A review of acne scars pathogenesis

 Acne scars pathogenesis

Introduction

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Skin healing and scar tissue generation is a complex process entails a number of overlapping phases, including inflammation, epithelialization, angiogenesis and collagen deposition [1]. Ultimately these processes are resolved leading to a mature wound and macroscopic production of scars as a result of prolonged acne. This process occurs in formation of acne scarring as most resolving acne lesions are associated with some degree of damage to the skin. Although inflammation and repair mostly occur concurrently, the sensitivity of the process is underscored by the consequences of disruption of the balance of regulatory cytokines. Consequently, cytokines, which are central to this constellation of events, have become targets for therapeutic intervention to modulate the wound healing process [2]. One example is use of nicotinamide in treatment of acne by blocking IL8 causing downregulation of P.acnes -induced IL-8 promoter activation [3]. Depending on the cytokine and its role, it may be appropriate to either enhance (recombinant cytokine, gene transfer) or inhibit (cytokine or receptor antibodies, soluble receptors, signal transduction inhibitors, antisense) the cytokine to achieve the desired outcome [4]. Comparison of scar-free wound healing in embryo to adult scars signifies role of transforming growth factor-beta, (TGF-beta) family in controlling the outcome [5]. TGF-beta3 elicits a scar-free healing regenerative healing response, whereas TGF-beta1 and TGF-beta2 elicit a fibrotic scarring response [5].

TGF-oriented view of response to injury and scar development

Response to injury in the skin initiated by coagulation and an acute local inflammation. This follows by mesenchymal cell migration, proliferation and matrix synthesis. Failure to resolve the inflammation can lead to chronic nonhealing wounds, whereas uncontrolled matrix accumulation, often involving aberrant cytokine pathways, leads to excess scarring and fibrotic sequelae. Reduced and more transient expression of TGF-beta and their receptors was observed in non fetal wounds compared with adult wounds [6]. Manipulation of cytokines using exogenous growth factors provides therapeutic opportunities to control abnormal wound healing and acne scar formation [7].

Connective tissue repair and acne scars development: where repair cannot be accomplished with resolution, scar tissue forms. One challenging question here would be why scars are  mostly associated with atrophy rather than a hypertrophic changes. One hypothesis is that an imbalance in the ratio of matrix metaloproteinases to tissue inhibitors of metaloproteinases results in the development of trophic or hypertrophic scars. Inadequate response results in diminished deposition of collagen factors and formation of an atrophic scar while, if the healing response is too exuberant, a raised nodule of fibrotic tissue forms hypertrophic scars [8].

Fibroblasts migrate to the site of injury and proliferate following stimulation by TGF-beta and many other cytokines and growth factors. The presence of TGF-beta in the granulation tissue was expected to be important for efficient healing, since TGF-beta was shown to stimulate angiogenesis, fibroblast proliferation, myofibroblast differentiation and matirix deposition [9]. Their biological effects are mediated by heteromeric recepotor complexes, which activate intracellular signaling cascades [10]. Immediately after wounding, TGF-beta1 is released in large amounts from platelets [11]. which in turn causes chemotaxis for neutrophils, macrophages and fibroblasts. These cells further release TGF-betas. This includes all isofroms of TGF-beta that are in demand during the whole process of wound healing [12]. The presence of TGF-beta in the granulation tissue was expected to be important for efficient healing, since TGF-beta was shown to stimulate angiogenesis, fibroblast proliferation, myofibroblast differentiation and matrix deposition [13]. Aberrant expression of TGF-beta is associated with wound healing defect seen in glucocorticoid treated mice [14].

New endothelial cells proliferate upon induction by VEGF. This forms granulation tissue within 3-5 days of injury. Granulation tissue is pink in appearance and characterized by the formation of new vessels, production of ECM, fibrosis, and initial repair that lays down the structure on which the final scar will be formed. Angiogenesis proceeds by generation of new leaky vessels from existing vessels [15]. Basic fibroblast growth factor and VEGF induce angiogenesis [16]. Fibrosis develops with deposition of ECM by fibroblasts. Collagen synthesis and decreased degradation of collagen gives strength to the healing wound. IL-1, TNF, TGF-beta, b-FGF all work to increase the production of collagen locally. Keratinocytes interacts with fibroblasts in a TGF-beta dependent manner during the wound healing process [17].

Re-epithelialization: Specialized enzymes released from macrophages degrade collagen (metalloproteinases, gelatinases, and collagenases) to remodel the wound and form the final scar. Keratinocytes strongly express TGF-beta1 and TGF-beta3 and waakly express TGF-beta2 [18]. TGF-beta1 modulates differentiation of fibroblasts to myofibroblasts which contribute to generation of a contractile force [19].

The following cascade explain sequence of events occur in tissue injury:

Skin injury, blood vessel damage, coagulation response, platelet aggregation, release of cytokines from aggregated, degranulating platelets, TGF-beta (transforming growth factor), PDGF (platelet derived growth factor), VEGF (vascular endothelial growth factor), leakage of plasma proteins influenced by VEGF, involvement of TGF-beta in all steps of wound healing from the initial clot generation to matrix formation and remodeling. Of much importance, is aggregation of platellets to themselves and to exposed collagen, releasing TGF-beta which, in turn, initiates the repair process [20].

Release of adhesion molecules, (VCAM, ICAM, ELAM) induced by cytokines, facilitated extravasation of leukocytes by adhesion molecules, release of proteases from leukocytes mediated by TGF-beta, IL-1, TNF. This causes phagocytosis of debris, microbes and degraded matrix components. Neutrophil recruitment typically peaks around 24-48 hours post wounding, followed by an increasing representation of monocytes which are essential for optimal wound healing.

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