Chapter 3 - Inflammation, The Inflammatory Response, And Fever Flashcards
What are the general Features of inflammation?
Inflammation is the reaction of vascularized tissues to cell injury or death. It is characterized by the production and release of inflammatory mediators, and the movement of fluid and leukocytes from the vascular regions into the extra vascular tissues. They are commonly named by adding the suffix -itis to the affected organ or system appendicitis. Can be acute or chronic. Acute is triggered by noxious stimuli, such as infection or tissue injury, is rapid in onset and is of relatively short duration, lasting from a few minutes to several days.Chronic inflammaation is of a longer duration, lasting for days to years, and is often associated with the proliferation of blood vessels, tissue necrosis, and fibrosis.
What are cells of inflammation?
Endothelial cells - which make up the single-cell-thick linings of blood vessels, help to separate the intravascular and extra vascular spaces. They normally have a nonthrombogenic surface and produce agents that maintain vessel patency, as well as vasodilators and vasoconstrictors that regulate blood flow. Are also key players in the inflammatory response. They provide a selective permeability barrier to exogenous and endogenous inflammatory stimuli; regulate leukocyte extravasation by expression of adhesion molecules and receptor activation; contribute to the regulation and modulation of immune responses through synthesis and release of inflammatory mediators; and regulate immune enzymes proliferation through secretion of hematopoietic colony-stimulating factors.
Platelets - are small, membrane-bound disks circulating in the blood that play an active role in normal hemostasis. Activated platelets also release a number of potent inflammatory mediators, thereby increasing vascular permeability and altering the chemotactic, adhesive, and proteolytic properties of the endothelial cells. When activated, is releases 300 proteins. Many help mediate inflammation.
Leukocytes - or white blood cells - are the major cellular components of the inflammatory response see next card
What are leukocytes? What do the different types do?
Are the major cellular components of the inflammatory response. Granulocytes (neutrophils, eosinophils, and basophils).
Neutrophils - are the most numerous leukocytes in the circulating blood, accounting for 60-70% of all white blood cells. These leukocytes have nuclei that’s are divided into three to five lobes; therefore, they often are referred to as polymorphonuclear neutrophils. Because of their ability to form pseudopods used in ameboid movement, neutrophils are highly mobile, and are the first cells to appear at the site of accrue inflammation, usually arriving within 90 minutes of injury. They are scavenger cells capable of engulfing bacteria and other cellular debris through phagocytosis. Also have oxygen-dependent metabolic pathways that generate toxic sa give oxygen and nitrogen species that aid in the destruction of engulfed pathogens. Have a short life span, They die by apoptosis and disappear within 24-48 hrs after entering the site of inflammation. Stain neutral.
Eosinophils - account for 2-3% of circulating leukocytes and are recruited to tissues in a similar way as the neutrophils. Their appearance at the site of inflammation occur 2=3 hrs after the neutrophils this is in part because of their slower mobility and comparatively slower reaction to chemotactic stimuli. They stain pink with acid dye eosin. Contain a protein that is highly toxic to large parasitic worms that cant be phagocytosis. Also play an important role in allergic reaction by controlling the release of specific chemical mediators.
Basophils and mast cells - are granulocytes with granules that stain blue with a basic dye. Although they account for less than 1% of the circulating leukocytes, they are important participants in inflammatory reactions and are most prominent in allergic reactions mediated by immunoglobulin E. Triggers release of histamine and vasoactive agents from the basophils granules. Mast cells derive from the same hematopoietic stem cells as basophils but don’t develop until they leave the circulation and lodge in tissue sites. They are particularly prevalent along mucosal surfaces of the lung, Gi tract and dermis of the skin. this distribution places them in a sentinel position between environmental antigens and the hosts for a variety of acute and chronic inflammatory conditions. Activation of mast cells results in release of the performed contents of their granules stimulates cytokines and chemokine synthesis by other inflammatory cells such as monocytes and macrophages.
Monocytes/Macrophages - constitute 3%-8% of the white blood cell count. They have a single kidney shaped nucleus and are the largest of the circulating leukocytes. The half-life is about a day, after which they begin to migrate to the site of injure and matur into larger macrophages, which have a longer half-life and greater phagocytosis ability than do blood monocytes. Macrophages produce potent vasoactive mediators including prostaglandins and leukotrienes, platelet activating factor PAF, inflammatory cytokines, and growth factors that promote regeneration of tissues. They are capable of phagocytosis and are active in bacterial killing.They lived three to four times longer and help to destroy the causative agent, aid in the signaling processes of immunity, serve to resolve the inflammatory process, and contribute to initiation of the healing processes. They are especially important in maintaining chronic inflammation.
Lymphocytes and plasma cells - lymphocytes are the smallest of the leukocytes and have a thin rim of cytoplasm surrounded by a deeply staining nucleus. They participate in immune mediated inflammation caused by infectious agents as well as non immune mediated inflammation associated with cell injury and death. Both T and B lymphocytes migrate into inflammatory sites using some of the same adhesion molecules and chemokines that recruit neutrophils and other leukocytes. They communicate in a bidirectional way, and these interactions play an important role in chronic inflammation. Plasma cells develop from B lymphocytes that have become activated after encountering an antigen and receiving T cell help. They produce antibodies directed against persisten antigens and altered tissue components.
What is cell adhesion molecules?
There are several families of cell adhesion molecules, including selectins, integrins, and the immunoglobulin superfamily are involved in leukocyte recruitment and trafficking. The selectins are a family of three closely related proteinsE L P that differ in their cellular distribution but all function in adhesion of leukocytes or platelets to endothelial cells. The integrins consist of different types of structurally similar transmembrane receptor proteins that function as heterodimers to promote cell to cell and cell to extra cellular matrix interactions. Cell adhesion molecules of the immunoglobulin superfamily include intercellular adhesion and vascular adhesion molecules, which interact with integrins on leukocytes to mediate their recruitment. The importance of the leukocyte adhesion molecules is demonstrated in person with an inherited disorder LAD leukocyte adhesion deficiency type 1 , in which deficiency of a member of the integrins superfamily leads to server leukocytosis and recurrent infections.
What is Acute inflammation?
Is the early or almost immediate reaction of local tissues and their blood vessels to injury. It typically occurs before the adaptive immune response becomes established and is aimed primarily at removing the injurious agent and limiting the extent of tissue damage. Can be triggered by a variety of stimuli, including infections, immune reactions, blunt and penetrating trauma, physical or chemical agents and tissue necrosis from any cause.
What are the stages of acute inflammation?
- Vascular stage - the vascular changes that occur with inflammation involve the arterioles, capillaries and ve joes of the micro circulation. These changes begin almost immediately after injury and are characterized by vasodilation and changes in blood flow followed by increase vascular permeability and leakage of protein rich fluid into the extra vascular tissue space. Vasodilation, which is one of the earliest manifestation of inflammation, follows a transient constriction of the arterioles, lasting a few seconds, dilation begins in the arterioles and opens capillary beds in the area. The area becomes congested, causing the redness and warmth associated with acute inflammation. It is induced by the action of several mediators, most notably histamine and nitric oxide. P 53.
Cellular stage - of acute inflammation is marked by the changes in the endothelial cells lining the vasculature and movement of phagocytosis leukocytes into the area of injury or infection. Although attention has been focused on the recruitment of leukocytes from the blood, a rapid response also requires the release of chemical mediators from certain resident cells in the tissues. The sequence of events in the cellular response to inflammation includes leukocyte 1. Marigination and adhesion 2. Transmigration, 3. Chemotaxis 4. Activation and phagocytosis. Chemotaxis is a dynamic and energy directed process of cell migration
- Inflammatory mediators - may be derived from the plasma or produced locally by cells at the site of inflammation. The plasma derived mediators, which are synthesized in the liver include the acute phase proteins, coagulation factors. They are present in the plasma in a precursor form that’s must be activated by a series of proteolytic processes to acquire their biologic properties. Cell derived mediators are normally sequestered in intracellular granules that need to be secreted or newly synthesized in responses to a stimulus. Mediators can act on one or a few target cells, have diverse targets or have differing effects on different types of cells. Most are short lived.
- Plasma derived mediators - the plasma is the source of inflammatory mediators that are products of three major protein cascades or systems; the kallikrein - kininogen system which generates kinins; the coagulation system, which includes the important fibrin end product; and the complement system that includes the various complement protein. Their roles are 1. Causing vasodilation and increasing vascular permeability, 2. Promoting leukocyte activation, adhesion, and chemotaxis, 3. Augmenting phagocytosis.
What are cell derived mediators?
Are released from cells that are present at sites of inflammation. Tissue macrophages, mast cells, endothelial cells, as well as leukocytes that are recruited to the site from the blood are all capable of releasing the different mediators of inflammation as are platelets.
Histamine and serotonin - are classified as vasoactive amines, meaning they are derived from amino acids and act by producing changes in blood vessel tone. Both are stored as preformed molecules in mast cells and other cells and are among the first mediators to be released in acute inflammatory reactions. It produces dilation of arterioles and increases the permeability of venules. It acts at the level of the microcirculation by binding to histamine, receptors on endothelial cells and is considered the principal mediator of the immediate transient phase of inc vascular permeability in the acute inflammatory response. Serotonin mediator, with effects similar to histamine is found primarily within platelet granules and is released during platelet aggregation.
Arachidonic Acid Metabolites - is a20 carbon unsaturated fatty acid found in the phospholipids of cell membranes. Release of it by phospholipases initiates a series of complex reactions that lead to the production of the eicosanoid family of inflammatory mediators. These synthesize prostaglandins which induce inflammation and potent Kate the effects of histamine and other inflammatory mediators
Omega 3 polyunsaturated fatty acids - There has been recent interest in dietary modification of the inflammatory response through the use of omega - polyunsaturated fatty acids. That are present in oily fish and fish oil but can be derived in limited quantities from linolenic acid - flax seed, canola oil, green leafy vegetables, walnuts and soybeans. This acid can’t be produced in the body and must be obtained through the diet. It’s results in partial replacement of omega 3 in inflammatory cell membranes, a change that leads to decreased production of arachidonic acid-derived inflammatory mediators.
Platelet-activating factor - PAF is generated from the membrane phospholipids of virtually all activated inflammatory cells and affects a variety of cell types. In addition to activating platelets, the stimulate neutrophils, monocytes/macrophages, endothelial cells, and vascular smooth muscle. Platelet activating factor induces platelet aggregation and degranulation at the site of injury enhances serotonin release, thereby causing changes in vascular permeability. Also enhances leukocyte adhesion, chemotactic, and leukocyte degranulation and stimulates the synthesis of other inflammatory meadow toes, especially the prostaglandins.
Cytokines and chemokines - are low molecular weight proteins that are important cellular messenger. They modulate the function of cells by paraffins and autocrine mechanisms to cause responses in neighbouring cells and the cells that produced the cytokines. TNF and interleukin can be stimulated by bacterial toxins, immune cells, injury and a variety of inflammatory stimuli. Features of these systemic responses include fever, hypotension and inc heart rate, anorexia, release of neutrophils into the circulation, and increased levels of corticosteroid hormones. Chemokines are a family of small proteins that act primarily as chemoattractants that both recruit and direct the migration of inflammatory and immune cells. Two types inflammatory and homing chemokines.
Nitric oxide - which is produced by a variety of cells, plays multiple roles in inflammation, including relaxation of vascular smooth muscle; antagonism of platelet adhesion, aggregation and degranualation; and as a regulator of leukocyte recruitment. Thus, production of NO appears to be an endogenous compensatory mechanism that reduces the cellular phase of inflammation.
Reactive oxygen species - may be released extracellularly from leukocytes after exposure to microbes, cytokines, and immune complexes or in the phagocytosis process that occurs during the cellular phase of the inflammatory process. The superoxide radical, hydrogen peroxide and hydroxyl radical are the major species produced within the cell. These species can combine with NO to form other reactive nitrogen intermediates. They can increase the expression of cytokines and endothelial adhesion molecules, amplifying the cascade that elicits the inflammatory process and increase cell proliferation.
What are local manifestations? What is an abscess? What is ulceration?
Are determined by severity of the reaction, its specific cause, and the site of involvement, can range from mild swelling and redness to abscess formation or ulceration. It can injure adjacent tissues. As a normal attempt to clear damaged and dead tissues the inflammatory response may prolong and exacerbate the injurious consequences of the infarction. It produces exudates which there are 5.
- Serous - are watery fluids low in protein content that result from plasma entering the inflammatory site.
- Hemorrhagic 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.
- Fibrinogen contain large amounts of fibrinogen and form a thick and sticky mesh work, much like the fibers of a blood clot.
- Membranous develop on mucous membrane surfaces and are composed of necrotic cells enmeshed in a fibropurulent exudate.
- Purple to contains pus, which is composed of degraded white blood cells, proteins, and tissue debris. Phone if refers to pus forming such as staphylococcus are more likely to induce localized suppurations inflammation than others
An abscess is a localized area of inflammation containing a purple tissue exudate. They typically have a central necrotic core containing purulent exudates surrounded by a layer of neutrophils.
An ulceration refers to a site of inflammation where an epithelial surface has become necrotic and eroded, often with associated subepithelial inflammation. May occur as the result of traumatic injury to the epithelial surface or because of vascular compromise
What is resolution?
Although manifestation of acute inflammation are largely determined by the nature and intensity of injury, the tissue affected, and the person’s ability to mount a response, the outcome generally results in one of three processes; resolution, progression to chronic inflammation or substantial scarring and fibrosis. It involves neutralization or degradation of inflammatory mediators, normalization of vascular permeability, and cessation of leukocyte infiltration.
What is chronic inflammation?
Is self-perpetuating and may last for weeks, months, or even years. It may develop as a result of a recurrent or progressive acute inflammatory process or from low grade, smouldering responses that fail to evoke an acute response. It is characterized by infiltration with mononuclear cells and attempted connective tissue repair involving angiogenesis and fibrosis. It often begins insidiously as slow grade, smouldering and a symptomatic process. Might lead to tumor development and growth.
What are the causes of chronic inflammation?
Typically are low grade, persistent infections or irritants that are unable to penetrate deeply or spread rapidly. Among the causes of chronic inflammation are foreign agents such as talc, silica, asbestos, and surgical suture materials. Many viruses provoke chronic inflammatory responses, as do certain bacteria such as tubercle bacillus, as well as fungi and larger parasites of moderate to low virulence. Diseases that cause excessive and inappropriate activation of the immune system are increasingly being recognized as causes of chronic inflammation.
What is granulomatous inflammation?
A granulomatous lesion is a distinctive form of chronic inflammation. It is typically small 1-2 mm lesion in which there is a massing of macrophages surrounded by lymphocytes. The macrophages are modified and because they resemble epithelial cells, sometimes are called epithelioid cells. These are derived originally from blood monocytes. Granulomatous inflammation is associated with foreign bodies such as splinters, sutures, silica, and asbestos and with microorganisms that cause tuberculosis, syphilis, sarcoidosis, deep fungal infections and brucellosis. These types of agents have one this in common; they are poorly degraded and usually are not easily controlled by other inflammatory mechanisms.
What is systemic manifestations of inflammation?
Local injury can result in prominent systemic manifestation as inflammatory mediators are released into the circulars ion. The most prominent are the acute phase response, alterations in white blood cell count, and fever. It may extend to the lymphatic system and lead to a reaction in the lymph nodes that drain the affected area.
What are acute phase response? What are the three?
A constellation of systemic effects occur. It includes changes in the concentrations of plasma proteins, skeletal muscle catabolism, negative nitrogen balance, elevated erythrocytes sedimentation rate and increased numbers of leukocytes. Others are fever, increased heart rate, anorexia, somnolence and malaise.
Acute phase proteins - the liver dramatically increases the synthesis of acute phase proteins such as fibrinogen, C-reactive protein CRP, and serum amyloid A protein that serve several different defence functions. CRP is thought to be protective, in that’s it binds to the surface of invading microorganisms and targets them for destruction by complement and phagocytosis.
White blood cell response - The increase in white blood cells, is a frequent sign of an inflammatory response, especially those caused by bacterial infection. In acute inflammatory conditions, the wbc count commonly increases from a normal value of 4000-10000 to 15000-20000. Bacterial infections produce a relatively selective increase in neutrophils, while parasitic and allergic responses induce eosinophilia. Viral infection tend to produce a decrease in neutrophils. And an increase in lymphocytes. A decrease in white blood cells may also occur in persons with overwhelming infections or impaired ability to produce white blood cells.
Systemic inflammatory responses - in severe bacterial infection, the large quantities of microorganisms in the blood result in an uncontrolled inflammatory response with the production and release of enormous quantities of inflammatory cytokines and development of what is referred to as the systemic inflammatory response syndrome. A decrease in total white blood cells may occur in person with overwhelming infections or impaired ability to produce white blood cells.
What is fever? What are the systems that help regulate it?
Is an elevation in body temperature caused by an upward displacement of the set point of the thermoregulatory center in the hypothalamus. It is one of the most prominent manifestations of the acute phase response.
Body temperature regulation - the temp in the deep tissues of the body is normally maintained within a range of 36-37.5. Within this range, there are individual differences and diurnal variations; internal core temperatures reach their highest point in late afternoon and evening and their lowest point in the early morning hours. It is regulated by the thermoregulatory center in the hypothalamus. 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. It regulates the temp in core of the body. It does so by inter rating input from cold and warmth receptors located throughout the body and participating in negative feedback mechanisms. When it raises above set point heat dissipating behaviours are initiated and when below heat production is increased. Spinal cored injuries above T6 can seriously impair temp regulation
