Module 4

phagocyte margination and Diapedesis

Margination: Phagocytes adhere to the endothelium via interaction of leukocyte and endothelial adhesion molecules and then roll down the endothelial surface toward the area of injury. This is called margination. Endothelial and leukocyte adhesion molecules include selectins, integrins, intercellular adhesion molecules (ICAM), and vascular adhesion molecules (VCAM). Diapedesis: Phagocytes squeeze between retracted endothelial cells and cross the basement membrane into the tissues. Additional adhesion molecules help the phagocytes move between the endothelial cells.

What are the three kinds of barriers of innate immunity?

Physical, mechanical, and biochemical barriers

How are platelets involved in inflammation?

Platelets are activated by tissue injury and by inflammatory chemicals (e.g., platelet-activating factor from mast cells). In addition to their primary role in forming thrombi to stop bleeding, they also can degranulate alpha and dense granules that contain a broad range of chemicals including growth factors, protease inhibitors, adhesion molecules, adenosine and serotonin which play an important role in the innate immune response.

What is wound contraction?

it is necessary for all wound closure especially those of secondary intention. Contraction is noticeable 6-12 days after injury.

What is epithelialization, and how does it occur?

sealing of the wound

Learning Objectives

1) Describe the human defense mechanisms that comprise the first line of defense. 2) Describe the basic characteristics of the vascular acute inflammatory response. 3) Describe the inflammatory role of plasma proteins, including the complement, clotting, and kinin systems. 4) Describe the basic features of the cellular mediators of inflammation, including receptors. 5) Identify the role of mast cells in the inflammatory response. 6) Describe the major chemicals that mediate inflammation. 7) Define the roles of the major inflammatory cells, including polymorphonucleocytes, macrophages, eosinophils, natural killer cells, and platelets. 8) Describe the actions of the inflammatory cytokines, including tumor necrosis factor, interleukins, and interferon. 9) Identify the local and systemic manifestations of acute and chronic inflammation. 10) Describe the processes of resolution and repair. 11) Identify the mechanisms of dysfunctional inflammation and wound healing. 12) Compare and contrast mechanisms of self-defense in the pediatric and older adult populations.

What are the major features of inflammation?

1. blood vessel dilation 2. Increased vascular permeability and leakage of fluid out of the vessel 3. white blood cell adherence to the inner walls of vessels and their migration through vessel walls to the site of injury.

What are the benefits of inflammation?

1. prevent infection and further damage by contaminating microorganisms through the influx of fluid to dilute toxins produced by bacteria and released from dying cells. 2. limit and control the inflammatory process through the influx of plasma protein systems that prevent the inflammatory response from spreading to healthy tissue. 3. interact with the components of adaptive immunity to elicit a more specific response to contaminating pathogens through the influx of macrophages and lymphocytes 4. Prepare the area for healing through removal of bacterial products, dead cells, and other products of inflammation, and initiation of mechanisms for healing and repair.

What do the interferons do?

A second type of cytokine is interferon. There are three types of interferon (IFN). IFN-alpha and IFN-beta are produced by macrophages and serve to protect healthy cells from viral infection by stimulating the cellular production of antiviral proteins. IFN-gamma is produced by T helper lymphocytes and stimulates macrophages (see Module 05: Adaptive Immunity). IFN-alpha is used therapeutically to treat hepatitis B and C infections and certain cancers.

What is the major role of tumor necrosis factor-alpha (TNF-α)?

A third type of cytokine, tumor necrosis factor-alpha (TNF-alpha) is secreted by many cells, especially by macrophages after stimulation of TLRs, and by mast cells after being stimulated to degranulate. TNF-alpha is important to the inflammatory response and stimulates adhesion molecules, fibroblasts, and monocytes. It is also important in destroying cancer cells, thus its name. Unfortunately, other effects of TNF-alpha include fever, increased hepatic inflammatory protein production, and muscle wasting. Chronic inflammatory conditions characterized by sustained high levels of TNF-alpha such as cancer, heart disease, and infections are frequently associated with severe weight loss and wasting called cachexia. Very high levels of TNF-alpha contribute to life-threatening conditions such as septic shock.

What is a contracture, and how should it be managed?

Excessive wound contraction can result in deformities called contractures. Although the term "contracture" is used most commonly to refer to skin and joint deformities, excessive wound contraction can occur in viscera as well.

What are the phases of inflammation?

Acute Inflammation Acute inflammation is self-limiting and usually resolves within 8 to 10 days with elimination of invaders and/or healing of tissue injury. An example of acute inflammation is the response of the upper respiratory tract to invasion by a virus that causes the common cold. The inflammatory response is what causes the symptoms of an upper respiratory tract infection (runny nose, swollen mucous membranes, sore throat), but the virus is usually eliminated within a few days and symptoms resolve with little or no persistent tissue damage. Acute inflammation is frequently symptomatic, but usually has a good outcome. Chronic Inflammation Chronic inflammation occurs when the invader or injury cannot be eliminated such that there is ongoing stimulation for weeks and even months of the innate and adaptive immune responses. In some cases of chronic inflammation, an invader or a site of injury is walled off by macrophages and scar tissue, resulting in what is called granulomatous inflammation. An example of chronic inflammation is seen in a condition called rheumatoid arthritis in which persistent immune-mediated inflammation of the joints leads to joint dysfunction and permanent deformity. Chronic inflammation may or may not be symptomatic, but is more frequently associated with persistent tissue damage.

What are the major features of the adaptive immune response?

Adaptive immunity is relatively slow to develop but has memory and more rapidly targets and eradicates a second infection with a particular disease causing organism

other cells of inflammation

Although they are not phagocytes, eosinophils play an important role in some forms of inflammation. Eosinophils contain numerous granules that contain cytokines that 1) control the vascular effects of serotonin and histamine and 2) contribute to tissue damage through the release of toxic substances, such as major basic protein and eosinophil cationic protein. They are called to an area of injury by eosinophil chemotactic factor-A (ECF-A), which is released from mast cells. In allergy and asthma, eosinophils are activated by interleukin 5 (IL-5) produced by T helper 2 cells. (See Module 05: Adaptive Immunity.) Eosinophils and their release of toxic substances contribute to the acute allergic and asthmatic response by denuding epithelial membranes and making them more vulnerable to noxious stimuli. They also participate in chronic inflammatory changes that can lead to fibrosis and permanent changes in tissues. An additional role for these caustic substances released from eosinophils is to attack parasites. Eosinophils use antibodies and C3b as opsonins on the surface of parasites and release their cationic proteins directly into the membrane of the parasite, killing it.

What are bacteria-derived chemicals that can contribute to the body's defenses?

Bacteria-derived chemicals: Each surface of the body is colonized by nonpathogenic bacteria and fungi Glossary (microbiome) that contribute to innate immunity in several ways: They compete with pathogens for nutrients and block attachment to epithelial surfaces. Bacteria on the skin and mucous membranes produce chemicals that are toxic to pathogenic microorganisms. Bacteria in the gut prevent overgrowth of toxic microorganisms Nonpathogenic microorganisms "train" the immune system to react more quickly to pathogen invasion. Diminished colonization by these normal bacterial flora (e.g., use of antibiotics) can lead to increased invasion by potentially pathogenic microorganisms such as fungi. Furthermore, if the host becomes immunocompromised, some of the normal flora become "opportunistic" meaning they may cause disease when the hosts defenses are weakened.

other cells of inflammation

Basophils play a relatively minor role in innate immunity. They have large granules that contain many of the same substances as mast cells. They also contain large quantities of interleukin 4 (IL-4), which is important in adaptive immunity and in allergy (see Modules 5 and 6). Fibroblasts are cells that synthesize the extracellular matrix that supports tissues, especially collagen fibers. This is essential to providing tissue integrity and to wound healing. They are diverse in their appearance; for example, skin fibroblasts are very different from synovial fibroblasts, and some even have several characteristics of muscle cells (myofibroblasts). Recently, it has been discovered that fibroblasts may contribute to the transition from acute to chronic inflammation through the secretion of cytokines and chemokines that contribute to a persistent inflammatory response.

How does the acute vascular response contribute to the symptoms of inflammation?

The vascular response consists of vasodilation (hyperemia) and retraction of endothelial cells, leading to increased vascular permeability and fluid exudation. This helps dilute toxins and brings important inflammatory cells and chemicals to the area of injury, but it also causes the clinical manifestations of acute inflammation, including warmth, redness, edema, and exudates.

What are epithelial-derived chemical barriers?

Chemicals produced by both host cells and the normal microbiome can help to prevent pathogen invasion as a part of innate immunity's first line of defense. Epithelial-derived chemicals: Mucus, perspiration, saliva, tears, and earwax can trap organisms and contain substances such as lysozyme that can disable or kill pathogens. They are also frequently too acidic to support bacterial growth. Sebum (produced by sebaceous glands) contains antibacterial and antifungal fatty acids that can kill bacteria. Antimicrobial proteins are secreted by epithelial cells. Cathelicidins and defensins insert into and disrupt bacterial membranes. Collectins (surfactant proteins) promote phagocytosis and interact with the immune system. Other epithelial microbials produced in the intestines Resistin-like molecule b protects against helminth invasion. Bactericidal/permeability-inducing protein causes gram-negative bacterial lysis. Antimicrobial lectin resists infection by gram-positive bacteria.

Other products of mast cell degranulation include the chemotactic cytokines: neutrophil chemotactic factor and eosinophil chemotactic factor of anaphylaxis (ECF-A).

Chemotactic cytokines call cells to the area of injury. As the chemotactic factors are released from the mast cells, they diffuse through the tissues and their concentrations diminish as they move away from the area of injury. Neutrophils and eosinophils (as well as macrophages) can detect chemotactic factors with surface receptors and will move toward the area of highest concentration, thus moving the phagocytes toward the injured mast cells.

What are complement receptors

Complement receptors: Most cells of the immune system have receptors for complement and complement breakdown products. Complement has numerous functions that require interaction with cellular receptors such as mast cell degranulation, chemotaxis and opsonization. (See Screen 34.) Complement receptors on neutrophils and monocyte/macrophages facilitate phagocytosis (opsonization)

What are the key factors involved in wound dehiscence?

Dehiscence results when a wound does not contract normally and pulls apart. This term usually refers to wounds that have been sutured and occur due to wound sepsis or excessive strain on the wound as can occur in obesity or premature return to activity.

What is meant by the maturation phase of healing?

During wound maturation, the tissue filling the area of injury undergoes remodeling. This remodeling results in the disappearance of the capillaries and formation of a stronger tissue repair. This process differs in the various tissues of the body. Mature healing of wounds of the skin is usually easy to recognize. Wound healing in many other tissues such as lung often results in fibrosis that can only be seen on biopsy or on x-rays.

What are the roles of the endothelium in inflammation? The endothelial cell-derived vasodilator, nitric oxide (NO), plays an important role in inflammation. This gas is produced when endothelial cell nitric oxide synthetase is activated by cellular injury. NO causes vasodilation which contributes to the hyperemia (increased blood flow) seen in local inflammatory responses (area becomes red and hot). This helps to bring more phagocytes to the area of injury and can promote healing. However, if there is systemic inflammation such as can be caused by trauma or blood stream infection (sepsis), then the excessive production of NO causes widespread systemic vasodilation. This vasodilation causes blood to be diverted to nonessential tissues while vital organs become deprived of adequate oxygen and nutrients. This can result in hypotension and organ dysfunction associated with shock.

Endothelial cells line the walls of blood vessels and serve many important functions. First, they control the activity of platelets by preventing contact with the underlying connective tissue matrix of the vessel wall and by secreting anticoagulant chemicals. Second, endothelial cells produce the vasodilators nitric oxide and prostacyclin. In innate immunity, inflammatory cytokines produced from mast cells and macrophages cause adhesion molecules to be expressed on the endothelium thus promoting leukocyte adhesion and diapedesis outside of the vessel and into the inflamed tissue. Furthermore, injury to the endothelium itself causes inflammation and clotting, and chronic conditions such as hyperglycemia in diabetes can inhibit normal endothelial function and contribute to decreased innate immunity.

What causes fever?

Fever: An increase in body temperature (febrile response) can be important to ridding the body of some temperature-sensitive microorganisms, but it can also be detrimental if it is too severe or prolonged. It results from the effect of inflammatory cytokines TNF-alpha, IL-1, IL-6, and prostaglandins (endogenous pyrogens) on the hypothalamus and vasomotor center.

How do macrophages and natural killer cells contribute to inflammation?

For macrophages to kill certain infectious agents most effectively, they require activation by lymphokines produced from T helper cells, especially interferon. (See Module 05: Adaptive Immunity.) These lymphokines make the macrophage increase in size, have more phagocytic activity, and increase the number of lysosomes. When there is immune dysfunction such that the T helper cells do not secrete adequate lymphokines, certain infections may persist within macrophages for long periods of time (latency) without being killed. The organism may be contained for long periods by the formation of a granuloma. Among these types of infections include those caused by mycobacterium (tuberculosis and leprosy), Salmonella typhi (typhoid fever), and Listeria monocytogenes (listeriosis). If an individual with one of these latent infections becomes more immunocompromised later in life, these organisms will begin replicating and cause disease. Natural killer (NK) cells have their own unique receptors that can recognize damaged cells. Although they are usually considered a part of the adaptive immune response, they play a role in innate immunity as well. In addition to their primary role in the detection and elimination of cancer cells, they can also recognize some cells that are damaged by intracellular infection, especially viruses. After recognition and binding to damaged cells, NK cells release toxic molecules that kill the target cell.

Mast cell degranulation results in the release of numerous preformed mediators within seconds of the injury. The major preformed mediators are histamine and chemotactic factors.

Histamine is a vasoactive amine that stimulates 4 different types of receptors (H1-H4). The two most important of these are histamine 1 (H1) and histamine 2 (H2) receptors. Histamine contributes to the inflammatory response by interacting with H1 receptors. Stimulation of these receptors causes brief vasoconstriction followed by vasodilation. Histamine also causes an increase in capillary permeability by stimulating endothelial cells to retract, opening the spaces between cells, which allow cells and proteins to move out of the vessel and into the tissues (edema). Histamine receptors located on white blood cells help to activate neutrophils and macrophages that provide the cellular inflammatory response. Thus, the vasoactive effects of histamine and serotonin result in hyperemia and the movement of fluid, cells, and proteins out of vessels and into the injured tissues. Histamine binding to the H2 receptor is anti-inflammatory and serves as a control to the inflammatory response. The H2 receptor is abundant in the parietal cells of the stomach and induces gastric acid secretion.

What are the mechanisms of cellular injury: Discuss at least one example of each mechanism.

Hypoxic injury- ischemia Reactive Oxygen Species and free radical induced injury- ROS produced by neutrophils or vascular cells chemical injury- carbon monoxide, carbon tetrachloride, lead

What are the steps in collagen deposition?

Immature collagen is secreted by fibroblasts. Crosslinking by bonds changes procollagen fibrils to collagen fibers and this is repeated to keep adding strength to the final collagen matrix.

What are the major types of inflammatory exudate?

In addition to tissue swelling, the fluid exudation may result in the formation of exudates that can be serous (clear fluid with few cells, e.g., blister), fibrinous (thick fluid with proteins, e.g., pericarditis), purulent (thick fluid with white blood cells and microorganisms, e.g., abscess), or hemorrhagic (sanguineous, or full of red blood cells).

What are pathogen recognition receptors and pathogen-associated molecular patterns?

In order for cells to recognize that invasion by a pathogen has occurred, they must have receptors that allow them to recognize foreign proteins and to respond to stimulatory chemicals. Receptors on lymphocytes, which are the primary cells of adaptive immunity, are highly specific and will be discussed in Module 5, Adaptive Immunity. The cells of the innate immune system have less specialized receptors. These receptors, sometimes called pattern recognition receptors (PRRs), recognize pathogen-associated molecular patterns (PAMPs) or the chemical products of cellular damage (damage-associated molecular patterns or DAMPS):

What can cause impaired collagen synthesis and how might it present clinically?

Inadequate intake or absorption of nutrients such as vitamin C, iron, alpha-ketoglutarate, manganese, copper, and calcium can contribute to abnormal synthesis of collagen by fibroblasts. An important example of a nutritional deficit that can impair collagen synthesis is scurvy. Scurvy results from inadequate vitamin C intake. This was a well-recognized condition among sailors prior to the 19th century and resulted in serious illness due to abnormal connective tissue formation and poor wound healing. Sailors complained of bodily weakness, inflamed and bleeding gums, loose teeth, swollen and tender joints, and easy bruising. Citrus fruits were distributed to British sailors beginning in 1795. Ehlers-Danlos syndrome is an example of a congenital disorder that results in impaired collagen synthesis. There are several different forms of this syndrome that result in abnormal collagen production. Although the condition varies widely in terms of the severity of symptoms, typical complaints include joint subluxations and dislocations, easily injured and stretchy skin, poor wound healing, and visual difficulties. Examination may also show evidence of mitral valve prolapse, malformed teeth and periodontitis, and deformed corneas. Diagnosis is made by collagen testing and serum ceruloplasmin. There is no treatment, but genetic counseling should be offered. Overproduction of collagen can cause the formation of a keloid, which is an overgrowth of scar that extends beyond the original boundaries of the wound and can invade surrounding tissue. It is most common in African Americans and runs in families. Treatment requires the use of steroid injections, compression, cryotherapy, radiation, or interferons since surgical removal alone usually results in recurrence of the keloid.

To what types of infection are older adults more susceptible?

Infections of the lungs, urinary tract, and skin.

What are the two pathways of activation of the coagulation cascade?

Injured cells or collagen exposure

What is the major role of interleukins?

Interleukins are important cytokines to both innate and acquired immunity. They are produced by activated macrophages and lymphocytes and act on other cells and tissues to regulate the inflammatory and immune responses to injury or invasion. One of the most important interleukins is IL-1 which causes fever (pyrogen) and activates phagocytes. It can also serve as a growth factor and induces the proliferation and chemotaxis of inflammatory cells such as PMNs. IL-6 is produced by macrophages and lymphocytes and stimulates the proteins of inflammation. IL-10 is an anti-inflammatory interleukin that balances the inflammatory and immune response. It works mainly by reducing the production of inflammatory cytokines from macrophages and by suppressing lymphocyte proliferation and activity.

What are the major phagocytes of the inflammatory response and what is the role of each in the inflammatory response?

It is necessary to be able to recognize the many interchangeable names of this important phagocyte: polymorphonuclear neutrophils, polymorphonucleocytes, neutrophils, PMNs, and segmented neutrophils. On many clinical units, even shorter nicknames are used to identify neutrophils: "segs" or "polys." Immature neutrophils are also known as "bands." These phagocytes are a part of the "white blood count" that is obtained from the blood of patients to evaluate many diseases. (See Module 13: Alterations of Leukocyte, Lymphoid, and Hemostatic Function.) Frequently, in addition to a complete blood cell count (CBC), a "white blood cell differential" is also obtained, which lists the relative proportions (expressed as a percentage) of each of the white blood cells present in the patient's blood. Neutrophils are normally the most numerous leukocytes in the blood and are the first cells to be identified in the differential. They are essential to adequate innate immunity, especially the protection against microorganisms. Note the characteristic multi-lobed or segmented nucleus and the cytoplasm that appears dappled due to the presence of lysosomal granules. These granules are what identify the neutrophil as being derived from the granulocyte line of blood cell maturation. Neutrophils are the first phagocytes to arrive at the inflammatory site, usually arriving within 6 to 12 hours. Their main role is phagocytosis of bacteria and debris, and they are responsible for the release of many inflammatory substances into the area of injury. They also are the primary components of purulent exudates (pus).

What is meant by leukocytosis and a "left shift"?

Leukocytosis, an increase in the white blood cell count (WBC), is a common finding associated with the inflammatory response. The neutrophil is the first phagocyte that is activated in inflammation. It is also the most numerous white blood cell, or leukocyte, in the blood. With the release of IL-1 and TNF-alpha early in the inflammatory response, the bone marrow releases more neutrophils, even some that are still a bit immature (called bands). In most individuals with an inflammatory condition (especially a bacterial infection), the WBC will be elevated and the percentage of neutrophils will be increased on the white blood cell differential. Because the percentage of each white blood cell type is reported in a horizontal fashion from most laboratories and because the bands and neutrophils are reported first, the differential count is described as having a "left shift" when there is a significant neutrophilia. Inflammation associated with viral infections often causes a greater increase in the lymphocyte count than the neutrophils, and no left shift is seen.

What are the indicators of chronic inflammation?

Lymphocytes and macrophages are the primary cells of chronic inflammation.

What is a granuloma and what causes it to be formed?

Lymphocytes and macrophages are the primary cells of chronic inflammation. Macrophages may differentiate into epithelioid cells (which are inefficient phagocytes) or fuse into giant cells (which are excellent phagocytes and can envelop large particles). These cells gather around foreign bodies or infectious agents and form what is called a granuloma. A granuloma consists of a wall of epithelioid cells surrounding the nidus (focal point) of persistent inflammation, often with necrotic tissue at its core. Fibrin deposition and calcification of the lesion may also occur. A classic example of this kind of chronic inflammation process is tuberculosis. Mycobacterium tuberculosis is an important cause of pneumonia. It is difficult to clear this infection by the acute inflammatory response and it frequently results in chronic inflammation. Epithelioid cells surround the organism and form a granuloma that is frequently calcified. These lesions are often seen on chest x-ray films and are seen as larger areas of infiltrate in combination with calcified granulomas in the hilar area (Ghon complex). Sarcoidosis is an idiopathic autoimmune disorder characterized by granuloma formation, especially in the lungs and the skin.

What are epithelioid cells, and what are giant cells?

Macrophages may differentiate into epithelioid cells (which are inefficient phagocytes) or fuse into giant cells (which are excellent phagocytes and can envelop large particles). These cells gather around foreign bodies or infectious agents and form what is called a granuloma

phagocytes continued (macrophages)

Monocytes are easy to distinguish from neutrophils in that they are larger and have a single nucleus that is indented but not segmented. The monocyte also has a dappled nucleus with numerous lysozymes, although these frequently do not show up as clearly on routine blood cell staining as do those of the neutrophil. Monocytes move into tissues and remain there for long periods of time. They are then called macrophages and have different names depending on where they reside (e.g., liver macrophages are called Kupffer cells and brain macrophages are called microglial cells). Monocytes and macrophages move more slowly toward the area of inflammation (3 to 7 days) but once they arrive, they can survive longer than neutrophils in the inflammatory environment and provide long-term defense against the invader. Macrophages serve many important functions in the inflammatory response: Provide prolonged phagocytosis at the site of inflammation Process and present antigens to the immune system (See Module 05: Adaptive Immunity.) Release numerous inflammatory cytokines such as IL-1 and TNF alpha Promote healing through the release of growth factors and angiogenesis factors (promote new blood vessel formation)

What basic concepts underlie current understandings of cellular aging and death?

Necrosis (coagulative, liquefactive, caseous, fat, and gangrenous necrosis) Apoptosis and Autophagy

What is the process of phagocytosis?

Neutrophils and macrophages are very efficient phagocytes and can ingest dead cells, cellular debris, foreign bodies, and microorganisms. Some bacteria have capsules, and the process of opsonization is necessary for effective phagocytosis. (Review the actions of complement components.) The process of phagocytosis proceeds in four steps: 1) opsonization, recognition, and adherence, 2) engulfment (or endocytosis) and formation of a phagosome, 3) fusion with lysosomal granules inside the phagocyte, and 4) destruction of the invader by lysosomal enzymes. Neutrophils are faster at getting there but don't last as long as the macrophages. Both cells are attracted to the site of injury by chemotactic factors released from the mast cell and from the protein systems such as neutrophil chemotactic factor, complement C3a and C5a, and clotting and kinin cascade products. Once at the scene, neutrophils also can release chemotactic factors for macrophages.

What characteristics make older adults at risk for impaired inflammation and wound healing?

Older adults also have impaired inflammatory and immune function. In addition to a natural decline in inflammatory cell function, older adults are also more likely to have other illnesses and/or to be on medications that further interfere with the ability to respond to infections and other inflammatory insults. Natural barriers such as skin and mucous membranes also lose many of their structural features that help them protect against invaders. Many older adults do not demonstrate clear signs and symptoms of inflammatory conditions such as infection until late in the course of the disease; therefore they often receive delayed treatment and have an increased morbidity and mortality related to these disorders.

What are the different active components of complement, and what do they do? C3a and C5a - chemotaxis and degranulate mast cells (anaphylatoxins); C3b and C5b - opsonize encapsulated bacteria; C5-C9 - membrane attack complex.

Once complement is activated, its components perform several important inflammatory actions: opsonize encapsulated bacteria making them easier to phagocytose, serve as chemotactic factors for other leukocytes, induce mast cell degranulation (anaphylatoxins), and induce cell lysis and death (membrane attack complex). Opsonization means that complement C3b and C5b (along with antibodies) make it easier for phagocytes to ingest bacteria, especially those organisms that have capsules that make them difficult to phagocytose. Phagocytes have receptors on their surfaces for complement and antibodies and can thus "grab" onto the bacteria and pull them into the cell to be destroyed. Chemotaxis describes the chemical signaling that causes leukocytes to move toward an area of inflammation. C3a and C5a are the complement components most involved in chemotaxis. Chemotaxis will be discussed in more detail later in this module. Mast cell degranulation by complement C3a and C5a results in the release of vasoactive chemicals such as histamine and serotonin which cause hyperemia and fluid exudation. View the Mast Cell Degranulation Animation. (This will be explored in more detail later in this module.) The membrane attack complex is a group of complement components (C5-C9) that bind to the lipid bilayer of cell membranes forming cylindrical channels (pores). These pores in the membranes of target cells allow water to pour in, leading to cell lysis and cell death.

What can cause impaired epithelialization and how can it be prevented?

Processes that inhibit migration of epithelial cells over the area of injury include anti-inflammatory steroids, hypoxemia, radiation, and zinc deficiency. Commonly, epithelialization is impaired by the use of toxic solutions for wound cleaning (e.g., hydrogen peroxide) and by the application of dry wound dressings that debride the healthy granulation tissue when they are removed.

What are some of the important control systems for inflammation?

Some of the inhibitors include carboxypeptidase, histaminases, kinases, and c1 esterase inhibitor.

What is meant by the term "debridement"?

The cleaning up of the lesion, which involves dissolution of fibrin clots by fibrinolytic enzymes

What else does the clotting system contribute to inflammation? An abbreviated coagulation cascade is depicted in Figure 7-6 on page 199 in your textbook

The clotting system is not only vital to preventing bleeding from injured blood vessels, it also plays a role in inflammation by promoting chemotaxis of neutrophils and increasing vascular permeability. The coagulation cascade consists of many components that form via the extrinsic and intrinsic pathways. Injured cells, bacterial products, and exposed collagen can begin the cascade of events leading to the production of a fibrin clot that: Stops bleeding. Helps prevent the spread of inflammation and infection. Keeps the invader near the site of injury, thus maximizing the access of inflammatory cells and proteins. Results in the formation of two peptides (fibrinopeptides A and B) that are released during the formation of fibrin and are chemotactic for neutrophils and increase vascular permeability Provides a framework for repair and healing

What is complement?

The complement system is made up of a group of plasma proteins, and its components participate in almost every step of the inflammatory response.

How do blood vessels respond to cellular injury?

The first cell to react to direct tissue injury is the mast cell. Within seconds of cellular injury from any cause, the mast cell releases chemicals that initiate a vascular response. This response consists of a brief vasoconstriction followed by vasodilation and increased vascular permeability in the area of injury. These vascular changes allow cells and proteins to move out of the blood vessels and into the injured tissues. This results in four easily recognized characteristics: redness, heat, swelling, and pain.

What are the shared characteristics of inflammatory cytokines? The major inflammatory cytokines are: Interleukins Interferons Tumor necrosis factor-alpha

The functions of the inflammatory cytokines include the following: Most enhance inflammation (pro-inflammatory) (TNF-alpha, IL-1, IL-6, interferons). Some initiate and promote the adaptive immune response (IL-2, IL-4, IL-5). A few are anti-inflammatory (IL-10, transforming growth factor beta, histaminase). Most act on the cells and tissues in their immediate vicinity. When a significant inflammatory response is initiated, these products may spill into the blood stream and cause systemic manifestations such as fever (TNF-alpha, IL-1). They bind to receptors on inflammatory cells. Activity may vary depending on the target cell and its receptors. They may act synergistically or antagonistically. Some are more active in some stages of inflammation than others. Growth factors, angiogenic factors, and metalloproteinases contribute to healing.

What is granulation tissue?

The growing inward of surrounding healthy connective tissue filled with new capillaries that is red and granular in appearance and is surrounded by fibroblasts and macrophages.

How do healing by primary intention and by secondary intention differ from one another?

The inflammatory response, with its removal of foreign invaders, is necessary for wound healing. Further preparation of the injured tissue includes debridement by fibrinolytic enzymes followed by reversal of the vasodilation and endothelial permeability. Repair begins with the goals of filling, sealing, and shrinking the wound. If the wound is small and the edges are clean and closely apposed, then healing occurs by primary intention. If the wound is larger, then healing takes much longer and occurs through secondary intention. To review wound repair by primary or secondary intention see Figure 7-19 on page 217

What is the kinin system, and what are its effects?

The kinin system is activated by essentially the same stimuli as the clotting system and is characterized by a cascade of events that create active substances. Activation of the kinin system causes: Vasodilation (hyperemia) Increased vascular permeability (fluid exudation) Chemotaxis of inflammatory leukocytes Smooth muscle contraction (bronchoconstriction) Pain The kinin system often works in concert with mast cell cytokines to promote inflammation.

What are the purposes of the acute inflammatory response?

The purposes of the acute inflammatory response include, Prevent serious infection and further damage by microorganisms through the dilution of toxins and destruction of microorganisms by complement and phagocytes. Limit and control the inflammatory response so it does not damage healthy tissue. Activate the adaptive immune response to elicit a more specific response. Prepare the area for healing.

How is complement activated? What are the classic and alternative pathways?

The system can be activated by several inflammatory stimuli, including activation by lysosomal enzymes released by neutrophils. However, it is most often activated by antigen-antibody complexes via what is called the classic pathway and by bacterial and fungal products via the alternative pathway. A third pathway, called the lectin pathway, is initiated by the carbohydrates contained in some bacterial walls

Engulfment of the target leads to the formation of an intracellular vacuole called a phagosome. Lysosomes fuse to the phagosomes, thereby forming a phagolysosome. These lysosomes contain several destructive substances: lysozyme, myeloperoxidase, elastase, cationic protein, lactoferrin, lactic acid, and defensins.

The term "respiratory burst" is used to describe an intracellular shift in metabolism that occurs inside the phagocyte once it has formed a phagolysosome. This involves the production of reactive oxygen species (ROS), such as superoxide, peroxide, and nitric oxide. These substances are toxic to many pathogens. ROS are not only produced by phagocytes; they are also produced in the mitochondria of cells throughout the body. However, ROS are often called "toxic oxygen radicals" because they can injure healthy cells if they leak into surrounding tissues. Phagocytes often die at the site of inflammation, causing their cell membranes to lyse, thereby allowing lysosomal enzymes and ROS to destroy surrounding tissues. The substances within the lysosomes are effective at digesting the invader but are released during the inflammatory response into surrounding tissues causing damage to healthy tissue. Inflammatory damage to tissues is associated with many diseases; examples include emphysema, peptic ulcer disease, atherosclerosis, and septic shock. In order to limit tissue damage from release of lysosomal enzymes, there are several circulating inhibitors including endogenous antioxidants and antiproteases, such as alpha 1-antitrypsin. Antioxidants are examples of therapies directed at the toxic oxygen radicals that are released during the inflammatory process.

What are chemokines and what is their role in inflammation? The major chemokines are: CC-chemokines CXC-chemokines

The term chemokines is used to describe a family of peptides that are produced by a wide variety of inflammatory cells and serve to induce leukocyte chemotaxis and activation. Most of these peptides are named as CC-chemokines or CXC-chemokines. CC-chemokines primarily affect monocytes, lymphocytes and eosinophils. CXC-chemokines affect mostly neutrophils. Chemokines have been extensively studied and are implicated in a wide variety of inflammatory, infectious and malignant diseases. For example, CXC-chemokines (CXCR4) and CC-chemokines (CCR5) have been found to be crucial for human immunodeficiency virus (HIV) fusion and penetration into host cells. New therapies for HIV infection are aimed at blocking these chemokines and their receptors and thus preventing HIV fusion. The first such drug (maraviroc), which is a CCR5 antagonist, was approved for use in the United States in August, 2007

What are the systemic manifestations of acute inflammation?

The three major features of the systemic response to acute inflammation are fever, leukocytosis (increased white blood cell count), and an increase in acute phase proteins in the plasma.

To what types of infection are neonates most susceptible?

These defects lead to increased risk for a variety of infections especially those of the skin and respiratory tract. meningitis, sepsis, or respiratory distress syndrome

Why is control of the plasma protein systems essential?

These three protein systems (complement, clotting, and kinin) must interact with one another in order to derive maximum responses to invasion and injury. However, control of these systems is also essential to prevent tissue damage. Three examples of interacting control mechanisms include Formation of plasmin during clot formation which degrades fibrin, but at the same time can activate complement Inactivation of complement anaphylatoxins and chemotactic products by carboxypeptidase Histaminase degrades histamine and kinins Inhibition of the classical complement cascade by C1 esterase inhibitor, which also inhibits both the clotting and the kinin systems Hereditary angioneurotic edema is a clinical example of a lack of control over the plasma protein systems. This disorder results from an inherited lack of C1 esterase inhibitor, resulting in recurrent widespread tissue edema.

How are the various manifestations of cellular injury similar and different from each other?

They all cause a sense of fatigue or malaise, loss of well being, and altered appetite. Fever is frequently present because of biochemicals produced during the inflammatory response.

How do toll-like receptors mediate inflammation?

Toll-like receptors (TLRs): There are at least 10 different functional toll-like receptors. These receptors are located on mucosal epithelial cells, mast cells, neutrophils, macrophages and dendritic cells. They can recognize a variety of pathogen-associated molecules such as lipopolysaccharide (endotoxin), peptidoglycans, yeast and viral proteins, flagellin, and nucleic acids. Perhaps the most important of these is TLR2 which recognizes gram-positive bacteria and TLR4 which recognizes gram-negative bacteria. (See Module 07: Infection) Once the TLRs bind to a PAMP, the cell is activated to release a number of cytokines that amplify the innate immune response and induce the adaptive immune response

Read Chapter 7, pages 205-207 in your textbook.

What are mast cells, what causes their degranulation, and how do they contribute to the inflammatory response? The mast cell is one of the most important inflammatory cells. Mast cells originate in the bone marrow and are derived from the granulocyte line of hematologic cells. They contain a large number of granules filled with preformed chemicals. The mast cell will release these chemicals in response to physical injury (e.g., pressure, heat, radiation), chemical agents (e.g., venom, toxins, proteases), immunologic mechanisms (e.g., binding of IgE or complement), or activation of toll-like receptors by bacteria and viruses. In addition, mast cells will begin synthesizing many important inflammatory cytokines that will be released into the area of injury or insult.

Read Chapter 7, pages 197-201 in your textbook. Reviewing complement pages 197-199 The inflammatory response includes the activation of three plasma protein systems: Complement system Clotting system Kinin system

What are proenzymes, and how are they typically activated? proenzymes are proteins that circulate in inactive forms. They are activated by products of tissue damage or infection.

Read Chapter 7, pages 201-205 in your textbook.

What are some of the most important cells of inflammation? Some of the most important cells are mast cells, macrophages, neutrophils, endothelial cells, eosinophils, platelets, and natural killer cells. These cells use their receptors to respond to molecules that are on pathogens, are produced by tissue injury, or are activated by plasma protein systems (such as complement). Activation of the cells of inflammation leads to their release of a variety of cellular products that increase inflammation. Furthermore, inflammatory cells work to confine the extent of damage, kill microorganisms, and remove cellular debris.

Read Chapter 7, pages 192-195 in your textbook.

What are some of the physical and mechanical barriers that protect the body from invasion? The physical and mechanical barriers to pathogen invasion can be organized into three major categories: Tight junctions between epithelial cells The epithelial cells of the skin and mucous membranes are held tightly together and can prevent many organisms from passing through them and into the body. Mechanical clearance Pathogens may be sloughed off with dead skin, expelled by sneezing, coughing, vomiting, or urination, or removed from the lungs through mucociliary clearance. Body surface temperature For optimal growth, most microorganisms require a temperature of approximately 37°C (98.6°F); therefore, the low temperature on the body's surface generally inhibits growth of microorganisms. Individuals who have suffered burn injuries have lost these important physical and mechanical barriers and are at high risk for infection by serious pathogenic microorganisms.

Read Chapter 7, pages 214-215 in your textbook.

What are the differences between acute and chronic inflammation? Chronic inflammation occurs when the invader or injury cannot be eliminated such that there is ongoing stimulation of the innate and adaptive immune responses. It can occur because of an unsuccessful acute inflammatory response such as when there is a persistent foreign body or infection. Some infections never cause much acute inflammation due to their unique cell walls, but they can cause chronic inflammation. In most cases, chronic inflammation is idiopathic, which means the cause of the inflammation is not known. There are many examples of chronic inflammation. In fact, virtually every chronic disease has an element of chronic inflammation including arthritis, heart disease, hypertension, chronic obstructive pulmonary disease, and even Alzheimer Disease. Unfortunately, anti-inflammatory medications do not always help with these disorders and have many side effects when used chronically.

Read Chapter 7, 195-197 in your textbook.

What are the major components of the inflammatory response? Vascular response, cellular response, and biochemical response The vascular response is complemented by a cellular response mediated primarily by neutrophils and macrophages that help to remove foreign invaders and prepare the wound for healing. The entire process is coordinated and amplified by a chemical response that is mediated by a complex group of plasma proteins and cytokines. These processes collectively result in the symptoms of inflammation, and although this process is vital to defense of the individual, exaggerated inflammatory responses can lead to tissue injury and even death.

Read Chapter 2, pages 49-100 in your textbook

What are the major mechanisms of cellular adaptation? Provide examples of each. Atrophy- decrease in cellular size hypertrophy-increase in cellular size hyperplasia- increase in the number of cells dysplasia- abnormal changes in size, shape, and organization of mature cells metaplasia- replacement of one cell by another

Read Chapter 7, pages 218-220 in your textbook.

What are the mechanisms by which healing can become dysfunctional during the acute inflammatory response? Normal wound healing can be compromised during the acute inflammatory response by prolonged bleeding, excessive fibrin, hypovolemia, anti-inflammatory drugs, immunocompromise, poor nutrition, diabetes, and wound sepsis. These and other complicating conditions can result in impaired collagen synthesis, impaired epithelialization, wound disruption, and impaired contraction.

Read Chapter 7, pages 213-214 in your textbook.

What causes the local manifestations of acute inflammation? The symptoms of acute inflammation are due to the vasodilation with hyperemia and fluid exudation that occur in response to the release of vasoactive substances from the mast cell and activation of plasma protein systems. In addition, prostaglandins and bradykinin stimulate pain fibers and contribute to clotting. Thus, the symptoms of acute inflammation are redness, heat, swelling, pain, and loss of function.

Read Chapter 7, page 220 in your textbook.

What characteristics make neonates prone to infection? Young children, especially neonates, are deficient in: Neutrophil and monocyte chemotaxis and activation. Complement. Collectins (help macrophages identify respiratory pathogens). Oxidative and lysosomal activity in phagocytes.

Read Chapter 7, pages 215-218 and review Figure 7-19 in your textbook.

What do the terms regeneration, resolution, and repair mean? The term regeneration refers to the process in which a tissue is able to stimulate new cell division that allows for the restoration of damaged tissue. Resolution is the result of complete regeneration and restoration of normal tissue function and structure after injury. Repair is the replacement of damaged tissue with scar, which is mostly composed of collagen. An example of all of these processes can be seen in acute and chronic liver injury. In acute injury, the liver has a great capacity for regeneration, often allowing for complete resolution and return to normal liver structure and function. However, with chronic liver damage like that seen with alcoholic cirrhosis, the liver repair results in scar formation that does not support normal liver function. In this image, nodules of hepatic scarring can be seen to replace the normal hepatic parenchyma

Read Chapter 7, pages 191-195 in your textbook.

What is meant by the term "innate immunity"? The natural epithelial barrier and inflammation confer innate resistance and protection

What are the important acute-phase reactants?

Within hours to days of the inflammatory response, the liver begins increasing production of many plasma proteins that can be measured in the blood. Several of these are listed in your text in Table 7-4 on page 214. Some of these are anti-inflammatory, others help in binding to microbial cell walls acting as opsonins, and others contribute to the sequelae of chronic inflammation. Acute-phase reactants are plasma indicators of inflammation. Two are now recognized as important in assessing the risk for coronary heart disease. Increased levels of fibrinogen and C-reactive protein are associated with a significant increased risk for atherosclerosis and ischemic heart disease.

What are the steps in the reconstructive phase of healing?

Wound reconstruction begins within 3 to 4 days of injury and includes clotting, debridement, formation of granulation tissue, epithelialization, fibroblast proliferation, collagen deposition and early wound contraction.

What are damage-associated molecular patterns?

chemical products of cellular damage

What are some examples of tissues that have differing responses to inflammation?

injury to cardiac tissue such as an MI that produces a result of dead tissue turning into a fibrinous scar. The same injury to brain tissue is more likely to result in the formation of an abscess filled with necrotic tissue. Destruction of liver cells stimulates the regrowth, or regeneration of liver cells.

What is an example of a disease caused by inadequate control of plasma inflammatory systems?

hereditary angioedema- a self limiting edema of cutaneous and mucosal layers resulting from stress, illness, or relative minor or unapparent trauma.