Metformin Improves Burn Wound Healing by Modulating Microenvironmental Fibroblasts and Macrophages

Abstract

Metformin, a biguanide, exerts different functions through various signaling pathways. In order to investigate the function and mechanism of metformin in burn wounds, we established burn rat models, subcutaneously injected metformin to treat the wounds, and observed the morphologies and the expression of collagen I, collagen III, fibronectin, and pro-inflammatory markers. In vitro experiments were performed to investigate the effects of metformin on the proliferation, migration, and collagen I synthesis of the mouse embryonic fibroblast (NIH 3T3) cell line and on the proliferation, apoptosis, and immune response of the mouse mononuclear macrophage (RAW 264.7) cell line. Finally, we studied the regulatory effects of metformin on a co-culture of RAW 264.7/NIH 3T3 cells. We found that 100 mM of metformin reduced dermal thickness, collagen I deposition, and mRNA expression of IL1β and CCL2 in rat burn wounds. In vitro experiments revealed that metformin inhibited the proliferation of NIH 3T3 and RAW 264.7 cells. Metformin attenuated NIH 3T3 cell migration via the AMPK/mTOR pathway and attenuated collagen I synthesis through the TGFβ1/Smad3 pathway. Metformin inhibited the apoptosis of RAW 264.7 cells induced by 10 μg/mL LPS. Metformin downregulated the mRNA expression of IL1β and CCL2 in RAW 264.7 cells under 1 μg/mL LPS induction by inhibiting NF-κB p65 phosphorylation. In a RAW 264.7/NIH 3T3 co-culture, metformin attenuated collagen I synthesis in NIH 3T3 cells by inhibiting RAW 264.7 paracrine secretion of TGF-β1. This provides new evidence related to the development of metformin for potentially improving burn wound healing.

Unremitting pro‐inflammatory T‐cell phenotypes, and macrophage activity, following paediatric burn injury

“…This has been observed in a murine model, 54 where macrophage hyperactivity post‐burn is independent of burn size. Removing available glucose for M1‐like macrophages to use and increasing the insulin sensitivity with metformin, switches the phenotype to M2‐like 55 . Insulin also promotes the phenotype switch of M1‐like to M2‐like in diabetic rat models 56 .…”

“…Removing available glucose for M1-like macrophages to use and increasing the insulin sensitivity with metformin, switches the phenotype to M2-like. 55 Insulin also promotes the phenotype switch of M1-like to M2-like in diabetic rat models. 56 A greater proportion of macrophages expressing TGF-b were seen post-burn (Figure 1).…”

Compound 13 Promotes Epidermal Healing in Mouse Fetuses via Activation of AMPK

“…While AMPK has been implicated in atherosclerosis and cancer metastasis, little is known concerning its underlying mechanisms [ 22 ]. However, AMPK’s ability to regulate cell migration suggests that it is associated with wound healing [ 23 ]. In particular, administration of drugs such as AICAR and A769662, which cause AMPK activation, has been reported to cause actin cytoskeleton remodeling in epithelial cells [ 11 ].…”

Integrative Transcriptomic Analysis Reveals Upregulated Apoptotic Signaling in Wound-Healing Pathway in Rat Liver Fibrosis Models

“…Both liver fibrosis and burn-wound healing exhibit a common characteristic: the excessive formation of fibrotic tissue. This underscores the significance of leveraging our insights regarding burn-wound healing to enhance our comprehension of liver fibrosis and its underlying mechanisms [ 45 ].…”

“…PARP, when cleaved by CASP3, loses its ability to repair DNA and maintain cell survival, thereby pushing the cell toward apoptosis [ 50 , 51 ]. Additionally, the tumor suppressor gene Tp53 acts as a proapoptotic factor and is triggered in response to cellular stresses, including oxidative stress [ 45 ]. The activation of the p53/Bax/Bcl2 signaling pathway intensifies cell apoptosis, thereby exacerbating the progression of liver fibrosis [ 46 ].…”