Inflammation, Tissue Repair, and Fever

The Inflammatory Response Inflammation is the reaction of vascularized tissue to local injury. The causes of inflammation are many & varied. Inflammation commonly results because of an immune response to infectious microorganisms. Other causes of inflammation are trauma, surgery, caustic chemicals, extremes of heat and cold, and ischemic damage to body tissues. Inflammatory conditions are named by adding the suffix-itis to the affected organ or system. Acute inflammation is the early (almost immediate) response to injury. It is nonspecific and may be evoked by any injury short of one that is immediately fatal. Cardinal Signs These signs are rubor (redness), tumor (swelling), calor (heat), and dolor (pain). These signs and symptoms, which are apparent when inflammation occurs on the surface of body, may not be present when internal organs are involved. In addition to the cardinal signs that appear at the site of injury, systemic manifestations (e.g., fever) may occur as chemical mediators produced at the site of inflammation gain entrance to the circulatory system. The Vascular Response The vascular, or hemodynamic, changes that occur with inflammation begin almost immediately after injury and are initiated by a momentary constriction of small blood vessels in the area. This vasoconstriction is followed rapidly by vasodilation of the arterioles and venules that supply the area. As a result, the area becomes congested, causing the redness (erythema) and warmth associated with acute inflammation. Accompanying this hyperemic vascular response is an increase in capillary permeability, which causes fluid to move into the tissues and cause swelling, pain, and impaired function. The exudation or movement of the fluid out of the capillaries and into the tissue spaces dilutes the offending agent. The Cellular Stage The cellular stage of acute inflammation is marked by movement of phagocytic white blood cells (leukocytes) into the area of injury. Two types of leukocytes participate in the acute inflammatory response the granulocytes and monocytes. Granulocytes Granulocytes are identifiable because of their characteristic cytoplasmic granules. These white blood cells have distinctive multilobed nuclei. The granulocytes are divided into three types (i.e., neutrophils, eosinophils, and basophils) according to the staining properties of the granules. The neutrophil is the primary phagocyte that arrives early at the site of inflammation, usually within 90 minutes of injury. The neutrophils cytoplasmic granules contain enzymes and other antibacterial substances that are used in destroying and degrading the engulfed particles.

 The cytoplasmic granules of the eosinophils stain red with the acid dye eosin. These granulocytes increase in the blood during allergic reactions and parasitic infections. The granules of the basophils stain blue with a basic dye. The granules of these granulocytes contain histamine and other bioactive mediators of inflammation. The Inflammatory Response Inflammation represents the response of body tissue to immune reactions, injury, or ischemic damage. The classic response to inflammation includes redness, swelling, heat, pain or discomfort, & loss of function. The manifestations of an acute inflammatory response can be attributed to the immediate vascular changes that occur (vasodilation and increased capillary permeability), the influx of inflammatory cells such as neutrophils, and, in some cases, the widespread effects of inflammatory mediators, which produce fever and other systemic signs and symptoms. The manifestations of chronic inflammation are due to infiltration with macrophages, lymphocytes, and fibroblasts, leading to persistent inflammation, fibroblast proliferation, and scar formation. Mononuclear Phagocytes The monocytes are the largest of the white blood cells and constitute 3% to 8% of the total blood leukocytes. The circulating life span of the monocyte is three to four times longer than that of the granulocytes, and these cells survive for a longer time in the tissues. The monocytes, which migrate in increased numbers into the tissues in response to inflammatory stimuli, mature into macrophages. Within 24 hours, mononuclear cells arrive at the inflammatory site, and by 48 hours, monocytes and macrophages are the predominant cell types. Cellular Response The sequence of events in the cellular response to inflammation includes: (1) pavementing, (2) emigration, (3) chemotaxis, and (4) phagocytosis. During the early stages of the inflammatory response, fluid leaves the capillaries, causing blood viscosity to increase. The release of chemical mediators (i.e., histamine, leukotrienes, and kinins) Emigration is a mechanism by which the leukocytes extend pseudopodia, pass through the capillary walls by ameboid movement, and migrate into the tissue spaces.The process by which leukocytes migrate in response to a chemical signal is called chemotaxis. During the next and final stage of the cellular response, the neutrophils and macrophages engulf and degrade the bacteria and cellular debris in a process called phagocytosis. Chronic Inflammation Characteristic of chronic inflammation is an infiltration by mononuclear cells (macrophages) and lymphocytes, instead of the influx of neutrophils commonly seen in acute inflammation. Chronic inflammation also involves the proliferation of fibroblasts instead of exudates. Local Manifestations of Inflammation Inflammatory exudates often are composed of a combination of these types. Serous exudates are watery fluids low in protein content that result from plasma entering the inflammatory site. Hemorrhagic exudates occur when there is severe tissue injury that causes damage to blood vessels or when there is significant leakage of red cells from the capillaries. 2

 Fibrinous exudates contain large amounts of fibrinogen and form a thick and sticky meshwork, much like the fibers of a blood clot. Membranous or pseudomembranous exudates develop on mucous membrane surfaces & are composed of necrotic cells enmeshed in a fibropurulent exudate. Systemic Manifestations of Inflammation White Blood Cell Response (Leukocytosis and Leukopenia) The white blood cell count usually increases to 15,000 to 20,000 cells/L (normal 4000 to 10,000 cells/L). After being released from the bone marrow, circulating neutrophils have a life span of only about 10 hours and therefore must be constantly replaced if their numbers are to be adequate. Bacterial infections produce a relatively selective increase in neutrophils (neutrophilia), whereas parasitic and allergic responses induce eosinophilia. Viral infections tend to produce neutropenia (decreased numbers of neutrophils) and lymphocytosis. Leukopenia is also encountered in infections that overwhelm persons with other debilitating diseases such as cancer. Lymphadenitis Localized acute and chronic inflammation may lead to a reaction in the lymph nodes that drain the affected area. Painful palpable nodes are more commonly associated with inflammatory processes, whereas non-painful lymph nodes are more characteristic of neoplasms. The systemic manifestations of inflammation include an increased ESR, fever, and leukocytosis (or in some cases, leukopenia). These responses are mediated by release of the cytokines. Localized acute and chronic inflammation may lead to a reaction in the lymph nodes and enlargement of the lymph nodes that drain the affected area. Tissue Repair & Wound Healing Body organs and structures contain two types of tissues: parenchymal and stromal. The parenchymal tissues contain the functioning cells of an organ or body part (e.g., hepatocytes, renal tubular cells). The stromal tissues consist of the supporting connective tissues, blood vessels, and nerve fibers. Injured tissues are repaired by regeneration of parenchymal cells or by connective tissue repair in which scar tissue is substituted for the parenchymal cells of the injured tissue. The primary objective of the healing process is to fill the gap created by tissue destruction and to restore the structural continuity of the injured part. Regeneration Regeneration involves replacement of the injured tissue with cells of the same parenchymal type, leaving little or no evidence of the previous injury. The ability to regenerate varies with the tissue and cell type. Body cells are divided into three types according to their ability to undergo regeneration: labile, stable, or permanent cells. Labile cells are those that continue to divide and replicate throughout life, replacing cells that are continually being destroyed. Labile cells can be found in tissues that have a daily turnover of cells.

Stable cells are those that normally stop dividing when growth ceases. However, these cells are capable of undergoing regeneration when confronted with an appropriate stimulus. Permanent or fixed cells cannot undergo mitotic division. The fixed cells include nerve cells, skeletal muscle cells, and cardiac muscle cells. These cells cannot regenerate; once destroyed, they are replaced with fibrous scar tissue that lacks the functional characteristics of the destroyed tissue. Connective tissue replacement is an important process in the repair of tissue. It allows replacement of nonregenerated parenchymal cells by a connective tissue scar. Depending on the extent of tissue loss, wound closure and healing occur by primary or secondary intention. A sutured surgical incision is an example of healing by primary intention. Larger wounds (e.g., burns and large surface wounds) that have a greater loss of tissue and contamination, heal by secondary intention. Wound healing is commonly divided into three phases: the inflammatory phase, the proliferative phase, and the maturational or remodeling phase

Connective Tissue Repair

Inflammatory Phase The inflammatory phase of wound healing begins at the time of injury and is a critical period because it prepares the wound environment for healing. It includes hemostasis and the vascular and cellular phases of inflammation. Proliferative Phase The proliferative phase of healing usually begins within 2 to 3 days of injury and may last as long as 3 weeks in wounds healing by primary intention. The primary processes during this time focus on the building of new tissue to fill the wound space. The key cell during this phase is the fibroblast. The fibroblast is a connective tissue cell that synthesizes and secretes collagen and other intercellular elements needed for wound healing. Remodeling Phase The third or remodeling phase of wound healing begins approximately 3 weeks after injury and can continue for 6 months or longer, depending on the extent of the wound. As the term implies, there is continued remodeling of scar tissue by simultaneous synthesis of collagen by fibroblasts and lysis by collagenase enzymes. Factors That Affect Wound Healing 1. Malnutrition Successful wound healing depends in part on adequate stores of proteins, carbohydrates, fats, vitamins, and minerals. It is well recognized that malnutrition slows the healing process, causing wounds to heal inadequately or incompletely. Carbohydrates are needed as an energy source for white blood cells. Carbohydrates also have a protein-sparing effect and help to prevent the use of amino acids for fuel when they are needed for the healing process. Although most vitamins are essential cofactors for the daily functions of the body, only vitamins A and C have been shown to play an essential role in the healing process. Vitamin C is needed for collagen synthesis. Vitamin A functions in stimulating and supporting epithelialization, capillary formation, and collagen synthesis. 4

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Blood Flow and Oxygen Delivery For healing to occur, wounds must have adequate blood flow to supply the necessary nutrients and to remove the resulting waste, local toxins, bacteria, and other debris. Impaired wound healing caused by poor blood flow may occur as a result of wound conditions (e.g., swelling) or pre-existing health problems. Arterial disease and venous pathology are well-documented causes of impaired wound healing. In situations of trauma, a decrease in blood volume may cause a reduction in blood flow to injured tissues.

Impaired Inflammatory and Immune Responses Inflammatory and immune mechanisms function in wound healing. Inflammation is essential to the first phase of wound healing, and immune mechanisms prevent infections that impair wound healing. Among the conditions that impair inflammation and immune function are disorders of phagocytic function, diabetes mellitus, and therapeutic administration of corticosteroid drugs. The therapeutic administration of corticosteroid drugs decreases the inflammatory process and may delay the healing process. These hormones decrease capillary permeability during the early stages of inflammation, impair the phagocytic property of the leukocytes, and inhibit fibroblast proliferation and function. 4. Infection, Wound Separation, and Foreign Bodies Wound contamination, wound separation, and foreign bodies delay wound healing. Infection impairs all dimensions of wound healing. It prolongs the inflammatory phase, impairs the formation of granulation tissue, and inhibits proliferation of fibroblasts and deposition of collagen fibers. Body Temperature Regulation The temperature within the deep tissues of the body (core temperature) is normally maintained within a range of 36.0C to 37.5C Body temperature reflects the difference between heat production and heat loss. Body heat is generated in the tissues of the body, transferred to the skin surface by the blood, and then released into the environment surrounding the body dissipation. The thermostatic set point of the thermoregulatory center is set so that the core temperature is regulated within the normal range. When body temperature begins to rise above the normal range, heat-dissipating behaviors are initiated; when the temperature falls below the normal range, heat production is increased. Metabolism is the bodys main source of heat production. The sympathetic neurotransmitters, epinephrine and norepinephrine, which are released when an increase in body temperature is needed, act at the cellular level to shift metabolism so energy production is reduced and heat production is increased. Shivering is initiated by impulses from the hypothalamus. The first muscle change that occurs with shivering is a general increase in muscle tone, followed by an oscillating rhythmic tremor involving the spinal-level reflex that controls muscle tone.

Mechanisms of Heat Loss 5

a. Radiation. Radiation involves the transfer of heat through the air or a vacuum. Heat from the sun is carried by radiation. The human body radiates heat in all directions. The ability to dissipate body heat by radiation depends on the temperature of the environment. Environmental temperature must be less than that of the body for heat loss to occur. b. Conduction. Conduction involves the direct transfer of heat from one molecule to another. Blood carries, or conducts, heat from the inner core of the body to the skin surface. Normally, only a small amount of body heat is lost through conduction to a cooler surface. However, loss of heat by conduction to air represents a sizable proportion of the bodys heat loss. c. Convection. Convection refers to heat transfer through the circulation of air currents. Normally, a layer of warm air tends to remain near the bodys surface; convection causes continual removal of the warm layer and replacement with air from the surrounding environment. d. Evaporation. Evaporation involves the use of body heat to convert water on the skin to water vapor. Water that diffuses through the skin independent of sweating is called insensible perspiration. Fever Fever, or pyrexia, describes an elevation in body temperature that is caused by a cytokineinduced upward displacement of the set point of the hypothalamic thermoregulatory center. Fever can be caused by a number of microorganisms and substances that are collectively called pyrogens . Many proteins, breakdown products of proteins, and certain other substances, including lipopolysaccharide toxins released from bacterial cell membranes, can cause the set point of the hypothalamic thermostat to increase. Patterns The patterns of temperature change in persons with fever vary and may provide information about the nature of the causative agent. These patterns can be described as intermittent, remittent, sustained, or relapsing. An intermittent fever is one in which temperature returns to normal at least once every 24 hours. Intermittent fevers are commonly associated with conditions such as gram-negative/positive sepsis, abscesses, and acute bacterial endocarditis. In a remittent fever, the temperature does not return to normal and varies a few degrees in either direction. It is associated with viral upper respiratory tract infections. In a sustained or continuous fever, the temperature remains above normal with minimal variations (usually less than 0.55C or 1F). Sustained fevers are seen in persons with drug fever. A recurrent or relapsing fever is one in which there is one or more episodes of fever, each as long as several days, with one or more days of normal temperature between episodes. Relapsing fevers may be caused by a variety of infectious diseases, including tuberculosis, The physiologic behaviors that occur during the development of fever can be divided into four successive stages: a prodrome; a chill, during which the temperature rises; a flush; & defervescence. During the first or prodromal period, there are nonspecific complaints, such as mild headache and fatigue, general malaise, and fleeting aches and pains. 6

Manifestations

During the second stage or chill, there is the uncomfortable sensation of being chilled and the onset of generalized shaking, although the temperature is rising. The third stage or flush begins, during which cutaneous vasodilation occurs and the skin becomes warm and flushed. The fourth, or defervescence, stage of the febrile response is marked by the initiation of sweating. Common manifestations of fever are anorexia, myalgia, arthralgia, and fatigue. These discomforts are worse when the temperature rises rapidly or exceeds 39.5C. Respiration is increased, and the heart rate usually is elevated. Dehydration occurs because of sweating and the increased vapor losses caused by the rapid respiratory rate.

Diagnosis and Treatment Sometimes it is difficult to establish the cause of a fever. A prolonged fever for which the cause is difficult to ascertain is often referred to as fever of unknown origin (FUO). FUO is defined as a temperature elevation of 38.3C or higher that is present for 3 weeks or longer. Among the causes of FUO are malignancies (i.e., lymphomas, metastases to the liver and central nervous system); infections such as human immunodeficiency virus or tuberculosis, The methods of fever treatment focus on modifications of the external environment intended to increase heat transfer from the internal to the external environment, a. Modification of the environment ensures that the environmental temperature facilitates heat transfer away from the body. Sponge baths with cool water or an alcohol solution can be used to increase evaporative heat losses. b. Care must be taken so that cooling methods do not produce vasoconstriction and shivering that decrease heat loss and increase heat production. c. Adequate fluids and sufficient amounts of simple carbohydrates are needed to support the hypermetabolic state and prevent the tissue breakdown that is characteristic of fever. d. Antipyretic drugs, such as aspirin and acetaminophen, often are used to alleviate the discomforts of fever and protect vulnerable organs, such as the brain, from extreme elevations in body temperature. 7

These drugs act by resetting the hypothalamic temperature control center to a lower level, presumably by blocking the activity of cyclooxygenase, an enzyme that is required for the conversion of arachidonic acid to prostaglandin E2