Acute Inflammation



Acute Inflammation

1. Know the causes of inflammation and how each induces and inflammatory response

The causes of inflammation are:

• microbial infection

• physical agents e.g. foreign bodies

• foreign bodies

• tissue necrosis or hypoxia

• injury

which stimulate phagocytes, either because they are foreign, or because they cause damage to host cells which then stimulate tissue macrophages.

2. Understand the patho-physiological mechanisms of the cardinal features of acute inflammation and relate these to the vascular and cellular events occurring at the tissue level

The cardinal signs of inflammation are:

• Rubor – redness

• Tumor - swelling

• Calor – heat

• Dolor – pain

• Functio laesa – loss of function

Acute inflammation is the immediate and early response to and injurious agent and has 3 major components:

1. alterations in vascular caliber that lead to an increased blood flow

2. structural changes in the capillaries that permit the plasma proteins and leukocytes to leave the circulation and

3. emigration of the leukocytes from the microcirculation and the accumulation on the focus of injury

• The tissues in the area are red and warm, as a result of the large amount of blood reaching the site.

• The tissues in the area are swollen, again due to the increased amount of blood and proteins that are present.

• The area is painful, due the expansion of tissues, causing mechanical pressure on nerve cells, and also due to the presence of pain mediators.

Changes in vascular flow and caliber

• After a transient vasoconstriction of arterioles (lasting a few seconds), vasodilatation occurs – first of the arterioles and then capillary beds in the area open. This causes increased blood flow which in turn is the cause of the heat and redness.

• Slowing of the circulation is brought about by increased permeability of the microvasculature. The outpouring of protein rich fluid into the extravascular tissues results in a concentration of the red blood cells in the small vessels and an increase in the viscosity of the blood. This is reflected by the presence of dilated small vessels packed with red cells – called stasis

• As stasis develops, leukocytes migrate to the periphery – leukocyte margination. leukocytes then stick to the endothelium, at first transiently (rolling), then more eagerly, and soon after, they migrate through the vascular wall into the interstitial tissue.

Increased vascular permeability

• leading to escape of a protein rich fluid (exudate) into the interstitium is the hallmark of acute inflammation. This causes swelling

• loss of protein from plasma → ↓ intravascular osmotic pressure and ↑ interstitial fluid osmotic pressure

• together with ↑ hydrostatic pressure due to vasodilation, leads to an outflow of fluid an its accumulation on the interstitial space

• net increase of interstitial fluid = oedema

In summary, redness and heat are due to increased blood flow to the inflamed area; swelling is due to accumulation of fluid; pain is due to release of chemicals that stimulate nerve endings; and loss of function is due to a combination of factors.

3. Understand the fundamental histological changes that occur in any acutely inflamed tissue

Polymorphonuclear neutrophils are the characteristic cells of acute inflammation, and predominate for the first 24 hours after which monocytes accumulate. This accompanied by dilated capillaries and accumulation of interstitial fluid.

[pic]

This image shows smooth muscle cells, neutrophils and oedema. Also see Robinns textbook (Fig 3-10 in 6th Ed).

4. Know the main chemical mediators responsible for the tissue response and understand their action

The main chemical mediators of the immune response are:

• Vasoactive amines

o histamine

o serotonin

• Plasma Proteases

o Complement System

o Kinin System

o Clotting System

• Arachidonic Acid metabolites

o prostaglandins

o leukotrienes

o lipoxins

• Platelet-Activating factor

• Cytokines and chemokines

o IL-1

o TNF

• Nitric Oxide

• Lysosomal Constituents of leukocytes

• Oxygen-derived free radicals

Vasoactive Amines

Histamine

• widely distributed in tissues with richest source being mast cells

• preformed histamine is present in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli:

o physical injury

o immune reactions involving binding of antibodies to mast cells

o fragments of complement termed anaphylatoxins (C3a and C5a)

o histamine-releasing proteins derived from leukocytes

o neuropeptides

o cytokines (IL-1 and IL-8)

• causes dilation of arterioles and increases vascular permeability of venules (but constricts large arteries)

• principle mediator of immediate phase of increased vascular permeability, causing venular gaps

Serotonin

• preformed vasoactive mediator similar to histamine

• present in platelets and enterochromaffin cells (found in epithelium of digestive tract)

• release from platelets is stimulated when platelets aggregate

• increased permeability

Plasma Proteases

Complement System

• consists of 20 component proteins (together with their cleavage products)

• greatest concentration in plasma

• functions in both innate and adaptive immunity for defense against microbial agents and culminates in lysing microbes by the membrane attack complex (MAC)

• in the process, several complement components are generated that cause increased vascular permeability, chemotaxis and opsonization

• MAC causes cell lysis by initial hydrophobic binding to the lipid bilayer of target cell, eventually forming cylindrical transmembrane channels

• complement-derived factors:

o C3a,C5a and to a lesser extent C4a (anaphylatoxins) cause increased vascular permeability and vasodilation, mainly by releasing histamine from mast cells

o C5a also activates lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes which leads to further release of inflammatory mediators

o C5a – chemotactic agent for neutrophils, monocytes, eosinophils and basophils, increases adhesion of leukocytes to endothelium

o C3b and C3bi, when fixed to bacterial cell wall, act as opsonins and favour phagocytosis by neutrophils and macrophages (which have cell surface receptors for C3b)

Kinin System

• generates vasoactive peptides from plasma proteins called kininogens by specific proteases called kallikreins

• results in release of bradykinin, which causes an increase in vascular permeability, contraction of smooth muscle, dilation of blood vessels and pain when injected into the skin

• kallikrein also has chemotactic activity and converts C5 into C5a

Clotting System

• clotting system and inflammation are intimately connected

• induces formation of thrombin, fibrinopeptides, and factor X, all of which have inflammatory properties

Arachidonic acid (AA) metabolites: Prostaglandins, Leukotrienes and Lipoxins

• AA found in cell membrane derived directly from diet

• products of AA metabolism affect variety of biological processes including inflammation

• best thought of as local, short-range hormones, which are formed rapidly, exert their effects locally and then either spontaneously decay or are enzymatically destroyed

• Cyclooxegenase pathway generates prostaglandins

o the most important prostaglandins in inflammation are prostacyclin and thromboxane

o prostacyclin – vasodilator, inhibitor of platelet aggregation, potentiates effects of other mediators

o thromboxane – vasoconstrictor and platelet aggregating factor

o prostaglandins are involved in the generation of pain and fever

• Lipoxegenase pathway generates leukotrienes

o chemotactic agent and activator of neutrophil functional responses e.g. adhesion of leukocytes to venular endothelium, generation of oxygen free radicals and release of lysosomal enzymes

o some cause vasoconstriction, bronchospasm and increased vascular permeability

• Lipoxins are generated from AA and transcellular biosyntheses (cooperation of different cell types, in this case platelets and neutrophils)

o proinflammatory and anti-inflammatory actions

o inhibit neutrophil chemotaxis and adhesion, but stimulate monocyte adhesion

Platelet Activating Factor (PAF)

• phospholipid-derived mediator

• causes vasoconstriction and bronchoconstriction and at extremely low concentrations it induces vasodilation and increased venular permeability with a potency of 100 – 10,000x that of histamine

• increased leukocyte adhesion to endothelium, chemotaxis, degranulation

• boosts synthesis of other mediators

Cytokines and Chemokines

Cytokines

• proteins produced by many cell types that modulate the function of other cell types

• numerous and many have multiple functions

• 5 classes according to their major function or nature of target cell:

1. Cytokines that regulate lymphocyte function e.g. IL-2 and IL-4

2. Cytokines involved in natural immunity e.g. TNF-α and IL-1β

3. Cytokines that activate Inflammatory Cells e.g. IFN-γ

4. Chemokines

5. Cytokines that stimulate hematopoiesis (blood cell growth and differentiation)

• TNF (α and β) and IL-1 are the major cytokines that mediate inflammation

• produced by activated macrophages

• their secretion can be stimulated by endotoxin, immune complexes, toxins, physical injury, and a variety of inflammatory processes

• they can act on the same cell that produces them, cells in the immediate vicinity or systematically

• their most important actions on inflammation are their effects on endothelium, leukocytes and fibroblasts and induction of the systemic acute-phase reactions

• Chemokines are small proteins that act primarily as activators and chemoattractants for specific types of leukocytes

Nitric Oxide

• produced by endothelial cells, neurons of the brain and macrophages

• potent vasodilator

• reduces platelet aggregation and adhesion

• regulator of leukocyte recruitment, blocking NO promotes leukocyte rolling and adhesion in venules, while production of NO reduces leukocyte recruitment

• involved in the pathogenesis of septic shock

Lysosomal Constituents of leukocytes

• Neutrophils contain smaller specific granules and larger azurophil granules that contain various enzymes with numerous effects

• specific granules are secreted extracellularly more readily and with lower amounts of agonists while the more destructive azurophil granules release their contents primarily within the phagosome and require high levels of agonists to be released extracellularly

Oxygen-derived free radicals

• released extracellularly from leukocytes after exposure to chemotactic agents, immune complexes or phagocytic challenge

• can increase expression of chemokines, cytokines and endothelial leukocyte adhesion molecules, thus amplifying the cascade that illicits the immune response

• at high levels can be damaging to the host (can cause endothelial cell damage, and injury to other cell types)

Summary of mediators of acute Inflammation

| | |Action |

|Mediator |Source |Vascular Leakage |Chemotaxis |Other |

|Histamine and serotonin |Mast cells, platelets |+ |- | |

|Bradykinin |Plasma substrate |+ |- |Pain |

|C3a |Plasma protein via liver |+ |- |Opsonic fragment |

|C5a |Macrophages |+ |+ |leukocyte adhesion, |

| | | | |activation |

|Prostaglandins |Mast cells, from membrane|potentiate other |- |Vasodilation, pain, fever |

| |phospholipids |mediators | | |

|Leukotriene B4 |Leukocytes |- |+ |leukocyte adhesion, |

| | | | |activation |

|Leukotriene C4, D4, E4 |leukocytes, mast cells |+ |- |Bronchoconstriction, |

| | | | |vasoconstriction |

|Oxygen metabolites |leukocytes |+ |_ |endothelial damage, tissue |

| | | | |damage |

|PAF |leukocytes, mast cells |+ |+ |bronchoconstriction, |

| | | | |leukocyte priming |

|IL-1 and TNF |macrophages, other |- |+ |Acute phase reactions, |

| | | | |endothelial activation |

|Chemokines |leukocytes, others |- |+ |leukocyte activation |

|Nitric oxide |macrophages, endothelium |+ |+ |vasodilation, cytotoxicity |

Most likely mediators in inflammation

Vasodilation

• prostaglandins

• nitric oxide

Increased vascular permeability

• vasoactive amines

• C3a and C5a (through liberating amines)

• bradykinin

• leukotrienes C4,D4,E4

• PAF

Chemotaxis Leukocyte activation

• C5a

• leukotriene B4

• chemokines

• bacterial products

Fever

• IL-1, IL-6, TNF

• prostaglandins

Pain

• prostaglandins

• bradykinin

Tissue Damage

• neutrophil and macrophage lysosomal enzymes

• oxygen metabolites

• nitric oxide

5. Understand the functions of the inflammatory response

The primary physical effect of the inflammatory response is for blood circulation to increase around the affected area. In particular, the blood vessels around the site of inflammation dilate, allowing increased blood flow to the area. Gaps appear in the cell walls surrounding the area, allowing leukocytes to pass through. As a result of the increased blood flow, the immune presence is strengthened. All of the different types of cells that constitute the immune system congregate at the site of inflammation, along with a large supply of proteins, which fuel the immune response. There is an increase in body heat, which can itself have an antibiotic effect, swinging the balance of chemical reactions in favour of the host.

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