VOL: 99, ISSUE: 25, PAGE NO: 63
Mark Collier, BA, ONC, RGN, RCNT, RNT, lead nurse/consultant, tissue viability, United Lincolnshire Hospital NHS Trust, Boston, Lincolnshire
Inflammation is the first stage in the wound-healing process. It is normally followed by two further phases: regeneration (sometimes also referred to as proliferation) and maturation. Inflammation is characterised by the classic signs of heat and redness, pain and swelling, raised temperature and fever. The overall function of inflammation is to neutralise and destroy any toxic agents at the site of an injury and to restore tissue homeostasis.
Wound healing involves cellular activity and the release of biologically active substances, such as growth factors, enzymes, carbohydrates and proteins (Krasner, 1990). However, the quality and extent of the inflammatory response in a wound will be dependent on the severity of the patient’s injury as well as their general health, for example, their nutritional state, hydration and existing comorbidity.
Recently, it has been acknowledged that inflammation can be subdivided into two distinct components: early and late inflammation (Calvin, 1998). This division is important for understanding the process of wound healing since delayed healing of chronic wounds often results from an imbalance in the wound that prevents progression from one phase to another in a predictable manner (Lazarus et al, 1994).
A chronic wound may be defined as any wound that is failing to heal as anticipated or that has been stuck in any one phase of wound healing for a period of six weeks or more (Collier, 2002). Chronic wounds result from an alteration in one or more of the phases of normal wound healing and may be caused by cellular imbalances. Examples of such cellular imbalances are increased levels of enzymes or matrix metalloproteinases (MMPs), a decreased number of available ‘active’ macrophages and/or a decreased number of ‘active’ growth factors (Calvin, 1998). It is now thought that most chronic wounds, such as chronic leg ulcers, are stuck in the phase known as early inflammation (Falanga et al, 1994).
Cells involved in the inflammatory process
Platelets - Platelets are the cells that initiate wound healing. They originate in the bone marrow, have a life expectancy of between eight and 12 days and are filled with cytokines that directly influence the activity of leucocytes (white blood cells) during the wound-healing process.
Platelets are released from damaged blood vessels and flow into the wound. When the platelets come into contact with mature collagen they are activated and clump together. During this process, granules from within the cell cytoplasm are released and liberate other enzymes, adenosine triphosphate (ATP), serotonin and growth factors - such as platelet-derived growth factor and epidermal growth factor - which further potentiate platelet aggregation (Krasner, 1990).
Leucocytes - There are five types of leucocyte that are classified by the presence or absence of granules in the cytoplasm of the cell. They include lymphocytes, neutrophils and macrophages.
Their function is the phagocytosis (engulfment and digestion) of bacteria, fungi and viruses in the blood. They also detoxify poisonous proteins that may have been produced as a result of allergic reactions and cellular injury (Calvin, 1998).
Lymphocytes - These white blood cells have a specific immune response. The response is slower but more accurate than that of other white cells. Lymphocytes can be differentiated into T (thymus-maturing) and B (bone-maturing) cells (Kingsley, 2002).
Neutrophils - Also known as granulocytes, neutrophils target bacteria. Neutrophil infiltration of the wound-bed peaks at approximately 24 hours and declines over the next few days. Neutrophils live for about 24 hours (Slavin, 1996).
Macrophages - Macrophages have a lifespan of between several months and two years, although the number present in a wound starts to decrease at the end of the inflammatory process as a result of apoptosis (programmed cell death). In the absence of macrophages, tissue debridement will be incomplete and the influx of fibroblasts to the wound will be significantly reduced. Fibroblasts are responsible for most of the collagen and elastin synthesis and, therefore, play a vital role in wound healing.
The major influences that macrophages have on wound healing may be summarised as:
- Phagocytosing damaged tissue and bacteria;
- Producing chemotaxins for continuing white-cell recruitment;
- Releasing proteases that break down necrotic tissue;
- Making cytokines to regulate new tissue formation (Calvin, 1998);
- Producing interleukin-6. The interleukin family is a group of multifunctional cytokines with wide-ranging effect in the wound-healing process. Interleukin-6 is specifically associated with the immune response of the inflammatory phase of wound healing and the pyrexia (raised temperature) experienced by patients (Johnston and Unsworth, 2001);
- The release of matrix metalloproteinases (MMPs), which actively break down proteins and inhibit growth factors. MMPs assist with the clearance of the damaged extracellular matrix (Kingsley, 2002).
The term ‘growth factor’ is used to describe a variety of proteins that are involved in coordinating the various processes that occur during normal wound healing (Davidson and Broadley, 1991). Put simply, growth factors may be considered as the key substances that activate the cells involved with the inflammatory process. There are several types of growth factor involved with inflammation, including:
- Platelet-derived growth factor;
- Epidermal growth factor;
- Angiogenesis growth factor;
- Basic fibroblastic growth factor;
- Transforming growth factor (Hart, 1999; Calvin, 1998; Krasner, 1990).
The overall functions of growth factors can be summarised as follows:
- Angiogenic - stimulating the growth of new transient blood vessels to support the wound-healing process;
- Chemotatic - attracting various cell types involved in wound healing to the wound-bed;
- Mitogenic - stimulating cellular proliferation;
- Influencing the synthesis of cytokines by neighbouring cells;
- Regulating the synthesis and degradation of the extracellular matrix (ECM) that promotes cell migration to the site of injury.
Review of the inflammatory process
Numerous events will happen within a short time of an injury occurring, which should result in a great number of cell types entering the wound. Early inflammation (in the first 24 hours) begins with haemostasis, a process in which platelets play a key role.
Once haemostasis is achieved, late inflammation (24 to 96 hours after the injury) involves the release of vasodilatory agents, such as histamine and serotonin, which increase the permeability of the local capillary bed. This allows serum and white cells, such as neutrophils and macrophages, to be released into the area surrounding the wound.
The transition from early to late inflammation depends on the replacement of neutrophils by lymphocytes and monocytes that have become activated. Macrophages continue the phagocytic role of neutrophils and have also been identified as playing an important role in the transition from the inflammatory phase to the regenerative/proliferative phase of wound healing. In total, the inflammatory phase of wound healing is thought to last for five days (Calvin, 1998).
Pathophysiological explanation of the ‘classic signs’ of inflammation
Following injury and endothelial damage, there is an initial vasoconstriction around the wound site followed by a rapid dilation of the arterioles and precapillary sphincters (cuffs of smooth muscle that regulate the flow of blood into the capillaries), resulting in reduced vascular resistance (Herbert, 1997).
A number of chemical mediators are released, which help to stimulate dilation and therefore increase capillary permeability and cellular migration. These include: histamine, prostaglandins (released from mast cells), bradykinin (released from damaged epithelial cells) and nitric oxide.
As a result of the increased blood flow - causing the classic signs of heat and redness (hyperaemia) - there is an increase in capillary hydrostatic pressure. This reduces the effectiveness of the normal blood osmotic pressure and increases the permeability of the capillaries. The increased permeability leads to protein-rich fluid leaking into the interstitial tissue spaces.
As fluid moves out of the capillaries the viscosity of the blood increases, slowing down blood flow. As the blood flow slows down, red blood cells clump together forcing white cells to move towards the endothelium of the vessels resulting in swelling and pain.
There is an increased demand for oxygen and nutrients in the damaged area. This raises the patient’s metabolic rate, which leads to an increased ‘core’ temperature. Clinically the patient may experience pyrexia. Additional platelet activity (the clotting mechanism involves the conversion of protein fibrinogen into insoluble fibrin forming a haemostatic plug) is mediated by the further release of substances that stimulate the synthesis of extracellular matrix (ECM) components.
In addition, growth factors released from activated platelets during coagulation regulate the recruitment of cells into the wound site and neutrophils infiltrate the wound. Normally neutrophil infiltration only lasts a few days but will be prolonged in contaminated wounds (Calvin, 1998; Cox, 1993; Krasner, 1990).
All practitioners should understand the role of inflammation and the inflammatory response in wound healing. This will enable them to assess when the process is not progressing as anticipated.