The scourge of excessive inflammation

Inflammation is a vital part of the normal response to infection or injury, and is what starts the healing process. It normally lasts for one day but, if it is prolonged or if the inflammatory response is excessive in intensity, it can prevent healing or even cause further damage to tissues. Prolonged inflammation, at a level below that which causes damage, is the cause of fibrosis, seen as hypertrophic scarring in wounds. Inflammation in wounds also causes discomfort for patients and problems in dressing the wounds, because of the large amounts of exudate associated with it.

The prostaglandins are part of the inflammatory response. They give rise to pain and cause small arteries to open, increasing blood pressure locally and giving rise to oedema in the area of the wound, and exudation of plasma from the wound. Suppression of inflammation, as well as reduction of pain, reduces the oedema and exudate. The pressure building up in tissues from oedema can slow the healing process, as it restricts the flow of blood through the capillaries (Chant, 1999), thus starving the tissues of the oxygen and nutrients that are vital for leukocytes to fight infection and for fibroblasts to multiply for wound healing. The swelling also increases the distance for diffusion of oxygen and nutrients from the capillaries to the cells (Sinclair and Ryan, 1994).

The inflammatory response is initiated by the reaction of leukocytes when in contact with substances from bacterial cells, or to tissue factors released when there is physical damage. (In the case of burn injuries, there are large quantities of these tissue factors released, which accounts for the severe inflammation associated with burns.) Phagocytes that are activated as part of the initial inflammatory response produce hydrogen peroxide to destroy the bacteria and debris that they engulf. Some of this hydrogen peroxide leaks out of the cells, which serves to give a feed-back amplification of the inflammatory response, as the hydrogen peroxide attracts and stimulates other leucocytes to proliferate (Flohé et al, 1985). If this continues unchecked, the feed-back amplification can result in a vicious cycle that gives excessive levels of inflammation. Hydrogen peroxide was once widely used as an antiseptic, but has gone out of favour because it causes this inflammation. Although the hydrogen peroxide produced in honey may have the potential to cause inflammation, it is produced at very low levels, equivalent to about one thousandth of that in the 3% solution of hydrogen peroxide used as an antiseptic (Bang et al, 2003). However, there is also protection via the anti-inflammatory properties of honey.

The hydrogen peroxide released by phagocytes can also be converted to reactive oxygen species ( free radicals) in the tissues (Flohé et al, 1985). These free radicals are very reactive and can break down proteins, nucleic acids and cell membrane lipids, thus damaging or destroying tissue. Far greater damage to tissues results from the activation of proteases in the wound tissues by reactive oxygen species (Weiss et al, 1985; Ossanna et al, 1986; Peppin and Weiss, 1986). These protein-digesting enzymes are normally present in an inactive form (in the case of the matrix metalloproteases), or are kept inactive by the presence of an inhibitor (in the case of the neutrophil serine protease). But, once activated, can destroy wound tissue. Thus, a wound can become ulcerated and a partialthickness burn can become full-thickness. These activated proteases also have the potential to destroy the tissue growth factors which, being proteins, are essential for activation of the repair process.

In the case of reperfusion injury, hydrogen peroxide produced by a biochemical process is the initiator of the inflammatory response and the ongoing vicious cycle. When tissues are deprived of oxygen through obstruction of circulation, production of xanthine and alteration of the enzyme xanthine dehydrogenase to catalyse an oxidase type of reaction
occurs. When the circulation is subsequently restored and the tissue is reperfused, the oxygen now available is used by the enzyme to oxidise xanthine, setting up production of hydrogen peroxide and reactive oxygen species (Bostek, 1989). This mechanism of initiation accounts for the inflammation in pressure ulcers (where circulation is cut off by pressure on the tissues then restored by relief of the pressure), and in varicose ulcers (where circulation is restricted by venous stasis then restored by elevating the legs), with the subsequent activation of proteases by the inflammatory reaction contributing to ulceration of the tissue.

Where the inflammation is less severe and insufficient to give erosion of tissue by activation of wound proteases, it can give excessive activation of fibroblasts, causing fibrosis, hypertrophic scarring and contractures. ( Fibroblasts are the precursors of muscle cells, and use the same contractile fibres as muscle cells to pull the edges of a wound together. They also produce collagen fibres which form scar tissue.) Although excessive or prolonged inflammation is a major problem in wounds, pharmaceutical anti-inflammatory substances are not generally used in wound treatment because they can impair healing through adverse effects on proliferating cells. Honey, however, has a potent anti-inflammatory action that not only has no adverse effects on the growth of cells, but actually gives a positive stimulation of their growth.

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