Cutaneous fibrosis results from suboptimal wound healing following significant tissue injury such as severe burns, trauma, and major surgeries. Pathologic skin fibrosis results in scars that are disfiguring, limit normal movement, and prevent patient recovery and reintegration into society. While various therapeutic strategies have been used to accelerate wound healing and decrease the incidence of scarring, recent studies have targeted the molecular regulators of each phase of wound healing, including the inflammatory, proliferative, and remodeling phases. Here, we reviewed the most recent literature elucidating molecular pathways that can be targeted to reduce fibrosis with a particular focus on post-burn scarring. Current research targeting inflammatory mediators, the epithelial to mesenchymal transition, and regulators of myofibroblast differentiation shows promising results. However, a multimodal approach addressing all three phases of wound healing may provide the best therapeutic outcome.

Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-β, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-β and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 μM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.

Background: One of the most pervasive complications of burn injury is wound progression, characterized by continuous tissue destruction in untreated wounds, which leads to wound infection, inflammation, oxidative stress and excessive scar formation. We determined whether additional tissue destruction could be attenuated with Livionex formulation (LF) lotion, which contains a metal-chelating agent and reduces inflammation in burn wounds.Methods: We subjected male Sprague Dawley rats to a 2% total body surface area (TBSA) burn using a brass comb model and topically applied LF lotion (containing ethylenediaminetetraacetic acid and methyl sulfonyl methane) to the affected area every 8 hours over 3 days. Inflammatory cytokine levels, cell apoptosis and wound healing were compared in LF lotion-treated and untreated rats. Statistical analysis was performed using a one-way analysis of variance in conjunction with Tukey’s post-hoc test.Results: Serum inflammatory cytokines were not detectable after 3 days, suggesting that small burn wounds induce only an immediate, localized inflammatory response. Microscopy revealed that LF lotion improved burn site pathology. Deoxynucleotidyl transferase biotin-d-UTP nick-end labeling staining showed reduced cell death in the LF-treated samples. LF lotion prevented the spread of tissue damage, as seen by increased amounts of Ki-67-positive nuclei in the adjacent epidermis and hair follicles. Tumor necrosis factor-alpha, interleukin-6 and inducible nitric oxide synthase levels in LF-treated skin sections from burned rats were comparable to the levels observed in unburned control sections, indicating that LF lotion reduces inflammation in and around the burn site.Conclusions: These results establish LF lotion as a therapeutic agent for reducing inflammatory stress, cell death and tissue destruction when applied immediately after a burn injury. Further studies of LF lotion on large TBSA burns will determine its efficacy as an emergency treatment for reducing long-term morbidity and scarring.

Burn patients are prone to infections, which often warrants broad-spectrum antibiotic coverage. Vancomycin is a common antibiotic used at burn centers and is administered alone, or in combination with other agents such as piperacillin-tazobactam (Pip/Tazo). A recent study showed that this combination therapy was associated with increased rates of acute kidney injury (AKI) in adult and pediatric burn patients when compared to vancomycin in combination with other antibiotics. However, other studies failed to demonstrate these findings. The degree of nephrotoxic effect of the combination therapy relative to its drug components has not been demonstrated in burn patients. Using a large national database encompassing 41 health care organizations, we sought to determine whether a combination of vancomycin and Pip/Tazo exacerbates AKI in burn patients. Using the TriNetX Global Health Research Network, we identified the population of burn patients with ICD-10 codes T20-T25 and T30-T32 between 2000–2020. We then grouped this population into 4 cohorts based on the administration of broad-spectrum antibiotics they received after the burn incident: vancomycin, Pip/Tazo alone, combination, and neither vancomycin nor Pip/Tazo. All cohorts were balanced for age, gender, and race. We explored the distribution of these cohorts and conducted comparative outcome analysis to determine the relative risk of developing AKI using the ICD10 code N17. Comparative analysis showed burn patients who received vancomycin had a 4.81% increased associated risk with AKI compared to those who did not receive either vancomycin or Pip/Tazo (p< 0.0001, RR =3.35, 95%CI= 2.63–4.26). Patients who received Pip/Tazo monotherapy had a 5.1% increased association with AKI compared to those who did not receive either drug (p< 0.0001, RR =3.57, 95%CI: 2.33–5.45). The combination of vancomycin with Pip/Tazo increased the association with AKI by 9.49% compared to patients who did not receive either drug (p< 0.00001, RR=5.65, 95%CI: 4.40–7.26). Combination therapy also increased the risk of AKI when compared to the vancomycin monotherapy (5.01%, p< 0.00001, RR= 1.69, 95%CI: 1.42–2.00) and Pip/Tazo monotherapy (4.85%, p< 0.00002, RR= 1.62, 95%CI: 4.40–7.26). The use of broad-spectrum antibiotics in burn patients is associated with a higher risk of AKI. The combination of these drugs affords an increased relative risk of AKI when compared to monotherapy with the respective component drugs. Whether this is associated with selection bias or drug-effect warrants further investigation.