Abstract
Trauma-hemorrhage (T-H) is known to impair tissue perfusion, leading to tissue hypoxia, and thus affecting mitochondria, the organelles with the highest oxygen demand. In a model of T-H and prolonged hypotension without fluid resuscitation, administration of a small volume of 17beta-estradiol (E2), but not vehicle, prolonged the survival of rats for 3 h, even in the absence of fluid resuscitation. The main finding of this study is that T-H followed by prolonged hypotension significantly affects mitochondrial function, endoplasmic reticulum (ER) stress markers and free iron levels, and that E2 ameliorated all these changes. All of these changes were observed in the liver but not in the kidney. The sensitivity of mitochondrial respiration to exogenous cytochrome c can reflect increased permeability of the outer mitochondrial membrane for cytochrome c. Increased levels of free iron are indicative of oxidative stress, but neither oxidative nor nitrosylative stress markers changed. The spliced isoform of XBP1 mRNA (an early marker of ER stress) and the expression of C/EBP homologous protein (CHOP) (a protein regulating ER stress-induced apoptosis) were elevated in T-H animals but remained unchanged if T-H rats received E2. Both the prevention of elevated sensitivity of mitochondrial respiration to cytochrome c and a decrease in ER stress by E2 maintain functional integrity of the liver and may help the organ during prolonged hypotension and following resuscitation. A decrease in free iron levels by E2 is more relevant for resuscitation, often accompanied by oxidative stress reaction. Thus, E2 appears to be a novel hormonal adjunct that prolongs permissive hypotension during lengthy transportation of the injured patient between the injury site and the hospital in both civilian and military injuries.
Highlights
Trauma-hemorrhage (T-H) followed by resuscitation is often fatal in civilian and military trauma
It appears that similar to hypoxia or ischemia followed by reperfusion, oxidative stress may be triggered during the reoxygenation phase of resuscitation, indicating that oxidative stress development requires increased function, endoplasmic reticulum (ER) stress markers and free iron levels, and that E2 diminishes these changes
The effects of E2 during prolonged hypotension can be divided into two groups, the first may have beneficial effects during hypotensive phase, and the second can exert beneficial effects mainly during resuscitation
Summary
Trauma-hemorrhage (T-H) followed by resuscitation is often fatal in civilian and military trauma. It has been found that deleterious effects of T-H are influenced by sex hormones [5] and that estrogen (E2) improves immune and cardiovascular response parameters [6]. T-H consists of two phases: the hypovolemic phase, characterized by systemic hypotension, which can lead to circulatory failure if not followed by resuscitation; and the subsequent resuscitation phase, which restores blood flow and oxygen delivery to the tissues. When a small volume of E2, and not vehicle, was administered after 62% blood loss, the animals demonstrated an acute survival during prolonged hypotension (3 h), and prolonged survival after fluid resuscitation. The mechanism by which small volume E2 administration (0.4 mL/kg body weight [BW]) sustains prolonged permissive hypotension and improves survival remains unknown.
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