; cells recover and tissue returns to normal in a short period of time (e.g., mild sunburn). Regeneration: Occurs in damaged tissue in which cells are capable of mitosis; damaged tissue is replaced by identical tissue from proliferation of nearby cells (e.g., hepatocytes in the liver can undergo mitosis when needed to regenerate) Replacement: Connective tissue (scar or fibrous tissue) forms after extensive damage or when cells are incapable of mitosis (e.g., chronic inflammation in the brain or heart results in normal tissue being replaced by Healing Healing by first intention means that a wound is free of foreign material and necrotic tissue, with edges close together. Healing by second intention refers to a large break in tissue, increased inflammation, a longer healing period, and more scar tissue formation  Tissue repair begins after injury with a blood clot forming, inflammation developing, and phagocytosis beginning After 3 to 4 days, foreign material and cell debris have been phagocytized Granulation tissue from nearby connective tissue grows into the gap caused by the injury Granulation tissue is highly vascular. It appears moist and is pink or red, containing many new capillary buds Nearby epithelial cells undergo mitosis, extending across the wound from the outside edges inward Collagen is produced by fibroblasts, which strengthens the repairing tissue. Cross- linking and shortening of the collagen fibers form a strong, tight scar. The scar gradually fades from red to white. It is not as strong as normal, uninjured skin tissue. The phases of healing Inflammation: Beginning immediately and lasting for 2 to 5 days, the inflammatory phase involves both hemostasis and inflammation. Hemostasis is divided into the processes of vasoconstriction, platelet aggregation, and the formation of a clot via the actions of thromboplastin Inflammation involves the processes of vasodilation and phagocytosis. Proliferation: Lasting from day 2 until 3 weeks after injury, the proliferative phase includes the processes known as granulation, contraction, and epithelialization. Granulation occurs as fibroblasts lay a bed of collagen, filling defects and producing new capillaries Contraction is the process of wound edges pulling together to reduce defects. Epithelialization involves a moist surface to cross the area, with cells traveling about 3 centimeters from the point of origin, in all directions. Maturation: Also known as the “remodeling phase,” this lasts from 3 weeks to 2 years. New collagen forms, which increases tensile strength to wounds, but scar tissue is only 80% as strong as the original tissue. Factors Affecting Healing Small gaps in tissue are healed quickly, with minimal scar tissue formation. Large or deep gaps take much longer and result in large scars. Healing is promoted by younger age, good nutrition, adequate hemoglobin, effective circulation, a clean and undisturbed wound, and no complications. Healing may be delayed by advanced age, poor nutrition, dehydration, low hemoglobin, circulatory problems, other disease states, irritation, bleeding, excessive mobility, infection, foreign materials, radiation, lack of insulin, chemotherapy, and prolonged use of glucocorticoids. When scars are formed, there are often complications to the wound area. Loss of function may result from loss of normal cells and lack of specialized structures such as hair follicles, glands, and sensory nerve endings. Scar tissue tends to shrink over time, restricting range of joint movement, fixation, and joint deformity. Scar shrinkage can also cause shortening or narrowing (stenosis) of structures such as tubes or ducts Adhesions are bands of scar tissue that join two surfaces that are normally separated, such as between loops of the intestine or between the pleural membranes. Hard ridges of scar tissue or the formation of keloids may occur due to excessive collagen deposits. Contact inhibition is defined as cessation of replication of dividing cells that come into contact, as in the center of a healing wound. When it occurs, a monolayer is formed. Epibole is defined as growth of epithelium that surrounds underlying mesenchymal tissue. This is to keep premature closure of wound edges from occurring, and both of these processes can cause poor, insufficient wound healing. Regarding bone healing, there are three primary (yet overlapping) stages Inflammatory stage (2–4 weeks after fracture): A hematoma forms within the fracture site during the first few hours and days. Inflammatory cells infiltrate the bone. Granulation tissue, vascular tissue, and immature tissue are formed Repair stage (1–2 months after fracture): The bone ends become joined and stabilized. New bone tissue (fracture callus) forms, but it is weak and requires protection. Cartilage hardens near the end of the fracture and sweeps toward the center. New blood vessels (for new growth) develop. Smokers should stop their habit during this phase because nicotine greatly slows down these processes. Late modeling (remodeling) stage (months to years after fracture): The body changes weak bone material into strong bone material. The body remodels the fracture callus down to normal sized bone. In general, the bone is restored to its original shape, structure, and mechanical strength. Mechanical stress (weight bearing) actually helps during this stage as the bone must endure the weight placed upon it, strengthening its structure. Summary The ability of the body to repair damaged tissues is variable The inflammatory response is a nonspecific defense mechanism Other defenses include the barriers (skin, mucous membranes, and secretions) and phagocytosis. The five signs of acute inflammation include redness, warmth, pain, swelling, and loss of function. There are two types of inflammation: acute and chronic Injured tissues are repaired by regeneration of parenchymal cells or by connective tissue repair, in which scar tissue replaces the parenchymal cells of the injured tissue Chronic inflammation results in formation of fibrotic or scar tissue Anti-inflammatory drugs include aspirin (acetylsalicylic acid) and nonsteroidal antiinflammatory drugs. Healing in a small area of damage often occurs because of regeneration where cells are capable of mitosis. Extensive damage often causes formation of fibrotic or scar tissue Factors promoting healing include youth, good nutrition, good circulation, and lack of infection or disease. Other factors include contract inhibition, epibole, and three stages of bone healing These stages are the inflammatory stage, the repair stage, and the late modeling (remodeling) stage The phases of healing include inflammation, proliferation, and maturation Inflammation is subdivided into hemostasis and the processes of vasodilation and phagocytosis Proliferation is made up of the processes of granulation, contraction, and epithelialization The final phase, maturation, is also known as the “remodeling phase,” as new collagen forms and scar tissue develops. Thank You