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 Burns

 Chemical irritants

 Frost bite

 Toxins

 Infection by pathogens

 Immune reactions due to hypersensitivity

 Physical injury, blunt or penetrating ionising radiation

 Foreign bodies including splinters, dirt and debris

 Stress

 Trauma

 Alcohol

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42 2.12.2 Types of inflammation

(i) Acute inflammation

Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increase movement of plasma and leukocytes (especially granulocytes) from the blood into injured tissues. A cascade of biochemical events propagates and matures the inflammatory response involving the local vascular system, the immune system and various cells within the injured tissue. Acute inflammation starts rapidly (rapid onset) and quickly becomes severe.

Signs and symptons are only present for a few weeks. Examples of disease conditions and situation which can result in acute inflammation include acute bronchitis, infected toe nail, sore throat from a cold or flu, a stratch, cut on the skin, acute appenditis, acute dermatitis, acute menigitis, acute sinutisis or a blow. Within a few seconds or minutes after tissue is injured, acute inflammation starts occurring. The damage may be a physical one or might be caused by an immune response. Three main processes occur before and during acute inflammation :

(i) Arterioles, small branches of artieries that leads to the damaged region, dilate thereby resulting in increased blood flow. The capillaries become more permeable, so fluid and blood protein can move into interstitial spaces between tissues.

(ii) Neutrophils and possibly some macrophages migrate out of the capillaries and venules (small veins that go from a capiallary to vein) and move into interstitial spaces. A neutrophil is a type of granulocyte (white blood cells). It is filled with tiny sacs which contain enzymes that digest microorganisms. Macrophages are also a type of white blood cells that ingest foreign materials for example when the skin is scratched and it is not broken, one may see a pale red line. Soon the area around the scratch goes red, this is because the arteriole have dilated and the capillaries have filled up with blood and become more permeable to move.

Acute inflammation is a short term process usually appearing within a few minutes or hours and ceasing upon the removal of the injurious stimulus (Cotran et al., 1998). It is characterized by five cardinal signs (Parakama and Clive, 2005). The acronyms that may be used for this is PRISH for pain, redness, immobility (loss of function), swelling and heat. The traditional names for signs of inflammation comes from Latin. Dolor (pain), Color (Heat), Rubor (Redness), Tumour (Swelling) and Function laesa (loss of function) (Ruth, 2009).

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The first four classical sign were described by Celcius (30BC-38AD) (Vogel et al., 2009), while loss of function was added later by Galen Porth,( 2007).

The five cardinal signs of acute inflammation (PRISH)

Pain : The inflamed area is likely to be painful especially when touched. Chemicals that stimulate nerve endings are released, making the area much sensitive.

Redness : This is because the capillaries are filled up with more blood than usual.

Immobility : There may be some loss of function.

Swelling : Swelling is caused by accumulation of fluid.

Heat : More blood moves to the affected area and makes it feel hot to the touch. These five signs appear when acute inflammation occurs in the body surface whereas acute inflammation of internal organs may not result in the full set. The process of acute inflammation is initiated by cells already present in all tissue, mainly resident macrophages dendritic cells, histiocytes, kupffer cells and mastocytes. These cells present on their surface contain receptors named pattern recognition receptors (PRRs) which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively, referred to as pathogen.

Associated molecular patterns (PAMPs). At the onset of an infection, burn or other injuries these cells undergo activation (one of their PPRs recognize a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation, vasodilaton and its resulting increase blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels result in an exudation (leakage of plasma proteins and fluids into the tissue (edema) which manifests it self as tumour. Some of the released mediators such as bradykinins, increase the sensitivity to pain (hyperalgesia, dolor). The mediator molecules also alter the blood vessels (extravasation) into the tissues. The neutrophil migrate along a chemotactic gradient created by the local cells to reach the site of injury (Cotran et al., 1998).

The loss of function is probably the result of a neurological reflex in response to pain. In addition to cell-derived mediators, several cellular biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response.

These include the complement system activated by bacteria and the coagulation and fibrinolysis systems activated by necrosis e.g a burn or a trauma.The acute inflammatory response requires a

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constant stimulation to be sustained. Inflammatory mediators have short half life and are quickly degraded in the tissue. Hence, acute inflammation ceases once the stimulus has been removed.

(ii) Chronic inflammation

Chronic inflammation means long term inflammation which can last for several months and even years. It can result from failure to eliminate whatever was causing an acute inflammation.

An auto immune response to a self antigen, the immune system attack healthy tissues, mistaking it for harmful pathogens. Examples of diseases and conditions with chronic inflammation include asthma, chronic peptic ulcer, tuberculosis, rheumatoid, arthritis, chronic periondotitis, ulcerative colitis, chronic hepatitis. Chronic inflammation leads to a progressive shift in type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. It can also manifest, histologically, by the presence of lymphocytes, macrophages and result in fibrosis and tissue necrosis. Infections, wounds and any damage to tissue would never heal without inflammation. Tissues would become more and more damaged and the body or any organ would eventually perish.

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Table 2 : Comparison between acute and chronic inflammation (Graham et al., 1988)

Acute Chronic

Causative agent Pathogens, injured tissues. Persistent acute inflammation due to non degradable pathogens, persistent foreign bodies or autoimmune reaction.

Major cells involved Neutrophils, mononuclear cells (monocytes, macr phages).

Mononuclear cells (monocytes,

macrophages, lymphocytes, plasma cells), fibroblasts.

Primary mediators Vaso-active

Amines, eiocosanoids.

IFN-Y and other cytokines, growth factors, reactive oxygen species, hydrolytic

enzymes.

Onset Immediate Delayed

Duration Few days Up to many months

Outcomes Resolution, abscess

formation chronic inflammation

Tissue destruction, fibrosis, necrosis

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46 2.12.3 Mediators of inflammation

Inflammatory mediators are soluble diffusible molecules that act locally at the site of tissue damage and infection and at more distant sites. In appreciating the inflammatory process, it is important to understand the role of chemical mediators. These are the substances that tend to direct inflammatory response. These inflammatory mediators come from plasma proteins or cells including mast cells, platelets, neurtrophils and monocytes. They are triggered by bacterial product or host proteins. Chemical mediators bind to specific receptors on target cells and can increase vascular permeability and neutrophil chemotaxis, stimulate smooth muscle contraction, have direct enzymatic activity, induce pain or mediate oxidative damage. Most mediators are short lived but cause harmful effects (Cotran et al., 1998). Chemical mediators of the inflammatory process include a variety of substances originating in the plasma and the cells of the injured tissues and possibly from the damage tissues. The mediators of inflammation include: :

(a) Plasma protein such as complement and antibodies (b) Cytokine and chemokines such as IL-10

(c) Lipids such as prostaglandins and polyunsaturated fatty acids (d) Vasoactive amines such as histamine and serotonin

(e) Gases such as NO and O2

(f) Kinins such as bradykinin (g) Neuropeptides.

Once leukocytes have arrived at a site of infection or inflammation, they release mediators which control the later accumulation and activation of other cells. However, in inflammatory reactions initiated by the immune system, the ultimate control is exerted by the antigen itself, in the same way as it controls the immune response itself. For this reason, the cellular accumulation at the site of chronic infection or in auto immune reaction (where the antigen cannot ultimately be eradicated) is quite different from that at sites where the antigenic stimulus is rapidly cleared.

There are four major plasma enzymes systems which have an important role in homeostasis and control inflammation. These are complement system, the clotting system, the fibrinolytic

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system and the kinnin system. Inflammatory mediators can be divided into exogenous and endogenous mediators. Bacterial products and toxins can act as exogenous mediators of inflammation and noteable among this is endotoxin. The immune system of higher organisms has probably evolved in a veritable sea of endotoxin, so it is perhaps not surprising that this substance evokes powerful response. For example, endotoxin can trigger complement activation resulting in the formation of anaphylatoxins (C3a and C5a) which cause vasodilation and increase vascular permeability. In addition, endotoxin elicit T cell proliferation and have been described as super antigen for T cells.

Endogenous mediators of inflammation are produced from within the innate and adaptive immune system itself as well as other systems. For example, they can be derived from molecules that are normally present in the plasma in an active form such as peptide, fragments of some components of complements, coagulation and kinnin systems. Mediators of inflammatory responses are also released at the site of injury by a number of cells types that either contain them as preformed molecules within storages granules e.g histamine which can rapidly switch on the machinery requires to synthesize the mediators when they are required for example, to produce metabolites of arachidonic acid.

Monocular phagocytes (monocytes and macrophages) are central to inflammation as they produce many components which participate in or regulate the different plasma enzymes systems and hence the mediators of inflammatory response. Early phase mediators are produced by mast cells and platelets. They are especially important in acute inflammation and include mainly histamine, serotonin and other vasoactive substances. To the early phase mediators also belong chemoatractants e.g (5a and cytokines such as IL-1, IL-6 and TNF.