Ann. Medit. Burns Club - vol. V111 - n. I - March 1995

PATHOLOGICAL SCAR FORMATION IN BURNS: NEW BIOCHEMICAL AND MOLECULAR FACTORS IN THE HEALING PROCESS

Bocchi A., Caleffi E., Toschi S., Stabile M.

Cattedra di Chirurgia Plastica, UniversitA clegli Studi e Divisione di Chirurgia Plastica, USL 4, Parma, Italy

SUMMARY. A review is made of the principal biochemical and molecular factors that have most recently come to light in research into the processes involved in pathological scar formation due to bums. A better understanding of the biochemical events leading to pathological scar formation will help to improve prevention and therapy. The various vascular changes following tissue injury are considered, as well as the question of tissue repair. As shown by the most up-to-date research, it is now possible to accomplish the pharmacological and non-surgical therapy of burn scars by means of both chemical and physical agents. These various agents are systematically reviewed. Among the chemical agents, corticosteroids and zinc are considered to be the first-choice drugs; while among the physical agents, pressure would appear to be the most effective.

The principal steps of scar formation have been known for many years.
The most up-to-date studies concern the biochemical and molecular relationships among cells, plasma proteins, enzymes, coagulation factors, inflammatory agents, etc. which affect a multitude of biological phenomena, not occurring in a rigidly fixed course of events, and leading eventually to wound healing.
When a transient disequilibrium sets in among the biochemical mechanisms, either because of an increase in metabolic activity or due to unequal rates of collagen, synthesis and degradation, pathological scar formation may occur. Abnormal wound healing is most remarkable in burned patients: an understanding of the biochemical events leading to pathological scar formation may thus improve the chances of prevention and therapy.

Vascular changes are the first event following tissue injury: these consist of a brief period of vasoconstriction followed by vasodilatation and at the same time haemocoagulation.
Many goals thus have to be achieved: bleeding control, a mechanical barrier against bacteria, the weak approach of wound margins, and the creation of a biological framework in which the phenomena of wound repair may occur.
Another early aspect of wound healing is modulated by inflammatory cells through:

1. Vasodilatation and the increase of vasal permeability which allows migration, towards the site of the lesion, of several agents involved in wound healing; the activation of vasal contractile proteins by histamine, polypeptides and prostaglandins plays a crucial role.

2. Chemotaxis of leucocytes migrating to the inflammatory field in two stages: first the polymorphonuclear cells (PMN), which form a barrier against infection; and later the macrophages, the most important cellular elements in the healing process (phagocytosis of necrotic tissue, neoangiogenesis, fibroblast stimulation).

Another important step is the repair of lost tissue through collagen deposition proliferation, vascular buttons from wound margins and epithelialization. Wound contraction then follows, regulated by myofibroblasts, through the centripetal movement of the injured margins of the wound.To examine closely the biomolecular aspect of the healing process we must consider:

• factor X11 of haemocoagulation, which increases the resistance of the thrombus and the action of fibronectin, a plasma protein involved in collagen activation;

• thrombin, which stimulates fibroblasts and regulates the formation of fibrin (which also stimulates fibroblast growth);

• platelets, which contain a factor promoting fibroblast growth;

• histamine, which favours neoangiogenesis and collagen production;

• plasma proteins: most of these arrive at the site of tissue injury owing to increased vascular permeability without playing an important role in wound healing; only fibronectin is certainly important in wound repair because it facilitates fibroblast migration and adhesion.

We will now consider the pathogenetic aspects of abnormal scar formation.In hypertrophic scars and keloids, collagen synthesis is considerably increased; the arrangement of collagen fibres is not parallel to the epithelium,~ as in normal scars, but random. There is also a disequilibrium between collagenase because the collagen is covered by a coat of proteoglycans, which interfere with the activity of the enzyme.
Some researchers describe three populations of fibroblasts, which have a different distribution in normal and pathological scars.

In the light of the above molecular studies, the pharmacological and non-surgical treatment of burn scars may be accomplished through both chemical and physical agents.

Most of the drugs tested have only experimental significance either because of their aspecific effect (for exam~ ple, actinomycin D stops all protein synthesis) or because of the contradictory elements in their clinical application (Tables I, R).
Among the chemical factors which have proved useful for clinical application are lathyrogenic agents: BAPN and penicillamine, which inhibit collagen crosslink.
Better results are obtained through the association with colchicine, which stimulates collagenase activity.
However, further controls on therapeutic effectiveness and collateral effects must be carried out before routine clinical use is possible.Enzymes, in spite of their promising theoretical advantage (collagen degradation), have not yet achieved satisfactory clinical results.Corticosteroids are the most successful agents in the non-surgical therapy of burn scars. A few mechanisms of their action are known: they decrease collagen synthesis, inhibit fibroblast migration into the wound, and affect the inflammatory and local immune response. Collateral effects may be decreased by injection within the scar; inoculation in contiguous and underlying tissues should be avoided.0.05% retinoic acid solution given to burn patients twice a day for a few months can decrease the size of the lesion, possibly because of the inhibition of fibroblast and lymphocyte growth.
Vitamin E is a membrane stabilizer which inhibits the liberation of lysosomal contents, having an anti-inflammatory effect which decreases tissue repair.Zinc seems to inhibit fibroblast action, although there are reports of a stimulation of collagen synthesis.The physical agents employed in the treatment of hypertrophic and keloid scars in burn patients are irradiation and pressure.
Irradiation has a particularly favourable action on keloids associated with surgery and, in some cases, with chemotherapy. Nevertheless it should be employed only in carefully selected cases (failure of other therapies, multiple or relapsed lesions) because of the risks of late complications (radiodermitis, radionecrosis).
Pressure represents the basic moment of non-surgical treatment of a scar following a third-degree burn. Its mechanism lies in the induction of tissue hypoxia for a period of at least 12 to 18 months. The best results are obtained in the limbs; in the face, because of the irregular distribution of the pressure forces, only the cheeks and forehead receive uniform pressure.
Some clinical improvement has been observed in recent years by many researchers using silicone gel treatment in hypertrophic burn scars. The mode of action remains to be determined, but it is not due to pressure, temperature, oxygen tension or occlusion.

The above-described molecular mechanisms achieve their best expression in burned tissue repair because the burn injury produces an amplification of the inflammatory response, fibroblast activity and, in general, every physical response to trauma.
The study of the cellular and molecular phenomena affecting wound healing is thus of the greatest importance in burn scars, in which chemical and physical agents of various types and different mechanisms are involved, possibly in synergy.At present, among the pharmacological agents, corticosteroids and zinc are the first-choice drugs; among the physical agents, pressure seems to be the most effective in this pathology.

RESUME. Les auteurs considèrent les principaux facteurs biochimiques et moléculaires qui ont été découverts au cours des recherches les plus récentes sur les processus de la formation pathologique des cicatrices causées par les brûlures. La compréhension plus exacte des événements biochimiques qui conduisent à la formation pathologique des cicatrices sera utile pour améliorer la prévention et la thérapie. Les auteurs décrivent les diverses modifications vasculaires à la suite des lésions tissulaires et la question de la réparation tissulaire. Grâce aux dernières recherches en la matière, il est maintenant possible d'effectuer la thérapie pharmacologique et non chirurgicale des cicatrices dues aux brûlures moyennant des agents tant chimiques que physiques. Sur la base d'une étude systématique de tous ces agents les auteurs concluent que pour ce qui concerne les médicaments chimiques les corticostér6ides et le zinc sont les plus indiqués, tandis que pour les agents physiques la pression semble être la méthode la plus efficace.

B11BLIOGRAPHY

1. Ahn T.S., Monafo W.W.: Topical silicone gel: a new treatment for hypertrophic scars. Surgery, 106: 781-7, 1989
2. Clark R.A.: Potential roles of fibronectin in cutaneous wound repair. Arch. Dermatol., 124: 201-6,1988.
3. Cohen I.K., Diegelenan R.F.: The biology of keloids and hypertrophic scars and the influence of corticosteroids. Clin. Plast. Surg., 4:297,1977.
4. Ehrlich H.P., Tower H., Hunt T.K.: Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann. Surg., 175: 235, 1972.
5. Janssen A.L. Limpans A.H.P.: The local treatment of hypertrophic scars and keloids with topical retinoic acid. Br. J. Dermat., 103: 319, 1980.
6. Ketchum L.D., Cohen 1. et al.: Hypertrophic scars and keloids.Plast. Reconstr. Surg., 53: 140, 1974.
7. Knighton D.R., Doucette M.: The use of platelet derived wound healing formula in human clinical trials. Prg. Clin. Biol. Res., 266: 319-79, 1988.
8. Levitt W.M., Gillies H.: Radiotherapy in the prophylaxis and treatment of keloid. Lancet, 1: 440, 1942.
9. Parsa F.D.: Vitamin E: facts and fallacies. Plast. Reconstr. Surg., 8 1:201-20, 1980.
10. Peacock E.E.: Control of wound healing and scar formation in surgical patients. Arch. Surg., 116: 1325, 1981.
11. Peacock E.E. Jr: Wound contraction and scar contracture. Plast.Reconstr. Surg., 62: 601, 1978.
12. Peacock E.E., Madden JW.: Some studies on the effect of BAPN on collagen in healing wounds. Surgery, 60: 7, 1966.
13. Powando M.C., Moyen E.D.: Plasma protein and wound healing.Surg. Gynecol. Obst., 153: 749, 1981.
14. Prockop D. et al.: The biosynthesis of collagen and its disorders.New Engl. J. Med., 301: 13-77,1979.
15. Quinn K1.: Silicone gel in scar treatment. Bums, 13: 33-40, 1987.
16. Ryan G.B., Majno G.: Acute inflammation (a review). Am. J.Pathol., 86: 183, 1977.
17. Sandstead H.J., Lanier V.C. et al.: Zinc and wound healing; effects of zinc deficiency and zinc supplementation. Am. J. Cl. Nutr., 23: 154,1970.
18. Shons A.R., Rivers E.A., Salem D.L.: A rigid transparent face mask for control of scar hypertrophy. Ann. Plast. Surg.: 245, 1980.
19. Soderberg T. et al.: Treatment of keloids and hypertrophic scars with adhesive zinc tape. Scand. J. Plast. Rec. Surg., 16: 261, 1982.
20. Van Winkle W. Jr: The fibroblast in wound healing. Surg. Gynecol. Ost., 124: 369, 1967.