Time-Dependent and Organ-Specific Changes in Mitochondrial Function, Mitochondrial DNA Integrity, Oxidative Stress and Mononuclear Cell Infiltration in a Mouse Model of Burn Injury

Abstract

Severe thermal injury induces a pathophysiological response that affects most of the organs within the body; liver, heart, lung, skeletal muscle among others, with inflammation and hyper-metabolism as a hallmark of the post-burn damage. Oxidative stress has been implicated as a key component in development of inflammatory and metabolic responses induced by burn. The goal of the current study was to evaluate several critical mitochondrial functions in a mouse model of severe burn injury. Mitochondrial bioenergetics, measured by Extracellular Flux Analyzer, showed a time dependent, post-burn decrease in basal respiration and ATP-turnover but enhanced maximal respiratory capacity in mitochondria isolated from the liver and lung of animals subjected to burn injury. Moreover, we detected a tissue-specific degree of DNA damage, particularly of the mitochondrial DNA, with the most profound effect detected in lungs and hearts of mice subjected to burn injury. Increased mitochondrial biogenesis in lung tissue in response to burn injury was also observed. Burn injury also induced time dependent increases in oxidative stress (measured by amount of malondialdehyde) and neutrophil infiltration (measured by myeloperoxidase activity), particularly in lung and heart. Tissue mononuclear cell infiltration was also confirmed by immunohistochemistry. The amount of poly(ADP-ribose) polymers decreased in the liver, but increased in the heart in later time points after burn. All of these biochemical changes were also associated with histological alterations in all three organs studied. Finally, we detected a significant increase in mitochondrial DNA fragments circulating in the blood immediately post-burn. There was no evidence of systemic bacteremia, or the presence of bacterial DNA fragments at any time after burn injury. The majority of the measured parameters demonstrated a sustained elevation even at 20–40 days post injury suggesting a long-lasting effect of thermal injury on organ function. The current data show that there are marked time-dependent and tissue-specific alterations in mitochondrial function induced by thermal injury, and suggest that mitochondria-specific damage is one of the earliest responses to burn injury. Mitochondria may be potential therapeutic targets in the future experimental therapy of burns.

Toll-Like Receptor Signaling in Burn Wound Healing and Scarring

“…In a mouse model of *30% TBSA full-thickness scald injury, mitochondrial DNA (mtDNA) was elevated threefold in plasma at 3 h postburn, and it remained significantly elevated up to 4 days before returning to baseline by day 10. 36 In mice with 25% TBSA full-thickness burn, DAMPs (cytochrome C, HMGB1, fibronectin, and hyaluronan) were elevated in plasma as early as 3 h postburn at the same time that TNF-a, IL-6, and IL-10 were elevated, but these cytokines stayed elevated longer, until 24 h postburn. 37 However, by day 3, all the DAMPs and cytokines dropped to baseline, except hyaluronan which remained elevated out to the final time point on day 7.…”

Luteolin Promotes Cell Apoptosis by Inducing Autophagy in Hepatocellular Carcinoma

“…Autophagy is upregulated under various cellular stresses, such as infection, starvation, organelle damage, and protein aggregation [13, 14]. Autophagy has complicated functions in different stages of cancer [15]. On the one hand, autophagy prevents tumor initiation, acting as a suppressor pathway.…”

“…On the one hand, autophagy prevents tumor initiation, acting as a suppressor pathway. On the other hand, autophagy contributes to tumor growth and progression by attenuating cellular metabolic stress, acting as a survival pathway [15]. Autophagy is regarded as a potential target for anticancer therapy [15, 16].…”

The clinically used PARP inhibitor olaparib improves organ function, suppresses inflammatory responses and accelerates wound healing in a murine model of third‐degree burn injury

“…There are several studies implicating PARP activation in burn injury. A rapid and sustained activation of PARP -evidenced by increased cell and tissue accumulation of its product, poly(ADP-ribose) (PAR) -was demonstrated in various parenchymal organs as well as circulating leukocytes following burn injury Bartha et al, 2011;Lange et al, 2011;Szczesny et al, 2015). PARP inhibitors of various structural classes were found to exert protective effects in terms of inflammatory mediator production, tissue oxidative stress and neutrophil infiltration, intestinal barrier dysfunction and pulmonary dysfunction (Shimoda et al, 2003;Avlan et al, 2004;Hamahata et al, 2012).…”