Extensive burn injuries promote an increase in the lipolysis of white adipose tissue (WAT), a complication that enhances postburn hypermetabolism contributing to hyperlipidemia and hepatic steatosis. The systemic increase of free fatty acids (FFAs) due to burn-induced lipolysis and subsequent organ fatty infiltration may culminate in multiple organ dysfunction and, ultimately, death. Thus, reducing WAT lipolysis to diminish the mobilization of FFAs may render an effective means to improve outcomes postburn. Here, we investigated the metabolic effects of Acipimox, a clinically approved drug that suppresses lipolysis via inhibition of hormone-sensitive lipase (HSL). Using a murine model of thermal injury, we show that specific inhibition of HSL with Acipimox effectively suppresses burn-induced lipolysis in the inguinal WAT leading to lower levels of circulating FFAs at 7 days postburn (P < 0.05). The FFA substrate shortage indirectly repressed the thermogenic activation of adipose tissue after injury, reflected by the decrease in protein expression of key browning markers, UCP-1 (P < 0.001) and PGC-1α (P < 0.01). Importantly, reduction of FFA mobilization by Acipimox significantly decreased liver weight and intracellular fat accumulation (P < 0.05), suggesting that it may also improve organ function postburn. Our data validate the pharmacological inhibition of lipolysis as a potentially powerful therapeutic strategy to counteract the detrimental metabolic effects induced by burn.
Burns result in generalized catabolism, lipolysis, and hyperinflammation. NLRP3 inflammasome, a mediator of hyperinflammation, is upregulated in burn patients’ adipose tissue within 7 days post-burn. However, its role during the acute phase is unknown. Here, wild-type (WT) and NLRP3 knockout (NLRP3−/−) mice were exposed to 25% TBSA scald burn. Flow cytometric analysis demonstrated greater liver macrophage infiltration in NLRP3−/− yet decreased protein expression of NLRP3 components, ER stress, and apoptosis. NLRP3−/− had increased circulating free fatty acids (FFA), fatty deposition and liver weight 1 hour post-burn. Alterations in adipose fatty acid synthase (Fasn) expression affects FFA levels post-burn; WT have an early peak in Fasn gene and protein expression that is lost in NLRP3−/−, resulting in increased lipolysis and hepatic fatty deposition. In summary, our findings reveal that NLRP3 inflammasome activation is a double-edged sword. While prolonged inflammation and long-term effects of macrophage activation are associated with poor outcomes, acute inflammation may be beneficial. These results highlight the important metabolic role that NLRP3 inflammasome plays in the acute phase, ultimately affecting survival post-burn.
Burns are a common form of trauma that account for more than 300,000 deaths each year worldwide. Survival rates have improved over the past decades because of improvements in nutritional and fluid support, burn wound care, and infection control practices. Death, however, remains unacceptably high. The primary cause of death has changed over the last decades from anoxic causes to now predominantly infections and sepsis. Sepsis and septic complications are not only major contributors to poor outcomes, but they further result in longer hospital stay and higher healthcare costs. Despite the importance of infections and sepsis, the diagnosis and prediction remain a major challenge. To date, no clear diagnostic criteria or predictive formula exist that can predict reliably the occurrence of sepsis and infections. This review will highlight and discuss current definitions and criteria for diagnosis as well as predictive biomarkers of sepsis in patients with burns. It will also present the diagnostic tools employed, such as procalcitonin, C-reactive protein, and cytokines. We will discuss the benefits and shortcomings of different treatment modalities in the context of sepsis prevention. Last, we identify new therapeutic strategies for sepsis prediction and present future considerations to prevent sepsis in patients with burns. Minimizing and preventing septic complications through early detection would significantly benefit patients and necessitate continued research to unravel new biomarkers and mechanisms. Subsequent studies need to take a fresh perspective and consider the implementation of patient-centered therapeutic strategies.
The endoplasmic reticulum (ER) adapts to stress by activating a signalling cascade known as the ER stress response. While ER stress signalling is a central component of the cellular defence against environmental insult, persistent activation is thought to contribute to the progression of various metabolic complications via loss of protein function and cell death. Despite its importance however, whether and how ER stress impacts morbidity and mortality in conditions of hypermetabolism remain unclear. In this study, we discovered that chronic ER stress response plays a role in mediating adverse outcomes that occur after major trauma. Using a murine model of thermal injury, we show that induction of ER stress with Tunicamycin not only increased mortality but also resulted in hepatic damage and hepatic steatosis. Importantly, post‐burn treatment with chaperone ER stress inhibitors attenuated hepatic ER stress and improved organ function following injury. Our study identifies ER stress as a potential hub of the signalling network affecting multiple aspects of metabolism after major trauma and as a novel potential molecular target to improve the clinical outcomes of severely burned patients.
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