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Inflammation

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By: Dr Iana Ushko, PhD

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Inflammation

Inflammation is the response of the vascularized living tissue to injury. It may be evoked by microbial infections, physical agents, chemicals, necrotic tissue, or immune reactions. Inflammation is intended to contain and isolate injury, to destroy invading microorganisms and inactivate toxins, and to preparer the tissue for healing and repair. Although it is fundamentally a protective response, inflammation may also be harmful; it can cause life‐threatening hypersensitivity reactions or relentless and progressive organ damage from chronic inflammation and subsequent fibrosis (e.g., rheumatoid arthritis, atherosclerosis).

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Overview of Inflammation

The ability of organisms to get rid of damaged necrotic tissues and foreign invaders (microbes) is essential for their survival.

The host response that achieves these goals is called inflammation.

This process is a protective response designed to eliminate both the initial cause of cell injury (microbes, toxins) and the consequences of such injury (necrotic cells and tissue).

In the practice of medicine the importance of inflammation is that it can sometimes be inappropriately triggered or poorly controlled, and is thus the cause of tissue injury in many disorders.

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Examples of disorders associated with inflammation include:�

Acne vulgaris

Asthma

Autoimmune diseases

Chronic prostatitis

Glomerulonephritis

Hypersensitivities

Cancer

Diabetes

CVD

Inflammatory bowel diseases

Pelvic inflammatory disease

Reperfusion injury

Rheumatoid arthritis

Sarcoidosis

Transplant rejection

Vasculitis

Interstitial cystitis

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Characteristics of acute inflammation:
Rapid onset of action (typically minutes).
Short in duration (lasts for hours or a few days).
Exudation of fluid and plasma proteins (edema).
Emigration of leukocytes (mainly neutrophils) to the site of injury.

Characteristics of chronic inflammation:
May follow acute inflammation or be insidious in onset.
Long in duration.
Associated with the presence of lymphocytes and macrophages.
Angiogenesis, fibrosis and tissue destruction may occur.

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Inflammation is terminated when the offending agent is eliminated.

- mediators are broken down and dissipated.

- leukocytes have short life span in tissues.

- anti-inflammatory mechanisms are activated.

The inflammatory response is closely intertwined with the process of repair.

- repair begins during inflammation but reaches completion usually after the injurious influence has been neutralized.

- injured tissue is replaced through regeneration of native parenchymal cells, scarring or by a combination of these two processes.

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Acute Inflammation

Definition: It is a rapid host response that serves to deliver leukocytes and plasma proteins, such as antibodies, to sites of infection or tissue injury.

Acute inflammation has 3 major components:

(1) alterations in vascular caliber that lead to an increase in blood flow

(2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation, and

(3) emigration of the leukocytes from the microcirculation, their accumulation in the focus of injury, and their activation to eliminate the offending agent

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Infections (bacterial, viral, fungal, parasitic) and microbial toxins are among the most common and medically important causes of inflammation.

Tissue necrosis from any cause, including ischemia (as in a myocardial infarct), trauma, and physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to some environmental chemicals).

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Mammals possess many mechanisms for sensing the presence of microbes. Among the most important receptors for microbial products are the family of Toll-like receptors (TLRs), named after the Drosophila protein Toll, and several cytoplasmic receptors, which can detect bacteria, viruses, and fungi (Chapter 6). Engagement of these receptors triggers signaling pathways that stimulate the production of various mediators.
Several molecules released from necrotic cells are known to elicit inflammation; these include uric acid, a purine metabolite; adenosine triphosphate, the normal energy store; a DNA-binding protein of unknown function called HMGB-1; and even DNA when it is released into the cytoplasm and not sequestered in nuclei, as it should be normally. Hypoxia, which often underlies cell injury, is also itself an inducer of the inflammatory response. This response is mediated largely by a protein called HIF-1α (hypoxia-induced factor-1α), which is produced by cells deprived of oxygen and activates the transcription of many genes involved in inflammation, including vascular endothelial growth factor (VEGF), which increases vascular permeability.

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Foreign bodies (splinters, dirt, sutures) typically elicit inflammation because they cause traumatic tissue injury or carry microbes.�
Immune reactions (also called hypersensitivity reactions) are reactions in which the normally protective immune system damages the individual's own tissues.

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Reactions of blood vessels in acute inflammation

An exudate is an extravascular fluid that has a high protein concentration, contains cellular debris, and has a high specific gravity.

A transudate is a fluid with low protein content (most of which is albumin), little or no cellular material, and low specific gravity.

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Edema denotes an excess of fluid in the interstitial tissue or serous cavities; it can be either an exudate or a transudate.

Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells.

The vascular reactions of acute inflammation consist of:

- changes in the flow of blood.

- changes in the permeability of vessels.

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Edema in inflammation

Edema is a general term for swelling (usu. due to fluid)

Plasma proteins in blood maintain a “colloid osmotic pressure” to help draw fluid that leaks out into tissue bed via hydrostatic pressure

Dysregulation of hydrostatic pressure (e.g. heart failure) and/or colloid pressure (decresased protein synthesis/retention) pushes out more fluid (transudate) into tissue bed

Inflammation causes endothelial cells to separate, thus allowing fluid + protein (exudate) to enter tissue bed.

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Changes in Vascular Flow and Caliber

Vasodilation is one of the earliest manifestations of acute inflammation.

Increased permeability of the microvasculature, with the outpouring of protein-rich fluid into the extravascular tissues.

Stasis which occur as a result of small vessel dilation that are packed with slowly moving red cells.

Migration of leukocytes through the vascular wall into the site of injury.

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Vasodilation first involves the arterioles and then leads to opening of new capillary beds in the area. The result is increased blood flow, which is the cause of heat and redness (erythema) at the site of inflammation. Vasodilation is induced by the action of several mediators, notably histamine and nitric oxide (NO), on vascular smooth muscle.
The loss of fluid and increased vessel diameter lead to slower blood flow, concentration of red cells in small vessels, and increased viscosity of the blood.
As stasis develops, blood leukocytes, principally neutrophils, accumulate along the vascular endothelium. At the same time endothelial cells are activated by mediators produced at sites of infection and tissue damage, and express increased levels of adhesion molecules. Leukocytes then adhere to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue, in a sequence that is described later.�

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Increased Vascular Permeability (Vascular Leakage)

Contraction of endothelial cells resulting in increased inter-endothelial spaces.

Endothelial injury, resulting in endothelial cell necrosis and detachment.

Increased transport of fluids and proteins, called transcytosis, through the endothelial cell.

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Contraction of endothelial cells resulting in increased interendothelial spaces is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,] is the most common mechanism of vascular leakage and is elicited by histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many other chemical mediators.[6,][7] It is called the immediate transient response because it occurs rapidly after exposure to the mediator and is usually short-lived (15–30 minutes). In some forms of mild injury (e.g. after burns, x-irradiation or ultraviolet radiation, and exposure to certain bacterial toxins), vascular leakage begins after a delay of 2 to 12 hours, and lasts for several hours or even days; this delayed prolonged leakage may be caused by contraction of endothelial cells or mild endothelial damage. Late-appearing sunburn is a good example of this type of leakage.
Endothelial injury, resulting in endothelial cell necrosis and detachment.[8].[8] Direct damage to the endothelium is encountered in severe injuries, for example, in burns, or by the actions of microbes that target endothelial cells.[9] Neutrophils that adhere to the endothelium during inflammation may also injure the endothelial cells and thus amplify the reaction. In most instances leakage starts immediately after injury and is sustained for several hours until the damaged vessels are thrombosed or repaired.
Increased transport of fluids and proteins, called transcytosis, through the endothelial cell. This process may involve channels consisting of interconnected, uncoated vesicles and vacuoles called the vesiculovacuolar organelle, many of which are located close to intercellular junctions.[10], many of which are located close to intercellular junctions.[10] Certain factors, such as VEGF (Chapter 3), seem to promote vascular leakage in part by increasing the number and perhaps the size of these channels.

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Responses of the lymphatic vessels

Lymphatic vessels and lymph nodes filter and police the extra-vascular fluid.

In inflammation, lymph flow is increased and helps drain edema fluid that accumulates due to increased vascular permeability.

The lymphatic system may become secondarily inflamed (lymphangitis), as may the draining lymph nodes (lymphadenitis).

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Leukocyte Extravasation

Extravasation: delivery of leukocytes from the vessel lumen to the interstitium

In the lumen: margination, rolling, and adhesion
Migration across the endothelium (diapedesis)
Migration in the interstitial tissue (chemotaxis)

Leukocytes ingest offending agents (phagocytosis), kill microbes, and degrade necrotic tissue and foreign antigens
There is a balance between the helpful and harmful effects of extravasated leukocytes

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Sequence of Leukocyte Emigration

Neutrophils predominate during the �first 6 to 24 hours
Monocytes in 24 to 48 hours
Induction/activation of different adhesion molecule pairs and specific chemotactic factors in different phases of inflammation

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Sequence of Events - Injury

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Sequence of Events - Infection

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Termination of the acute inflammatory response

Mediators of inflammation are produced in rapid bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release.

Neutrophils have short half-lives in tissues and die by apoptosis within a few hours after leaving the blood.

A variety of stop signals are activated:

- a switch in the type of arachidonic acid metabolite produced

- the liberation of anti-inflammatory cytokines (TGF-β and IL-10)

- the production of anti-inflammatory lipid mediators called resolvins and protectins, and

- neural impulses (cholinergic discharge) that inhibit the production of TNF in macrophages

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Outcomes of acute inflammation

Complete resolution

- injury is limited or short lived

- little tissue destruction, and

- parenchymal cells can regenerate

Removal of cellular debris and microbes

Resorption of edema fluid by lymphatics

Healing by connective tissue replacement (fibrosis).

- substantial tissue destruction

- tissue involved is incapable of regeneration

- abundant fibrin exudation in tissues or serous cavities

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Complete resolution. In a perfect world, all inflammatory reactions, once they have succeeded in neutralizing and eliminating the injurious stimulus, should end with restoration of the site of acute inflammation to normal. This is called resolution and is the usual outcome when the injury is limited or short-lived or when there has been little tissue destruction and the damaged parenchymal cells can regenerate. Resolution involves removal of cellular debris and microbes by macrophages, and resorption of edema fluid by lymphatics.
Healing by connective tissue replacement (fibrosis). This occurs after substantial tissue destruction, when the inflammatory injury involves tissues that are incapable of regeneration, or when there is abundant fibrin exudation in tissue or serous cavities (pleura, peritoneum) that cannot be adequately cleared. In all these situations, connective tissue grows into the area of damage or exudate, converting it into a mass of fibrous tissue—a process also called organization.

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connective tissue grows into the area of damage or exudate (organization)

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Pulmonary vein completely obliterated by a thrombus with organization.

The thrombus was replaced by an immature granulation tissue, rich in newly formed capillaries,

fibroblasts, collagen and reduced inflammatory infiltrate.

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Morphologic Patterns of Acute Inflammation

Serous inflammation: Outpouring of thin fluid (serous effusion, blisters)
Fibrinous inflammation: Body cavities; leakage of fibrin; may lead to scar tissue (adhesions)
Suppurative (purulent) inflammation: Pus or purulent exudate (neutrophils, debris, edema fluid); abscess: localized collections of pus
Ulcers: Local defect of the surface of an organ or tissue produced by the sloughing (shedding) of inflammatory necrotic tissue

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Progression of the response to chronic inflammation

- persistence of the injurious agent

- interference of the healing process

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Progression of the response to chronic inflammation (discussed below). This may follow acute inflammation, or the response may be chronic from the onset. Acute to chronic transition occurs when the acute inflammatory response cannot be resolved, as a result of either the persistence of the injurious agent or some interference with the normal process of healing.[79] For example, bacterial infection of the lung may begin as a focus of acute inflammation (pneumonia), but its failure to resolve may lead to extensive tissue destruction and formation of a cavity in which the inflammation continues to smolder, leading eventually to a chronic lung abscess. Another example of chronic inflammation with a persisting stimulus is peptic ulcer of the duodenum or stomach. Peptic ulcers may persist for months or years and, as discussed below, are manifested by both acute and chronic inflammatory reactions.

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Types of Inflammation: acute vs. chronic�Types of repair: resolution vs. organization (fibrosis)

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Chronic inflammation

Definition: is inflammation of prolonged duration (weeks or months) in which inflammation, tissue injury, and attempts at repair coexist, in varying combinations.

Causes of chronic inflammation:

- Persistent infections by microorganisms that are difficult to eradicate

- Immune-mediated inflammatory diseases

- Prolonged exposure to potentially toxic agents, either exogenous or endogenous

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Persistent infections by microorganisms that are difficult to eradicate, such as mycobacteria, and certain viruses, fungi, and parasites. These organisms often evoke an immune reaction called delayed-type hypersensitivity (Chapter 6). The inflammatory response sometimes takes a specific pattern called a granulomatous reaction (discussed later).
Immune-mediated inflammatory diseases. Chronic inflammation plays an important role in a group of diseases that are caused by excessive and inappropriate activation of the immune system. Under certain conditions immune reactions develop against the individual's own tissues, leading to autoimmune diseases (Chapter 6). In these diseases, auto-antigens evoke a self-perpetuating immune reaction that results in chronic tissue damage and inflammation; examples of such diseases are rheumatoid arthritis and multiple sclerosis. In other cases, chronic inflammation is the result of unregulated immune responses against microbes, as in inflammatory bowel disease. Immune responses against common environmental substances are the cause of allergic diseases, such as bronchial asthma (Chapter 6). Because these autoimmune and allergic reactions are inappropriately triggered against antigens that are normally harmless, the reactions serve no useful purpose and only cause disease. Such diseases may show morphologic patterns of mixed acute and chronic inflammation because they are characterized by repeated bouts of inflammation. Fibrosis may dominate the late stages.
Prolonged exposure to potentially toxic agents, either exogenous or endogenous. An example of an exogenous agent is particulate silica, a nondegradable inanimate material that, when inhaled for prolonged periods, results in an inflammatory lung disease called silicosis (Chapter 15). Atherosclerosis (Chapter 11) is thought to be a chronic inflammatory process of the arterial wall induced, at least in part, by endogenous toxic plasma lipid components.

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Consequences of defective or excessive inflammation

Defective inflammation results in:

- increased susceptibility to infections

- delayed wound healing

Excessive inflammation is:

- the basis of many types of diseases (allergies, auto-immune)

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So that chronic Inflammation

Inflammation of prolonged duration (weeks or months)

Active inflammation, tissue destruction, and attempts at repair are proceeding simultaneously

May follow acute inflammation or begin insidiously and often asymptomatically

Persistent infections, exposure to toxic agents such as silica (silicosis), or by autoimmunity

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Chronic Inflammation

Persistent infections

Treponema pallidum [syphilis], viruses, fungi, parasites

Exposure to toxic agents

Exogenous: silica (silicosis)
Endogenous: toxic plasma lipid components (atherosclerosis)

Autoimmunity

Rheumatoid arthritis, systemic lupus erythematosus

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Chronic Inflammation

Histological features

Infiltration with mononuclear cells �(macrophages, lymphocytes, and plasma cells)
Tissue destruction �(induced by the inflammatory cells)
Healing by replacement of damaged tissue by connective tissue (fibrosis) �and new blood vessels (angiogenesis)

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Morphologic features

Chronic inflammation is characterized by:

- Infiltration with mononuclear cells, which include macrophages, lymphocytes, and plasma cells

- Tissue destruction, induced by the persistent offending agent or by the inflammatory cells�

- Attempts at healing by connective tissue replacement of damaged tissue, accomplished by proliferation of small blood vessels (angiogenesis) and, in particular, fibrosis

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Role of Macrophages

The macrophage is the dominant cellular player in chronic inflammation (predominates within 48 hrs).

Macrophages are one component of the mononuclear phagocyte system.

The half-life of blood monocytes is about 1 day, whereas the life span of tissue macrophages is several months or years.

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Maturation of mononuclear phagocytes.�(From Abbas AK et al: Cellular and Molecular Immunology, 5th ed. Philadelphia, WB Saunders, 2003.)

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Macrophages may be activated by a variety of stimuli:

- microbial products that engage TLRs and other cellular receptors

- cytokines (e.g., IFN-γ) secreted by sensitized T lymphocytes and by natural killer cells

The products of activated macrophages serve to:

- eliminate injurious agents such as microbes

- initiate the process of repair

- responsible for much of the tissue injury in chronic inflammation.

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Macrophages

Monocytes begin to emigrate into tissues early in inflammation where they transform into the larger phagocytic cell known as the macrophage
Macrophages predominate by 48 hours

Recruitment (circulating monocytes); division; immobilization

Activation results in secretion of biologically active products

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Macrophages

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Other cells in chronic inflammation

lymphocytes of different types (T and B cells).

Plasma cells.

Eosinophils are abundant in immune reactions mediated by IgE and in parasitic infections.

Mast cells.

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lymphocytes of different types (T and B cells) use various adhesion molecule pairs (selectins, integrins and their ligands) and chemokines to migrate into inflammatory sites. Cytokines from activated macrophages, mainly TNF, IL-1, and chemokines, promote leukocyte recruitment, setting the stage for persistence of the inflammatory response. Lymphocytes and macrophages interact in a bidirectional way, and these reactions play an important role in chronic inflammation (Fig. 2-25). Macrophages display antigens to T cells and produce membrane molecules (costimulators) and cytokines (notably IL-12) that stimulate T-cell responses (Chapter 6). Activated T lymphocytes produce cytokines, some of which recruit monocytes from the circulation and one, IFN-γ, is a powerful activator of macrophages.
Plasma cells develop from activated B lymphocytes and produce antibodies directed either against persistent foreign or self antigens in the inflammatory site or against altered tissue components.
A chemokine that is especially important for eosinophil recruitment is eotaxin. Eosinophils have granules that contain major basic protein, a highly cationic protein that is toxic to parasites but also causes lysis of mammalian epithelial cells.

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Other Cells in Chronic Inflammation

Lymphocytes

Produce inflammatory mediators
Participate in cell-mediated immune reactions
Plasma cells produce antibody
Lymphocytes and macrophages interact in a �bi-directional fashion

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Other Cells in Chronic Inflammation

Eosinophils

Immune reactions mediated by IgE
Parasitic infections

Eosinophil granules contain a protein that is �toxic to parasites

Mast cells

Release mediators (histamine) and cytokines

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Granulomatous Inflammation

Distinctive pattern of chronic inflammation

Predominant cell type is an activated macrophage with a modified epithelial-like (epithelioid) appearance
Giant cells may or may not be present

Granuloma: �Focal area of granulomatous inflammation

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Granulomatous Inflammation

Foreign body granulomas: �Form when foreign material is too large to be engulfed by a single macrophage
Immune granulomas: �Insoluble or poorly soluble particles elicit a cell-mediated immune response

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Mediators of inflammation

Mediators are generated either from cells or from plasma proteins.

Active mediators are produced in response to various stimuli.

One mediator can stimulate the release of other mediators.

Mediators vary in their range of cellular targets.

Once activated and released from the cell, most of these mediators are short-lived.

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Mediators are generated either from cells or from plasma proteins. Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins, cytokines) in response to a stimulus. The major cell types that produce mediators of acute inflammation are platelets, neutrophils, monocytes/macrophages, and mast cells, but mesenchymal cells (endothelium, smooth muscle, fibroblasts) and most epithelia can also be induced to elaborate some of the mediators. Plasma-derived mediators (e.g., complement proteins, kinins) are produced mainly in the liver and present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties.
Active mediators are produced in response to various stimuli. These stimuli include microbial products, substances released from necrotic cells, and the proteins of the complement, kinin, and coagulation systems, which are themselves activated by microbes and damaged tissues. This requirement for microbes or dead tissues as the initiating stimulus ensures that inflammation is normally triggered only when and where it is needed.
One mediator can stimulate the release of other mediators. For instance, the cytokine TNF acts on endothelial cells to stimulate the production of another cytokine, IL-1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying—or, in certain instances, counteracting—the initial action of a mediator.
Mediators vary in their range of cellular targets. They can act on one or a few target cell types, can have diverse targets, or may even have differing effects on different types of cells.
Once activated and released from the cell, most of these mediators are short-lived. They quickly decay (e.g., arachidonic acid metabolites) or are inactivated by enzymes (e.g., kininase inactivates bradykinin), or they are otherwise scavenged (e.g., antioxidants scavenge toxic oxygen metabolites) or inhibited (e.g., complement regulatory proteins break up and degrade activated complement components). There is thus a system of checks and balances that regulates mediator actions.

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Mediator	Principal Sources	Actions
CELL-DERIVED
Histamine	Mast cells, basophils, platelets	Vasodilation, increased vascular permeability, endothelial activation
Serotonin	Platelets	Vasodilation, increased vascular permeability
Prostaglandins	Mast cells, leukocytes	Vasodilation, pain, fever
Leukotrienes	Mast cells, leukocytes	Increased vascular permeability, chemotaxis, leukocyte adhesion and activation
Platelet-activating factor	Leukocytes, mast cells	Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst
Reactive oxygen species	Leukocytes	Killing of microbes, tissue damage
Nitric oxide	Endothelium, macrophages	Vascular smooth muscle relaxation, killing of microbes
Cytokines (TNF, IL-1)	Macrophages, endothelial cells, mast cells	Local endothelial activation (expression of adhesion molecules), fever/pain/anorexia/hypotension, decreased vascular resistance (shock)
Chemokines	Leukocytes, activated macrophages	Chemotaxis, leukocyte activation
PLASMA PROTEIN–DERIVED
Complement products (C5a, C3a, C4a)	Plasma (produced in liver)
Kinins	Plasma (produced in liver)
Proteases activated during coagulation	Plasma (produced in liver)

Endothelial activation, leukocyte recruitment

Increased vascular permeability, smooth muscle contraction, vasodilation, pain

Leukocyte chemotaxis and activation, vasodilation (mast cell stimulation)

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Chemical Mediators of Inflammation

General principles of chemical mediators

May be derived from plasma or cells
Most bind to specific receptors on target cells
Can stimulate release of mediators by target cells, which may amplify or ameliorate the inflammatory response
May act on one or a few target cells, have widespread targets, and may have differing effects depending on cell and tissue types
Usually short-lived
Most have the potential to cause harmful effects

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Chemical Mediators of Inflammation

Vasoactive mediators

Histamine
Bradykinin
Complement (C3a, C5a)
Prostaglandins/leukotrienes
Platelet activating factor
Nitric oxide

Chemotactic factors

Complement (C5a)
Leukotriene (B4)
Platelet activating factor
Cytokines (IL-1, TNF)
Chemokines
Nitric oxide

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Histamine

Mast cells (also basophils and platelets)
Release mechanisms

Binding of antigen (allergen) to IgE on mast cells releases histamine-containing granules
Release by nonimmune mechanisms such as cold, trauma, or other chemical mediators
Release by other mediators

Dilates arterioles and increases permeability of venules (wheal and flare reaction)

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Complement

Proteins found in greatest concentration in �the plasma
Require activation
Increase vascular permeability and cause vasodilation

Mainly by releasing histamine from mast cells

Increase leukocyte adhesion, chemotaxis, and activation
C3b attaches to bacterial wall and enhances phagocytosis by neutrophils & macrophages

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Bradykinin

Small peptide released from plasma precursors
Increases vascular permeability
Dilates blood vessels
Causes pain
Rapid inactivation

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Arachidonic Acid Metabolites

Prostaglandins

Vasodilators: prostacyclin (PGI₂), PGE₁, PGE₂, PGD₂
Vasoconstrictors: thromboxane A₂
Pain (PGE₂ makes tissue hypersensitive to bradykinin)
Fever (PGE₂)
Production blocked by steroids and nonsteroidal anti-inflammatory agents (NSAIDs)

Leukotrienes

Increase vascular permeability: leukotrienes C₄, D₄, E₄
Vasoconstriction: leukotrienes C₄, D₄, E₄
Leukocyte adhesion & chemotaxis: leukotriene B₄, �HETE, lipoxins
Production blocked by steroids but not conventional NSAIDs

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Figure 2-16 Robbins and Cotran Pathologic Basis of Disease, 7th Ed.

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Platelet Activating Factor

Subclass of phospholipids
Synthesized by stimulated platelets, leukocytes, endothelium
Inflammatory effects

Stimulates platelet aggregation
Vasoconstriction and bronchoconstriction
Vasodilation and increased venular permeability
Increased leukocyte adhesion to endothelium, chemotaxis, degranulation, and oxidative burst
Increases synthesis of arachidonic acid metabolites by leukocytes and other cells

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Cytokines

Proteins produced by many cell types �(principally activated lymphocytes & macrophages)
Modulate the function of other cell types
Interleukin-1 (IL-1) and tumor necrosis factor �(TNF) are the major cytokines that mediate inflammation

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Figure 2-18 Robbins and Cotran Pathologic Basis of Disease, 7th Ed.

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Chemokines

Small proteins that act primarily as chemoattractants for specific types of leukocytes (approximately 40 known)
Stimulate leukocyte recruitment in inflammation
Control the normal migration of cells through tissues (organogenesis and maintenance of tissue organization)
Examples: IL-8, eotaxin, lymphotactin

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Nitric Oxide

Figure 2-19 Robbins and Cotran Pathologic Basis of Disease, 7th Ed.

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�Other Mediators

Neutrophil granules:

Cationic proteins increase vascular permeability, immobilize neutrophils, chemotactic for mononuclear phagocytes
Neutral proteases generate other mediators and degrade tissue

Oxygen-Derived Free Radicals:

Produced during phagocytosis by neutrophils (“respiratory burst”)
Tissue damage including endothelium

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Summary of Inflammatory Mediators

Vasodilation

Prostaglandins
Nitric oxide
Histamine

Increased vascular permeability

Histamine, serotonin
Complement (C3a, C5a)
Bradykinin
Leukotrienes (C₄, D₄, E₄)
Platelet Activating Factor
Substance P

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Summary of Inflammatory Mediators

Chemotaxis, leukocyte activation

Complement (C5a)
Leukotriene B₄
Chemokines
IL-1, TNF
Bacterial products

Fever

Interleukin-1
Tumor necrosis factor
Prostaglandins

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Summary of Inflammatory Mediators

Pain

Prostaglandins
Bradykinin

Tissue Damage

Neutrophil and macrophage lysosomal enzymes
Oxygen metabolites
Nitric oxide

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Systemic effects of Inflammation

Fever

Acute-phase proteins synthesis

Leukocytosis

Miscellaneous

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Fever, characterized by an elevation of body temperature, usually by 1° to 4°C, is one of the most prominent manifestations of the acute-phase response, especially when inflammation is associated with infection. Fever is produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the vascular and perivascular cells of the hypothalamus. Bacterial products, such as LPS (called exogenous pyrogens), stimulate leukocytes to release cytokines such as IL-1 and TNF (called endogenous pyrogens) that increase the enzymes (cyclooxygenases) that convert AA into prostaglandins.[84] In the hypothalamus, the prostaglandins, especially PGE2, stimulate the production of neurotransmitters such as cyclic adenosine monophosphate, which function to reset the temperature set point at a higher level. NSAIDs, including aspirin, reduce fever by inhibiting prostaglandin synthesis. An elevated body temperature has been shown to help amphibians ward off microbial infections, and it is assumed that fever does the same for mammals, although the mechanism is unknown. One hypothesis is that fever may induce heat shock proteins that enhance lymphocyte responses to microbial antigens.

• Acute-phase proteins are plasma proteins, mostly synthesized in the liver, whose plasma concentrations may increase several hundred-fold as part of the response to inflammatory stimuli.[85] Three of the best-known of these proteins are C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. Synthesis of these molecules by hepatocytes is up-regulated by cytokines, especially IL-6 (for CRP and fibrinogen) and IL-1 or TNF (for SAA). Many acute-phase proteins, such as CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement. They also bind chromatin, possibly aiding in the clearing of necrotic cell nuclei. During the acute-phase response SAA protein replaces apolipoprotein A, a component of high-density lipoprotein particles. This may alter the targeting of high-density lipoproteins from liver cells to macrophages, which can use these particles as a source of energy-producing lipids. Fibrinogen binds to red cells and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than do individual red cells. This is the basis for measuring the erythrocyte sedimentation rate as a simple test for the systemic inflammatory response, caused by any stimulus. Acute-phase proteins have beneficial effects during acute inflammation, but as we shall see in Chapter 6, prolonged production of these proteins (especially SAA) in states of chronic inflammation causes secondary amyloidosis. Elevated serum levels of CRP have been proposed as a marker for increased risk of myocardial infarction in patients with coronary artery disease.[86] It is postulated that inflammation involving atherosclerotic plaques in the coronary arteries may predispose to thrombosis and subsequent infarction, and CRP is produced during inflammation. Another peptide whose production is increased in the acute-phase response is the iron-regulating peptide hepcidin.[87] Chronically elevated plasma concentrations of hepcidin reduce the availability of iron and are responsible for the anemia associated with chronic inflammation (Chapter 14).� • Leukocytosis is a common feature of inflammatory reactions, especially those induced by bacterial infections. The leukocyte count usually climbs to 15,000 or 20,000 cells/μL, but sometimes it may reach extraordinarily high levels of 40,000 to 100,000 cells/μL. These extreme elevations are referred to as leukemoid reactions, because they are similar to the white cell counts observed in leukemia and have to be distinguished from leukemia. The leukocytosis occurs initially because of accelerated release of cells from the bone marrow postmitotic reserve pool (caused by cytokines, including TNF and IL-1) and is therefore associated with a rise in the number of more immature neutrophils in the blood (shift to the left). Prolonged infection also induces proliferation of precursors in the bone marrow, caused by increased production of colony-stimulating factors. Thus, the bone marrow output of leukocytes is increased to compensate for the loss of these cells in the inflammatory reaction. (See also the discussion of leukocytosis in Chapter 13.) Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and German measles, cause an absolute increase in the number of lymphocytes (lymphocytosis). In bronchial asthma, allergy, and parasitic infestations, there is an increase in the absolute number of eosinophils, creating an eosinophilia. Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are associated with a decreased number of circulating white cells (leukopenia). Leukopenia is also encountered in infections that overwhelm patients debilitated by disseminated cancer, rampant tuberculosis, or severe alcoholism.� • Other manifestations of the acute-phase response include increased pulse and blood pressure; decreased sweating, mainly because of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin; rigors (shivering), chills (search for warmth), anorexia, somnolence, and malaise, probably because of the actions of cytokines on brain cells.� • In severe bacterial infections (sepsis) the large amounts of organisms and LPS in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1.[88,] the large amounts of organisms and LPS in the blood stimulate the production of enormous quantities of several cytokines, notably TNF and IL-1.[88,][89] As a result, circulating levels of these cytokines increase and the nature of the host response changes. High levels of cytokines cause various clinical manifestations such as disseminated intravascular coagulation, cardiovascular failure, and metabolic disturbance

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Systemic Manifestations

Endocrine and metabolic

Secretion of acute phase proteins by the liver
Increased production of glucocorticoids �(stress response)
Decreased secretion of vasopressin leads to reduced volume of body fluid to be warmed

Fever

Improves efficiency of leukocyte killing
Impairs replication of many offending organisms

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Systemic Manifestations

Autonomic

Redirection of blood flow from skin to deep vascular beds minimizes heat loss
Increased pulse and blood pressure

Behavioral

Shivering (rigors), chills (search for warmth), anorexia (loss of appetite), somnolence, and malaise

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Systemic Manifestations

Leukocytosis: increased leukocyte count in the blood

Neutrophilia: bacterial infections
Lymphocytosis: infectious mononucleosis, mumps, measles
Eosinophilia: Parasites, asthma, hay fever

Leukopenia: reduced leukocyte count

Typhoid fever, some viruses, rickettsiae, protozoa

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Wound Healing

A complex but orderly process involving many of the chemical mediators previously discussed, along with many other growth factors and cell-matrix interactions.

Occurs in the following steps:

Injury induces acute inflammation
Parenchymal cells regenerate
Both parenchymal and connective tissue cells migrate and proliferate
Extracellular matrix is produced
Parenchyma and connective tissue matrix remodel
Increase in wound strength due to collagen deposition

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Wound Healing Time Course

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Granulation Tissue

Hallmark of healing
Term comes from soft, pink, granular appearance when viewed from the surface of a wound
Histology: Proliferation of small blood vessels and fibroblasts; tissue often edematous

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Healing by 1^st intention vs. 2^nd intention

By 1^st intention:

“clean” incision
limited scarring or wound contraction

By 2^nd intention:

ulcers or lacerations
often scarring and wound contraction

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Ulcers: an example of healing by 2^nd intention

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Resolution of Inflammation:�“Regeneration” vs. “Healing”

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Variables affecting repair

Infection –prolongs inflammation, increases degree of tissue injury
Nutrition –protein or vitamin deficiency can impair synthesis of new proteins
Anti-inflammatory drugs –can impede fibrosis necessary for repair
Mechanical variables –tension, pressure, or the presence of foreign bodies can affect repair
Vascular disease –limits nutrient and oxygen supply required for repairing tissues
Tissue type –only tissues capable of renewing will regenerate, otherwise healing is by fibrosis
Degree of exudate removal –adequate removal of exudate allows RESOLUTION of the injury (general restoration of the normal tissue architecture); inadequate removal results in ORGANIZATION (abnormal, dysfunctional tissue architecture)
Regulation of cell proliferation –abnormal proliferation of connective tissue may inhibit re-epithelialization and/or raised scars (keloids)

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