The Molecular Mechanisms Involved in the Hypertrophic Scars Post-Burn Injury

Abstract

Scar formation is a normal response to skin injuries. During the scar-remodeling phase, scar tissue is usually replaced with normal, functional tissue. However, after deep burn injuries, the scar tissue may persist and lead to contractures around joints, a condition known as hypertrophic scar tissue. Unfortunately, current treatment options for hypertrophic scars, such as surgery and pressure garments, often fail to prevent their reappearance. One of the primary challenges in treating hypertrophic scars is a lack of knowledge about the molecular mechanisms underlying their formation. In this review, we critically analyze studies that have attempted to uncover the molecular mechanisms behind hypertrophic scar formation after severe burn injuries, as well as clinical trials conducted to treat post-burn hypertrophic scars. We found that most clinical trials used pressure garments, laser treatments, steroids, and proliferative inhibitors for hypertrophic scars, with outcomes measured using subjective scar scales. However, fundamental research using human burn injury biopsies has shown that pathways such as Transforming Growth factor β (TGFβ), Phosphatase and tensin homolog (PTEN), and Toll-like receptors (TLRs) could be potentially regulated to reduce scarring. Therefore, we conclude that more testing is necessary to determine the efficacy of these molecular targets in reducing hypertrophic scarring. Specifically, double-blinded clinical trials are needed, where the outcomes can be measured with more robust quantitative molecular parameters.

Keywords: Hypertrophic scars; molecular pathways; scarring; skin injury; thermal injury.

Figure 1

Various factors that can induce transformation of dermal fibroblasts to persistent hypertrophic scar fibroblasts. Burn injuries can lead to secretion of inflammatory cytokines such as IL-10 and TGFβ and alter the glucose homeostasis in the body. These along with the trauma injury may alter the activity of epigenetic modulators, lead to excessive extracellular matrix synthesis, dysregulate the mechanobiology and change the original microbiome. Several of these changes together may lead to persistence of hypertrophic scar tissue long after the initial burn trauma injury. The contribution of these and several other aspects needs to be explored.

Figure 2

Effect of Burn injury on Hippo signaling pathway in normal skin tissue. Second-degree deep burn injuries lead to formation of hypertrophic scars. The burn injury leads to conversion of fibroblasts to myofibroblasts. Within these myofibroblasts, there is dysregulation of Hipposignaling pathway, which does not lead to phosphorylation of MST and LATS proteins, due to non-phosphorylation of these upstream proteins, the YAP protein remains unphosphorylated, and the unphosphorylated YAP enters the nucleus, which leads to activation of cell proliferation genes. The net result is excessive proliferation of myofibroblasts.