Causes of keloids and hypertrophic scars
Healing of the skin is a deceptively complex process involving multiple interactions of intracellular cascades and signaling. These processes include among other elements bio-molecules, lipids, calcium, growth factors, cell surface receptors, mast cells, injury signals and cytokines. Extra-cellular matrix dynamics, as well as the proliferation, differentiation, migration and apoptosis of numerous cell types eventually lead through the healing cascade to healthy scar formation.
Keloidal and hypertrophic scarring remains a daunting problem both as a clinical and basic science issue. These scarring problems have been traditionally understood as post scarring proliferation disorders. New evidence suggest a physiological model involving mutated healing sequels with interruptions in the cyclic migration of lipids and other bio-molecules as well as raised activity of key adhesive nodal points. The healing of the lesion maybe stalled and left in a perpetual stage of scar tissue proliferation until it resolves itself or through scar management modalities.
If the etiology of these scarring disorders is to be understood, we need to make a correlation between physiological symptoms, molecular and cellular peculiarities. Further, a more encompassing theory can be developed through the genetic predisposition of keloidal scarring in tropical populations and families. The genetic pre-disposition is probably subtle when populations from tropical West Malaysia form keloid and their genetically near identical counterparts in mainland China do not. Additional questions surrounding the genetic predisposition of keloid formers can be posed due to the fact that random non-indigenous subjects who simply live in tropical climates may also develop a tendency towards keloid formation regardless of skin color. In the end we wish to provide the rational that perhaps some permutation of an anti-Cd36 antibody is present in the keloid former. Much like sickle cell anemia, this mutation man be induced through the transmission of the parasite plasmodium falciparum infected erythrocyte or malaria. The anti-body to Cd36 could theoretically be the source of several physiological problems leading to keloid formation, mainly adhesive nodal points and resurfacing of the stratum corneum.
Hyperprolific scarring can be profiled by;
1) Physiological features- high Trans Epidermal Water Loss (TEWL). 2) The role of bio-molecules, lipids and calcium 3) Cellular- fibroblast, growth factors, mast cells, adhesive nodal points 4) Multi legend CD36- surface cell and Scavenger cell receptor complex 5) Tropical populations predisposition to keloids
1) Physiological features-
A compromised stratum corneum and the unhealed scar. Recent measurements of hypertrophic scars and keloids show high water vapor loss, high stratum corneum turn over rate and high electric conductivity. In all three of these categories hyperprolific scars measured four times higher than normal atrophic scars and skin. Surprisingly, despite the proliferation of excessive scar tissue, these measurements reflect that hyper-prolific scars behave more like open blister lesions and unhealed wounds. High trans-epidermal water loss measurements coupled with symptomatic redness, itchiness and pain would support the rationale that hyper-proliferating scars are lesions stuck in an early phase of the wound healing sequel. The stratum corneum measurements also support the possible existence of healing signals generated from the stratum corneum and epidermis.
2) Molecular level-
Wound healing is mainly influenced on the molecular level through signal Transduction. Calcium and essential fatty acids transmit signals which prompt cells and cytokines in a certain manner. For instance a calcium rich environment will prompt fibroblast to produce collagen. If a calcium suppressor is added to the site, fibroblast produce collagenase, the enzyme responsible collegan degradation . Also bio-molecules such as nitric oxide are released by activated macrophages. NO is important in initiating angiogenesis and vascular repair. Dormant microphages could stall angiogenesis and the healing process.
-fibroblast: Recent in vivo and in vitro studies of keloid fibroblast reveal both high counts of Trans Growth Factor B1 as well as a tendency for the resistance to apoptotic pathway Fas ligand. This means that not only is there a chronic proliferation of collagen production, but there may be a decrease in apoptosis cycle of fibroblast.
- mast cells: There is a high number of mast cells in and around hyper-prolific scars. Mast cells have been identified as a synthesizing source of latent TGF- B1 coagulated bundles laying dormant at the lesion site until activated by the enzyme chymase 1 also secreted by mast cell granules. In the usual sequel of healing cascades, active macrophages secret Kinase receptor TBRI which activates the TGF-B1 to express Plasminogin activator inhibitor1 (PAI-1). One could suspect where macrophage activity is lower PAI-1 would also be found in low levels as in the case of lower PAI-1 on cell surface of keloid fibroblast. The imbalance of urokinase found in fibroblast cell media and cell surface has been shown to increase Thrombospodin-1 expression. Thrombospodin is a multifunctional extracellular matrix glycoprotien demonstrated to play a significant role in tumor progression and metastasis in wound healing.
4) Multi Ėlegand CD36
Adhesive nodal points- There is a high count of adhesive materials and activity in hyper-prolific scars. There are several key nodal points involving adhesive cell interactions, mainly thrombospondin-1, as well as adhesive cell surface receptors CD36 and CD68. Also there has been a noted imbalance in the plasmogin plasmonogin system which could involve CD36ís role as an adhesive surface cell receptor. The presence of high adhesive activity and a compromised stratum corneum could provide the rational that CD36 is not making the transition from its role as an adhesive nodal point to itís role of rafting cholesterol from the dermis to epidermal lammaler bodies and the reestablishment of the strateum corneum. Failure in transition in the role CD36 could then explain the physiology of keloids and hyper-prolific scarring. It may also provide the rational of why a certain tropical populations tend to form these scarring disorders. It may be due to the existence of an anti-body to CD36 due to another diverse role as a scavenger receptor of the malaria parasite. In the end, the mechanism of action of silicone sheeting may also be explained through its action on CD36.
CD36, receptor for Thrombospondin-1 (TSP)-1- Transforming growth factor (TGF)-B1 is an important regulator in inflammation and fibrosis. TGF-B1 is usually secreted as a biologically latent protein called latent TGF-B1 and has no biological effect until converted to its active state. Increased expression of the glycoprotein thrombospondin (TSP)-1 have been noted in keloid fibroblast compared to normal fibroblast. The cell surface receptor for TSP-1 is Cd36 which activates latent TGF-B1. CD36 is attracted to negatively charged oxidized lipids which releases CD36 from making TGF-1 to catobolizers and transporters of Cholesterol to the epidermis for its repair of the stratum corneum. The possibility that the action of silicone sheeting on these scars may be the affinity for negatively charged silicate particles to mimic oxizided lipids and activate CD36 to it role in cholesterol transport to the epidermis.
Cholesterol repair of stratum corneum- CD36 first it catabolises oxidized cholesterol clusters and a CD36 analogue called SR-B1 rafts smaller cholesterol segments to the lamalar bodies in the epidermis where the cholesterol is then distributed as newly formed stratum corneum. An interruption in this cascade might explain why the stratum corneum is completely compromised in both keloids and hypertrophic scars. It is thought by some researchers that a open wound signal from the epidermis initiates the signal leading to scar tissue proliferation. Conclusion- A malfunction in CD36 can provide a link to the an interruption in the healing process in both the dermis and epidermis.
Summary of Physiology
What appears to be a post wound proliferation disorder may actually be an unhealed lesion due to an epidermal-dermal inversion of lipids and adhesive materials. Inactive macrophages could be withholding vital enzymes and proteins needed to activate essential links in healing cascades. In the dermis prolonged adhesive activity could create boundaries preventing vascular migration providing a balanced plasminogen/plasmin system on the cellular level. Normalization would otherwise lead to decreasing growth factor populations as well as macrophage and collagenase elimination of scar tissue. The reestablishment of a functional skin barrier, which hyperprolific scars are lacking is accomplish through the successful migration of cholesterol and ceramide and other essential fatty acids to the stratum corneum. The catobolising of these lipids from larger oxidized lipid clusters and transport from the dermis to epidermis occurs through SRB1 or scavenger receptor cells, a phenotype of CD36 which immune histology studies have shown lacking in epidermis of keloids and hypertrophic scars. So the lack of migration of lipids and adhesive materials and catobolising as well as the failure to eliminate wound and scar debris by macrophages laying dormant is compounded by epidermal signaling to hyper-proliferate scar tissue due to a compromised stratum corneum. The repair and reestablishment of a functioning skin cover could possibly be traced back to cell surface receptors such as CD36, CD44, CD68 and the plasminogen system.