Inflammation- Acute And Chronic

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Inflammation

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host response to injury or infection

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defined events in the inflammatory response

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1. Recognition of the injurious agent.
2. Recruitment of leukocytes.
3. Removal of the injurious agent.
4. Regulation of the response.
5. Resolution and repair

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Inflammation vs. Infection

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-itis as a suffix refers to inflammation. For example, gingivitis means inflamed gingival tissue. While the inflammation may be caused by an infection, just having –itis does not mean infection. Tendinitis is not typically caused by an infection.

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Acute inflammation

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a process which develops in a few minutes to hours and typically resolves within a few days

hallmark cell :neutrophil

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Leukocytes

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white blood cells found within the bloodstream or present in the tissue

originate: bone marrow
released: into the blood and recruited to sites of inflammation

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normal numbers of white blood cells in the peripheral blood

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Range
(1000/μl)
White blood count 4.0 – 11.0
Neutrophils 1.8 – 7.8
Lymphocytes 1.0 – 4.5
Monocytes 0.1 – 0.6
Eosinophils 0.0 – 0.5

Neutrophils are the predominant cell, followed by lymphocytes. In normal individuals there are relatively few monocytes or eosinophils. Cells newly recruited to the site of inflammation typically come directly from the bloodstream

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Neutrophils

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major cell mediating acute inflammation

short-lived cells, typically circulate for less than 24 hours

survive in tissues for only a few days and do not recirculate back to the blood

Once in tissue, they ingest microorganisms or necrotic tissue and die shortly thereafter

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Histologically inflamed tissue

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when leukocytes are present in a location where they would not normally be found

Neutrophils within the alveolar spaces of the lung would be considered inflammation and is the classic appearance of bacterial pneumonia

lymphocytes normally found within the colon, such as Peyers patches, would not typically be considered evidence of inflammation

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Steps in acute inflammation

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Step 1. Hyperemia – dilatation of blood vessels

Step 2. Increased Vascular Permeability

Step 3. Emigration, accumulation, activation of leukocytes

three basic steps in acute inflammation, but this does not mean that the response moves in a linear fashion from one step to the next

can occur simultaneously

affected by many mediators

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Step 1 of Acute inflammation

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Hyperemia – dilatation of blood vessels

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Hyperemia – dilatation of blood vessels

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accounts for the calor (warmth) and rubor (redness) of acute inflammation

Increased blood flow occurs following vasodilatation of precapillary arterioles

Several mediators dilate arterioles:

Vasoactive amines: histamine and serotonin

Arachidonic acid (AA) metabolites

Nitric Oxide (NO)

Platelet activating factor

Bradykinin

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Vasoactive amines

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histamine and serotonin

the first mediators released

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histamine

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is stored in mast cells, basophils and platelets and is released in response to trauma, heat, or immune reactions

causes arteriolar dilation and increased vascular permeability

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Serotonin

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found pre-formed in platelets

causes arteriolar dilation and increased vascular permeability (similar to histamine)

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Arachidonic acid (AA) metabolites

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prostaglandins, leukotrienes and lipoxins

mediate many steps in inflammation including vasodilatation

produced by cyclooxygenase

Aspirin and other nonsteriodal anti-inflammatory agents (NSAIDs) work by inhibiting the enzyme that produces AA metabolites, cyclooxygenase

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Nitric Oxide (NO)

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a smooth muscle relaxant causing vasodilation especially when produced by endothelial cells

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Platelet activating factor

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molecule derived from cell membranes

causes platelet aggregation, vasoconstriction, bronchoconstriction, and leukocyte activation

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Bradykinin

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vasoactive peptides derived from plasma proteins (kinogens)

increases vascular permeability and causes contraction of smooth muscle, dilation of blood vessels and pain when injected into the skin

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Step 2 of acute inflammation

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Increased Vascular Permeability

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Increased Vascular Permeability

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Swelling is always present in acute inflammation

leakage of proteins from the plasma into the tissue interstitium

not hemorrhage since erythrocytes do not escape

Leakage occurs in the microcirculation, mainly in the post-capillary venules and does not occur across larger arterioles, arteries or veins

initial leakage occurs in venules between endothelial cells, which have retracted to expose openings to allow the escape of plasma proteins

Most of the mediators from Step 1 of acute inflammation (hyperemia) also increase vascular permeability

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Transudates

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low in protein concentration and cell numbers

occur normally, to a small degree, across capillary beds

hydrostatic (water pressure) and oncotic (protein concentration pressure) pressures of the blood and tissue result in an initial outward fluid flow from the inside of a capillary bed

fluid (a transudate) is reabsorbed on the venous side of the capillary bed or via the lymphatics

During inflammation, gaps between endothelial cells result in increased leakage of plasma proteins into the tissue (fibrinogen broken down to fibrin)

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exudate

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has higher concentrations of proteins and typically contains numerous inflammatory cells

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Edema

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accumulation of fluid within the interstitium of tissues

transudate or exudate

being “wet"

can not be directly aspirated with a needle or catheter

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edematous

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tissues with edema

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effusion

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accumulation of fluid in a sealed body cavity, such as between the lung and chest wall (pleural effusion)

can be directly aspirated through a needle or catheter,

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Purulent exudate

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large concentration of neutrophils usually due to bacteria that attract neutrophils

The cells result in a cloudy appearance

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Hemorrhagic exudate

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red blood cells due to capillary damage

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Step 3 of acute inflammation

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Emigration, accumulation, activation of leukocytes

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Emigration, accumulation, activation of leukocytes

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Leukocyte infiltration into inflamed tissue is the most important histologic sign of inflammation

transmigration occurs most prominently in post-capillary venules and, to a lesser extent, in the capillaries themselves

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sequence of leukocyte recruitment to tissue

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(A) margination
(B) rolling
(C) tight adhesion
(D) migration across vessel wall
(E) Migration into the tissue

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Margination

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leukocytes move to the margin of the blood stream and come into contact with the vascular wall in order to exit the blood stream

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Rolling

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following margination

leukocyte and the endothelium must adhere to each other in order to cross the vascular wall

initial adherence of leukocytes to endothelium is weak. Therefore, the leukocytes roll on the endothelial cell layer rather than abruptly stopping

there is intercellular contact, allowing the passing leukocyte to interact with adhesion molecules on the surface of the endothelium

. With appropriate pairing of the adhesion molecules on the neutrophil and the endothelium, leukocytes will tightly adhere and emigrate out of the bloodstream

leukocyte will cease rolling once it has passed out of the area of inflammation and continue in the venous circulation if it is not a match

specificity of cellular inflammation is, at least in part, regulated during the rolling phase

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Tight adhesion

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due to the ability of integrin molecules to rapidly increase their molecular avidity for integrin ligands on the endothelial cell surface

. Once tightly adherent, the shear force of the blood is not sufficient to cause the cell to continue to roll

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Migration across the vessel wall

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leukocyte migrates between two endothelial cells

requires the leukocyte to squeeze between two endothelial cell junctions, allowing those junctions to re-form after passage

Only minutes are typically required for passage of a leukocyte through the vascular wall

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Migration into the tissue

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Inflammatory cells will move toward specific chemotactic factors

There are several important neutrophil chemotactic agents

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Systemic Effects of Acute Inflammation

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Fever
Leukocytosis
Tachycardia
Tachypnea
Acute Phase reactants

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Fever

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caused by a collection of substances called pyrogens produced by the body

bacteria do not directly cause the fever, it is the body's response to the infection which causes fever

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pyrogens

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are molecules produced by the body

induce fever

stimulate prostaglandin synthesis in the hypothalamic thermoregulatory centers, thus altering the “thermostat” controlling body temperature

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leukocytosis

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increased number of leukocytes in the peripheral blood

number of circulating neutrophils typically increases during acute inflammation

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Tachycardia

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Increased heart rate duuring acute inflammation

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Tachypnea

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the respiratory rate will increase

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Benefits of acute inflammation

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remove invading pathogens or clear necrotic tissue

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Neutrophil activation

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an important component of the acute inflammatory response

neutrophils are activated when they come into contact with bacteria or dead tissue and function more effectively

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Neutrophil phagocytosis

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the neutrophil membrane binds to the bacteria, the neutrophil engulfs the bacteria and draws it into the cytoplasm (phagocytosis)

Opsins such as antibodies and fragments of the complement cascade will bind to the bacteria

opsonized bacteria will then bind to receptors on the cell surface to facilitate phagocytosis

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Neutrophil killing

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After neutrophils have phagocytosed the bacteria, the engulfed bacteria will be combined with the enzyme lysozyme in the phagolysosome to effectively destroy the pathogen

Pathogens are also destroyed through the generation of reactive oxygen and reactive nitrogen intermediates

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Tissue injury

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acute inflammation can cause damage to nearby tissues

Many of the processes involved in killing the bacteria, such as the generation of highly active proteases and reactive oxygen intermediates, can induce damage to nearby normal tissue

appropriate response to acute inflammation clears the pathogen or necrotic tissue without damaging normal cells and tissues

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Outcomes of acute inflammation

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resolution of the acute inflammatory response and restoration of normal tissues and hemostasis

may progress to fibrosis and/or chronic inflammation

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Chronic Inflammation

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present for weeks, months, or years

different microscopic patterns of chronic inflammation

all include abundant lymphocytes, macrophages, and some degree of fibrosis

an active process can be modulated or terminated

Example: rheumatoid arthritis, atherosclerosis, and Crohn's disease

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Chronic inflammatory cells

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Monocytes – Macrophages

Lymphocytes

Eosinophils

Basophils

mast cells

Fibroblasts

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Monocytes – Macrophages

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components of the mononuclear phagocytic system

originate in the bone marrow

moved into the bloodstream after maturation and become monocytes

monocytes then migrate to the tissue to become fixed cells where they are given specific names

mononuclear phagocyte system cells: are microglia (in the central nervous system), macrophages (connective tissue and lymphoid organs), and sinus lining cells (i.e., Kupffer cells of the liver and alveolar macrophages).

chronic inflammation

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Lymphocytes

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are composed of many different subtypes including T cells and B cells

chronic inflammation

Plasma cells which secrete immunoglobulins are also derived from B lymphocytes

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Eosinophils

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principal effector cell of antibody-dependent cellular cytotoxicity against helminths

express high levels of the IgE Fc receptor

found at local sites of inflammation in individuals with allergies

chronic inflammation

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Basophils and mast cells

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related cell types which become activated following the binding of antigen to surface-bound IgE

Basophils in blood

mast cells within tissues

stimuli, such as fragments of complement, certain drugs and chemicals, as well as certain physical stimuli (cold, heat, sunlight) can also activate these cells

Following activation basophils and mast cells promptly (within seconds to minutes) release pre-formed granules

acute and chronic inflammation

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Inflammatory mediators

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cell derived

plasma protein derived

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Cell derived inflammatory mediators

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produced within leukocytes and exported outside

At the start of acute inflammation, some of the mediators are already present within the cell so that they may be rapidly released

typically sequestered within granules inside the cell (histamine within mast cells or serotonin inside platelets)

synthesized de novo and may be proteins, lipids, reactive oxygen or reactive nitrogen species

distinction between pre-formed mediators and newly synthesized mediators has implications for how the inflammatory response is governed

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Newly synthesized mediators

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may be produced for long periods of time, even years

acute and chronic inflammation

Reduce impact by:
preventing their synthesis via cyclooxygenase inhibitors

prevent binding of formed mediators to their receptors

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Pre-formed mediators

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important in the first stages of acute inflammation or in acute exacerbation of chronic inflammation

Reduce impact by:
prevent their release

interfere with binding to their receptors

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Plasma protein derived mediators

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generated from proteins found within the plasma

proteins are normally circulating in the blood, but they were originally synthesized within cells typically in the liver

Many exist as larger forms which are inactive precursors, proteases cleave these larger proteins into smaller proteins, which are the biologically active forms, occurs within minutes

during chronic inflammation the liver keeps producing the acute phase proteins, never slowing down--increased concentrations of several proteins, termed acute phase proteins, which may be used as biomarkers for the level of inflammation

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Acute phase proteins

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"acute phase reactants"

proteins are rapidly increased during acute inflammation, but they stay chronically elevated unless the inflammation subsides

present in the blood

synthesized primarily by the liver

induced by the cytokine interleukin six (IL-6)

measured clinically as an index of inflammation- C reactive protein or the erythrocyte sedimentation rate

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Causes of chronic inflammation

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Prolonged exposure to tissue injury, irritants or potentially toxic agents

Immune mediated diseases

Allergic diseases

Persistent infections

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Prolonged exposure to tissue injury, irritants or potentially toxic agents

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cause chronic inflammation

inciting agent is never removed and the inflammatory process persists

example: gastric ulcer

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Gastric Ulcer: Acute Inflammation

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the top of the ulcer there is a fibrinopurulent exudate composed of the protein fibrin and neutrophils (same components present in the acute inflammatory response)

next layer contains granulation tissue, which is part of the healing response. Granulation tissue is composed of a rich capillary network embedded in a loose matrix of fibro-connective tissue. This matrix also contains numerous chronic inflammatory cells including macrophages, mast cells, lymphocytes and plasma cells---fibroblast, which is responsible for producing collagen that forms the deepest layer of the ulcer

bottom of the ulcer are bands of collagen that will become scar tissue

inflammation-> granulation tissue-> scar

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Immune mediated diseases

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autoimmune diseases and allergic diseases

body inappropriately recognizes host tissues as foreign antigens and mounts a specific inflammatory response

substantial infiltrate of lymphocytes -- perpetuate the inflammatory response

The two principal cells which interact with each other are activated macrophages and T cells (T cells are a type of lymphocyte)

inflammatory cross talk between the cells maintains the chronic inflammatory response

macrophage-> cytokines

cytokines + macrophage antigen presentation--> activate T cell

Activated T cells -> cytokines

cytokines-> activate macrophages

(cycle, includes B cells= increased antibodies)

Macrophages produce cytokines such as tumor necrosis factor (TNF). These cytokines, in combination with antigen presentation by the macrophages, activate T cells. These activated T cells then produce additional cytokines including TNF. The T cell-derived cytokines further activate the macrophages to result in continuous amplification of the chronic inflammatory proces

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Allergic diseases

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acute exacerbations but are chronic inflammatory conditions

Histologically, in the lungs of asthmatic patients there are chronic inflammatory cells including macrophages, lymphocytes, and eosinophils

eosinophil is the cell most closely identified with an asthmatic response. Eosinophils are also important in the clearance of parasitic infections, particularly helminths (worms)

Acute exacerbations allergic diseases are triggered by antibodies binding to the allergens such as pollen

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Persistent infections

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Granulomatous inflammation is another example of chronic inflammation

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Granulomatous Inflammation

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Granulomas are the predominant feature of granulomatous inflammation

granuloma is a small, microscopic focus of chronic inflammation

characteristic cell of the granuloma is a macrophage which has been transformed into a cell termed an epithelioid macrophage

epithelioid macrophage is a large cell with abundant, pale, pink cytoplasm, typically clustered in the center of the granuloma

Surrounding these macrophages is a collar of lymphocytes (cell to cell communication)

cytokines are critical for the granulomatous response

distinctive feature of granuloma is the presence of multi-nucleated giant cells (large cells with abundant eosinophilic cytoplasm and numerous nuclei formed by the fusion of individual macrophages)

may have an element of fibrosis

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Purpose of granuloma

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formed in an attempt to contain an offending agent that a single cell cannot handle alone

inciting agent is typically near the center of the granuloma

Determining the cause of the granuloma determines the therapy of the patient

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Causes of granulomatous inflammation

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1. Certain bacterial infections, most notably infections associated with mycobacteria, resulting in diseases such as tuberculosis and leprosy

2. Certain fungal and parasitic infections, such as histoplasmosis and schistosomiasis

3. Foreign bodies, i.e. suture threads, asbestos, talcum powder (once used for surgical gloves)

4. Unknown causes associated with specific diseases, such as sarcoidosis and Crohn’s disease

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Treatments of Chronic Inflammatory Disease

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inhibitors of inflammation

non-specific(glucocorticoids) which decrease multiple aspects of the inflammatory response

specific (cytokine inhibitors)--at least 5 TNF inhibitors approved by the Food and Drug Administration for the treatment of chronic inflammation

many of the cytokines in chronic inflammation are essential components to keep infections under control

blocking TNF significantly increases reactivation of tuberculosis

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Alveolar spaces

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Terminal air spaces the within the lung. They are the termination of the respiratory apparatus that directly connects to the outside air. Most of the gas exchange takes place between the air in the alveolar spaces and the capillaries.

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Autoimmune disease

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A disease where immune response incorrectly attacks normal tissue

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Chemotaxis

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Directed movement of leukocytes or other cells in a specific direction.

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Cytokines

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Protein mediators which activate and orchestrate the inflammatory response

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Leukocytes

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White blood cells that come from the bone marrow. They are critical components of the inflammatory response.

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Endothelial cells

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Cells that line the inside of blood vessels

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erythrocytes

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Red blood cells

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Helminths

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Parasitic worms

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Hyperemia

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Increased blood flow inside the vasculature

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Hypothalamus

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A portion of the brain responsible for regulating temperature

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Hydrostatic pressure

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Pressure due to the force of the fluid, usually it is directed to the outside. This is similar to the pressure in a hose

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Recirculate

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Move from the site of inflammation back into the bloodstream

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Integrin molecules

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Molecules on the surface of white blood cells responsible for their adherence to the lining of blood vessels

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Margination

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Moving to the edge. Typically describes one leukocytes move from the center of the bloodstream to the edge so that they come in contact with blood vessel wall

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Necrotic

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Dead. Cells, tissues, and entire organs may be necrotic.

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Oncotic pressure

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Pressure generated by concentrated liquids inside a blood vessel. This draws fluid into the blood vessel, to try and dilute the concentration of the plasma proteins and ions.

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Opsins

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Proteins that binds the outside of bacteria or dead tissue. Opsins are usually antibodies or fragments of the complement cascade

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Phagolysosome

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The fusion of phagocytosed particles with lysosomal enzymes

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Proteases

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Proteins that degrade other proteins

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Pyrogens

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molecules in the body that cause a fever by altering the “set point” for the temperature of the body