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Deep second-degree burns heal slowly, and promoting the healing process is a focus of clinical research. Sestrin2 is a stress-inducible protein with antioxidant and metabolic regulatory effects. However, its role during acute dermal and epidermal re-epithelialization in deep second-degree burns is unknown. In this study, we aimed to explore the role and molecular mechanism of sestrin2 in deep second-degree burns as a potential treatment target for burn wounds. To explore the effects of sestrin2 on burn wound healing, we established a deep second-degree burn mouse model. Then we detected the expression of sestrin2 by western blot and immunohistochemistry after obtaining the wound margin of full-thickness burned skin. The effects of sestrin2 on burn wound healing were explored in vivo and in vitro through interfering sestrin2 expression using siRNAs or the small molecule agonist of sestrin2, eupatilin. We also investigated the molecular mechanism of sestrin2 in promoting burn wound healing by western blot and CCK-8 assay. Our in vivo and in vitro deep second-degree burn wound healing model demonstrated that sestrin2 was promptly induced at murine skin wound edges. The small molecule agonist of sestrin2 accelerated the proliferation and migration of keratinocytes, as well as burn wound healing. Conversely, the healing of burn wounds was delayed in sestrin2-deficient mice and was accompanied by the secretion of inflammatory cytokines as well as the suppression of keratinocyte proliferation and migration. Mechanistically, sestrin2 promoted the phosphorylation of the PI3K/AKT pathway, and inhibition of PI3K/AKT pathway abrogated the promoting role of sestrin2 in keratinocyte proliferation and migration. Therefore, sestrin2 plays a critical role in activation of the PI3K/AKT pathway to promote keratinocyte proliferation and migration, as well as re-epithelialization in the process of deep second-degree burn wound repair., Competing Interests: Declaration of competing interest The authors state that they have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study introduced a novel method to reconstruct large areas of scarring caused by burns via combining autologous scar-related tissue with spit-thickness skin grafting (ASTCS)., Methods: 25 patients underwent reconstruction after scar resection surgeries around the joints were analyzed between Jan 2012 and Jan 2018. Patient demographics and clinical parameters were collected, autologous scar-related tissue was modified to meshed structure, and the split-thickness skin was acquired from the scalp. The scar was resected and punched by a meshing machine with a thickness of 0.3-0.5 mm at a ratio of 1:1. The secondary wounds were covered by the epidermis from a donor site. The surgical areas were bandaged for 7-10 days before the first dressing change., Results: 25 patients (mean [SD] age, 26.4 [18.8] years; 16 [64%] men) underwent wounds reconstructive operations due to scar resection were reviewed. Wound location of 9 (22%), 8 (19.5%), 9 (22%), 7 (17.1%) and 8 (19.5%) cases were reconstructed in axillary, hand and wrist, popliteal fossa, elbow and neck, respectively. 39 sites of transplanted tissues survived well, and 2 sites were cured after two weeks of dressing changes. Except the analysis of injury causes, nutritional status, wound area and hospital days, patients with scar deformities in joint areas achieved satisfactory function by assessing the Vancouver Burn Skin Score and the Barthel Index Scale Scores after 12-month follow-up., Conclusions: Combining autologous scar-related tissue with skin grafting provided a novel method for treating large areas of burn scars with better functional outcomes.

For over several decades, 595-nm pulsed dye laser (PDL) has been used effectively, reducing erythema and improving the pliability and texture of burn scars. Children usually tolerate PDL treatment as it is non-invasive and causes only mild pain compared to other laser treatments. However, currently, there are limited data on scar management in children who underwent PDL treatment, especially for Fitzpatrick skin types III and IV. The objective of the study was to identify the optimal parameters for the PDL treatment that induce inhibitory effects on scar tissue in children with Fitzpatrick skin types III and IV. Besides, the study assessed the usefulness of high-frequency ultrasound (20 MHz) and laser Doppler flowmetry in assessing these lesions. A total of 165 (79 males and 86 females) children with hypertrophic scars treated by PDL were assessed by the Vancouver scar scale (VSS), high-frequency ultrasound (20 MHz), and laser Doppler flowmetry. The parameters used for the 595-nm PDL treatment were pulse duration of 0.45 ms, fluence between 5 and 9 J/cm 2 , a spot size of 7 mm, and treatment intervals from 3 to 8 weeks. There were no significant differences between pretreatment and post-treatment in terms of the distribution of sex, type of skin color, and low and high fluences. While the mean scores of all scar parameters based on VSS, except thickness and pliability between pre and post-treatment, showed significant differences in ≤3-year-old children vs. to >3-year-old children, except for the subscore, a significant improvement was observed when PDL was initiated within 4 to 6 months of the scar age. In Chinese children with Fitzpatrick skin types III and IV, early intervention, appropriate treatment intervals, and low fluence of PDL were optimal parameters in treating hypertrophic burn scars. The combined high-frequency ultrasound and laser Doppler flowmetry assessment of scars helped assess these lesions and compare the efficacy of different treatment modalities., (© 2021. The Author(s), under exclusive licence to Springer-Verlag London Ltd. part of Springer Nature.)

Na/H exchanger 1 (NHE1) is a ubiquitously expressed protein on mammalian plasma membranes and involved in cell apoptosis and tissue injury. Our previous study found that NHE1 inhibition prevents burn-induced acute lung injury (ALI). However, the potential mechanism of NHE1 in burn-induced ALI is still unclear. This study investigated the role of NHE1 in burn-induced apoptosis of human pulmonary microvascular endothelial cells. Based on the western blot analyses, real-time PCR, fluorescence spectroscopy, and apoptosis analysis, we found that burn serum significantly induced NHE1 activation, promoted intracellular Na accumulation, and elevated apoptosis ratio. Inhibition of NHE1 with cariporide reversed burn-induced intracellular Na accumulation and cell apoptosis. Different doses of cariporide also significantly decreased Cai concentrations and calpain activity induced by burn serum. Furthermore, inhibition of PI3K contributed to the increase of NHE1 activation and cell apoptosis, whereas the inhibition of p38 MAPK led to inhibition of NHE1 activation and significant decreases of cell apoptosis. The data demonstrate that NHE1 activation facilitates burn-induced endothelial cell apoptosis, mediated by Ca-dependent pathway. PI3K-Akt and p38 MAPK were found to be upstream regulators of NHE1. This study provides new mechanisms underlying burn-induced ALI.

Background: The dysbiosis of gastrointestinal microbiome is an important reason for burn-induced intestinal injury. Clostridium butyricum (C.butyricum) and its production butyrate are beneficial for the homeostasis of intestinal microflora and suppression of inflammatory response., Purpose: The roles of C.butyricum and butyrate in burn-induced intestinal injury were explored. The effects of oral administration of C.butyricum on intestinal injury were observed in burned mice., Materials and Methods: The skin surface of mice was exposed to 95 °C water to induce a burn injury. Then the intestinal microbiome structure, abundance of C.butyricum and level of butyrate were respectively observed. The correction between intestinal permeability indicated by FITC dextran level and abundance of C.butyricum or level of butyrate was analyzed. C.butyricum was cultured and orally administrated to burned mice. The levels of butyrate, FITC dextran and pro-inflammatory cytokines, including interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) were respectively measured., Results: Burn injury altered the intestinal microbiome structure of mice, and especially decreased the abundance of C.butyricum and level of butyrate. Both the abundance of C.butyricum and the level of butyrate were negatively correlated with the intestinal permeability. Oral administration of C.butyricum increased the level of butyrate, decreased levels of TNF-α and IL-6, and suppressed intestinal damage in burn-injured mice., Conclusion: Oral administration of C.butyricum significantly alleviated the intestinal damage induced by burn injury. The therapeutic effects of C.butyricum and butyrate on burn injury should be further explored, which deserves further investigation., (Copyright © 2020 Elsevier Ltd and ISBI. All rights reserved.)

Genistein (Gen) exhibits strong anti-oxidative/antinitrative activity and cardioprotective effects in several models; however, its role in burn-induced myocardial injury is unknown. This study investigated the protective effect of Gen on burn-induced myocardial injury and aimed to elucidate the mechanism of protection. Mice were injected with Gen, intraperitoneally, at different dose immediately after burn injury. The expression levels of Notch-1 intracellular domain (NICD1) and hairy and enhancer of split (Hes-1) were determined by immunoblotting. Conditional Notch-RBP-J knockout mice were used to investigate the mechanisms of Gen-induced cardioprotection. Gen alleviated burn-induced myocardial injury, as shown by improved left ventricle ejection fraction, decreased serum lactate dehydrogenase and creatine kinase levels, and apoptosis. Moreover, Gen decreased expressions of inducible nitric oxide (NO) synthase and gp, reduced NO and superoxide anions production, and ameliorated their cytotoxic reaction product, peroxynitrite. More importantly, Gen significantly up-regulated the expression of NICD1 and Hes1 after burn injury. In addition, genetic knockout of Notch1 not only blocked the cardioprotection of Gen but also markedly attenuated Gen-induced anti-oxidative/antinitrative effect. These results demonstrate, for the first time, that Gen treatment attenuates burn-induced myocardial injury via the Notch1 mediated suppression of oxidative/nitrative stress.

We aimed to introduce a technique by combining free fascia flaps transfer with split-thickness skin graft for the reconstruction of deep burn wounds at the ankle. Fifteen patients from 2009 to 2016 were enrolled in this study. Patients in this series suffered from a deep burn injury around the ankle, which was accompanied with exposure of tendon and medial or lateral malleolus exposure due to severe soft-tissue defects (N = 15). All the 15 wounds were repaired combining free fascia flaps with split-thickness skin graft operations, including nine anterolateral thigh fascia lata flaps (ATFL flaps) and six superficial temporal fascia flaps (STF flaps). All the fascia flaps completely survived. Two patients showed partial grafting skin necrosis due to either wound infection or subcutaneous hematoma infection, and this was eventually healed satisfactorily after conventional dressing change. All patients achieved esthetic outcome and acceptable functionality without further revisions needed. Our present study reports a useful method that involves using free fascia flaps in combination with split-thickness skin graft to repair deep burn wounds around the ankle. This method provided reliable and durable soft-tissue coverage with good outcomes., (© American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Intense pulsed light (IPL) has been used to treat postinflammatory hyperpigmentation and telangiectasia in Fitzpatrick type I -II skin. However, its therapeutic effects after superficial second-degree burns in Asian populations with Fitzpatrick type III-IV skin are uncertain. Thirty-five Han Chinese patients with facial or hand hyperpigmentation and telangiectasia due to second-degree fire burns received treatment with IPL. Each patient underwent 2-6 treatments over 3-5 weeks. The laser wavelength was 560-615 nm. Skin pigmentation was evaluated by two plastic surgeons as well as by the patients themselves (self-evaluation) before treatment at the end of the treatment cycle and 1 year after the first treatment. Blood flow in telangiectasia skin was measured by laser Doppler flow. The results showed that IPL significantly lessened hyperpigmentation so that close to normal skin color was achieved after the treatment cycles, and pigmentation did not reoccur 1 year after the first treatment. Approximately 82.9% of the patients were satisfied with their treatment outcomes. There were no post-treatment complications. Doppler showed a significant decreased blood flow in telangiectasia after treatment. In conclusion, IPL is an effective and safe modality for Chinese patients with hyperpigmentation and telangiectasia after fire burns.

The aim of this study was to describe the scheme, surgical procedures, and clinical outcomes for the early repair of deep wounds of the posterior talocrural region in extensively burned patients with a method combining a superficial temporal fascia free flap with thin split-skin grafting.From January 2013 to February 2016, 9 extensively burned patients with deep tissue defects of the posterior talocrural region were treated in our department (2 patients had bilateral deep tissue defects of the posterior talocrural region). All 11 wounds were repaired using a superficial temporal fascia free flap and thin split-skin grafting. After the operation, survival of the fascia flaps and grafted skin was observed, and the appearance and functional recovery of the grafts were evaluated. Follow-up information was reviewed, and complications were documented.All 11 fascia flaps survived completely. Two cases of partial skin necrosis healed after the second application of skin grafts. The appearance and function of recipient sites were well restored in all patients over a follow-up period of 5 to 14 months.Deep tissue defects of the posterior talocrural region can be effectively repaired with our method combining a superficial temporal fascia free flap with thin split-skin grafting. This method offers the advantages of a good appearance, strong resistance to infection, minimal damage at the donor site, short course of disease, and good prognosis., (Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Oxidative stress plays an important role in burn-induced myocardial injury, but the cellular mechanisms that control reactive oxygen species (ROS) production and scavenging are not fully understood. This study demonstrated that blockade of Notch signaling via knockout of the transcription factor RBP-J or a pharmacological inhibitor aggravated postburn myocardial injury, which manifested as deteriorated serum CK, CK-MB, and LDH levels and increased apoptosis in vitro and in vivo. Interruption of Notch signaling increased intracellular ROS production, and a ROS scavenger reversed the exacerbated myocardial injury after Notch signaling blockade. These results suggest that Notch signaling deficiency aggravated postburn myocardial injury through increased ROS levels. Notch signaling blockade also decreased MnSOD expression in vitro and in vivo. Notably, Notch signaling blockade downregulated p-JAK2 and p-STAT3 expression. Inhibition of JAK2/STAT3 signaling with AG490 markedly decreased MnSOD expression, increased ROS production, and aggravated myocardial injury. AG490 plus GSI exerted no additional effects. These results demonstrate that Notch signaling protects against burn-induced myocardial injury through JAK2/STAT3 signaling, which activates the expression of MnSOD and leads to decreased ROS levels.

Background: Oxidative stress and inflammation exert central roles in burn-induced intestinal injury. Crocetin, a natural carotenoid compound from gardenia fruits and saffron, has been shown to inhibit oxidative stress and inflammatory response. However, the possibility of crocetin to be used in the treatment of intestinal injury after burn injury has not been investigated. The purpose of the present study was to investigate the effects and potential mechanisms of crocetin in burn-induced intestinal injury., Materials and Methods: Several free radical-generating and lipid peroxidation models were used to systematically assess the antioxidant activities of crocetin in vitro. A common burn model was used to induce the intestinal injury in rats. Changes in the levels of malondialdehyde, superoxidase dismutase, catalase, glutathione peroxidase, tumor necrosis factor α, interleukin 6, polymorphonuclear neutrophil accumulation, intestinal permeability, and intestinal histology were examined., Results: In several models of antioxidant activity, crocetin exhibited marked inhibitory action against free radicals and lipid peroxidation. Crocetin increased levels of antioxidant enzymes and reduced intestinal oxidative injury in burn models. In addition, crocetin inhibited polymorphonuclear neutrophil accumulation, ameliorated tumor necrosis factor α and interleukin 6 levels, intestinal permeability, and histological changes., Conclusions: Crocetin treatment may protect against burn-induced small intestinal injury, possibly by inhibiting burn-induced oxidative stress and inflammatory response., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Severe burns often initiate the prevalence of hyperglycemia and insulin resistance, significantly contributing to adverse clinical outcomes. However, there are limited treatment options. This study was designed to investigate the role and the underlying mechanisms of oral antibiotics to selectively decontaminate the digestive tract (SDD) on burn-induced insulin resistance., Materials and Methods: Rats were subjected to 40% of total body surface area full-thickness burn or sham operation with or without SDD treatment. Translocation of FITC-labeled LPS was measured at 4h after burn. Furthermore, the effect of SDD on post-burn quantity of gram-negative bacteria in gut was investigated. Serum or muscle LPS and proinflammatory cytokines were measured. Intraperitoneal glucose tolerance test and insulin tolerance test were used to determine the status of systemic insulin resistance. Furthermore, intracellular insulin signaling (IRS-1 and Akt) and proinflammatory related kinases (JNK and IKKβ) were assessed by western blot., Results: Burn increased the translocation of LPS from gut 4h after injury. SDD treatment effectively inhibited post-burn overgrowth of gram-negative enteric bacilli in gut. In addition, severe burns caused significant increases in the LPS and proinflammatory cytokines levels, activation of proinflammatory related kinases, and systemic insulin resistance as well. But SDD treatment could significantly attenuate burn-induced insulin resistance and improve the whole-body responsiveness to insulin, which was associated with the inhibition of gut-derived LPS, cytokines, proinflammatory related kinases JNK and IKKβ, as well as activation of IRS-1 and Akt., Conclusions: SDD appeared to have an effect on proinflammatory signaling cascades and further reduced severe burn-induced insulin resistance., (Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.)

The NLRP3 inflammasome is necessary for initiating acute sterile inflammation. However, its role in the pathogenesis of burn-induced acute lung injury (ALI) is unknown. This study aimed to determine the role of the NLRP3 inflammasome and the signaling pathways involved in burn-induced ALI. We observed that the rat lungs exhibited enhanced inflammasome activity after burn, as evidenced by increased levels of NLRP3 expression and Caspase-1 activity and augmented inflammatory cytokines. Inhibition of NLRP3 inflammasome by BAY11-7082 attenuated burn-induced ALI, as demonstrated by the concomitant remission of histopathologic changes and the reduction of myeloperoxidase (MPO) activity, inflammatory cytokines in rat lung tissue, and protein concentrations in the bronchoalveolar lavage fluid (BALF). In the in vitro experiments, we used AMs (alveolar macrophages) challenged with burn serum to mimic the postburn microenvironment and noted that the serum significantly upregulated NLRP3 inflammasome signaling and reactive oxygen species (ROS) production. The use of ROS scavenger N-acetylcysteine (NAC) partially reversed NLRP3 inflammasome activity in cells exposed to burn serum. These results indicate that the NLRP3 inflammasome plays an essential role in burn-induced ALI and that burn-induced NLRP3 inflammasome activity is a partly ROS-dependent process. Targeting this axis may represent a promising therapeutic strategy for the treatment of burn-induced ALI.

Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na(+)/H(+) exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-κB (NF-κB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn-induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown., (Copyright © 2013 Elsevier Ltd and ISBI. All rights reserved.)

Background: Severe burns initiate an inflammatory response characterized by the upregulation of proinflammatory cytokine, which contributes to multiple organ injury. Na(+)/H(+) exchanger 1 (NHE1) plays a significant role in several inflammatory processes. This study was designed to investigate the role of NHE1 in burn-induced inflammation and multiple organ injury., Materials and Methods: Rats were subjected to a 30% total body surface area full-thickness burn. Cariporide was used to assess the function of NHE1 in burn-induced multiple organ injury by biochemical parameters, histologic changes, and inflammatory cytokine production., Results: We found that NHE1 expression was significantly increased after burn injury. Inhibition of NHE1 by cariporide attenuated burn-induced edema and tissue injury in heart, lung, kidney, and small intestine. Cariporide also inhibited plasma levels of tumor necrosis factor α, interleukin 6, and myeloperoxidase activity., Conclusions: These results indicate that NHE1 inhibition prevents burn-induced multiple organ injury. The salutary effects afforded by NHE1 inhibition, at least in part, are mediated by attenuating systemic inflammatory response., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Abstract: Severe burns initiate an inflammatory cascade within the gut, which leads to intestinal mucosal injury. Although Na+/H+ exchanger 1 (NHE1) is recognised as a pivotal player in several inflammatory processes, its role in burn-induced intestinal injury is relatively unknown. We hypothesised that NHE1 might be involved in the increased intestinal permeability and barrier breakdown after severe burns. Thus, we here investigate whether the inhibition of NHE1 has a protective effect on burn-induced intestinal injury. Mice were subjected to a 30% total body surface area (TBSA) full-thickness steam burn. Cariporide was used to assess the function of NHE1 in mice with burn-induced intestinal injury by fluorescence spectrophotometry, Western blotting and enzyme linked immunosorbent assay (ELISA). We found that severe burn increased intestinal permeability, associated with the up-regulation of NHE1 and raised inflammatory cytokine levels. Mice treated with the NHE1 inhibitor cariporide had significantly attenuated burn-induced intestinal permeability and a reduced inflammatory response. NHE1 inhibition also reduced nuclear factor-κB (NF-κB) activation and attenuated p38 mitogen-activated protein kinase (MAPK) phosphorylation. Our study suggests that NHE1 plays an important role in burn-induced intestinal permeability through the regulation of the inflammatory response. Inhibition of NHE1 may be adopted as a potential therapeutic strategy for attenuating intestinal barrier breakdown. [Copyright &y& Elsevier]

Abstract: Background: Severe burns initiate an inflammatory response characterized by the upregulation of proinflammatory cytokine, which contributes to multiple organ injury. Na+/H+ exchanger 1 (NHE1) plays a significant role in several inflammatory processes. This study was designed to investigate the role of NHE1 in burn-induced inflammation and multiple organ injury. Materials and methods: Rats were subjected to a 30% total body surface area full-thickness burn. Cariporide was used to assess the function of NHE1 in burn-induced multiple organ injury by biochemical parameters, histologic changes, and inflammatory cytokine production. Results: We found that NHE1 expression was significantly increased after burn injury. Inhibition of NHE1 by cariporide attenuated burn-induced edema and tissue injury in heart, lung, kidney, and small intestine. Cariporide also inhibited plasma levels of tumor necrosis factor α, interleukin 6, and myeloperoxidase activity. Conclusions: These results indicate that NHE1 inhibition prevents burn-induced multiple organ injury. The salutary effects afforded by NHE1 inhibition, at least in part, are mediated by attenuating systemic inflammatory response. [Copyright &y& Elsevier]