The Burn Wound Microenvironment

Abstract

Significance: While the survival rate of the severely burned patient has improved significantly, relatively little progress has been made in treatment or prevention of burn-induced long-term sequelae, such as contraction and fibrosis. Recent Advances: Our knowledge of the molecular pathways involved in burn wounds has increased dramatically, and technological advances now allow large-scale genomic studies, providing a global view of wound healing processes. Critical Issues: Translating findings from a large number of in vitro and preclinical animal studies into clinical practice represents a gap in our understanding, and the failures of a number of clinical trials suggest that targeting single pathways or cytokines may not be the best approach. Significant opportunities for improvement exist. Future Directions: Study of the underlying molecular influences of burn wound healing progression will undoubtedly continue as an active research focus. Increasing our knowledge of these processes will identify additional therapeutic targets, supporting informed clinical studies that translate into clinical relevance and practice.

Rodney K. Chan, MD

Figure 1.

Multiple factors can impair wound healing, some of which are well-documented while others have only recently come to light. Inadequately debrided tissue can act as a nidus of inflammation as well as prevent proper vascularization of skin grafts placed over the necrotic tissue. Poor-quality skin replacement resulting from a less-than-ideal donor site or from repeated harvests is a well-characterized negative factor. The presence of burn eschar or infection can enhance local or systemic inflammation, leading to poor incorporation of skin grafts or enhanced contraction and fibrosis. Other factors may still be waiting discovery. The relative contribution to wound healing of any given factor can be difficult to ascertain, and the final outcome likely involves complex interactions among these factors.

Figure 2.

The stages of wound healing coincide with the presence of specific cohorts of immune cells and stromal cells, each contributing an array of growth factors and cytokines to the wound microenvironment. In nonburn wounds, the cell populations and cytokine/growth factor milieu are fairly well-characterized. While it is generally accepted that burn wounds induce more inflammation and have a more complex microenvironment, the relative proportions of cells and cytokines throughout the healing process have not been well-studied. Although the numbers of specific cells may change over time, the growth factor environment may not directly coincide with the presence of any given cell. For example, platelets arrive on the scene first and secrete vasoactive substances as well as cytokines like transforming growth factor (TGF)-β1. However, hemostasis and dissolution of the clot and loss of platelets does not coincide with a reduction of TGF-β1 because subsequent cellular cohorts, such as macrophages, fibroblasts, and keratinocytes, all secrete TGF-β1. Most inflammatory cytokines peak during the first few days following injury and are secreted by neutrophils and inflammatory macrophages. The resolution of inflammation coincides with apoptosis of neutrophils and transdifferentiation of inflammatory macrophages into tissue remodeling macrophages expressing TGF-β1, fibroblast growth factor (FGF), and epidermal growth factor (EGF).

Figure 3.

Jackson's burn wound model. The different zones of damage from a partial-thickness burn wound are shown in profile through skin layers. The determination of healing is primarily determined by outcomes in the zone of stasis. Insufficient perfusion can result in extension of necrosis within this zone.

Figure 4.

Paradigm of underlying responses to different insults. The Venn diagram indicates that multiple causes can lead to systemic inflammatory response syndrome (SIRS). Burns over 30% of total body surface area are three times more likely to result in SIRS, which may in turn lead to multiorgan failure. Similar patterns of gene expression are observed from sepsis-induced SIRS, suggesting that underlying molecular pathways respond similarly to quite different stimuli.