Molecular medicine
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Hemorrhagic coagulopathy (without neurological injuries) constitutes 40% of injury-related death in civilian hospitals and on the battlefield, and the underlying contributing mechanisms remain unclear. The purpose of this study is to investigate the effects of fibrinogen availability on coagulation function after hemorrhage in pigs. Sixteen crossbred commercial Yorkshire swine were randomized into the control group (group C) (n = 8) and hemorrhage group (group H) (n = 8). ⋯ Hemorrhage caused decreases in fibrinogen and platelets, and compromised clot strength. The rebound of fibrinogen at 24 h restored clot strength despite platelet deficit. These data suggest the potential compensatory role of fibrinogen in restoring coagulation function in vivo after hemorrhagic shock.
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Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. ⋯ A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology.
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Endogenous hydrogen sulfide (H(2)S) is naturally synthesized in many types of mammalian cells from L-cysteine in the reactions catalyzed by cystathionine-β-synthase and cystathionine-γ-lyase (CSE). H(2)S has been demonstrated to play a proinflammatory role in various animal models of hindpaw edema, acute pancreatitis, lipopolysaccharide-induced endotoxemia and cecal ligation, and puncture-induced sepsis. Full-thickness burns that exceed 25% of the total body surface area (TBSA) produce a profound systemic inflammatory reaction characterized by leukocyte activation and plasma leakage in the microvasculature of tissues and organs remote from the wound. ⋯ Prophylactic as well as therapeutic administration of PAG significantly reduced burn-associated systemic inflammation, as evidenced by MPO activity and histological changes in liver and lung. Injection of NaHS significantly aggravated burn-associated systemic inflammation. Therefore, our findings show for the first time the role of H(2)S in contributing to inflammatory damage after burn injury.
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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. ⋯ 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.
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To date there is no diagnostic biomarker for mild stroke, although elevation of inflammatory biomarkers has been reported at early stages. Previous studies implicated acetylcholinesterase (AChE) involvement in stroke, and circulating AChE activity reflects inflammatory response, since acetylcholine suppresses inflammation. Therefore, carriers of polymorphisms that modify cholinergic activity should be particularly susceptible to inflammatory damage. ⋯ Importantly, a cholinergic score combining the two cholinesterase activities discriminated between 94.3% matched pairs of patients and controls, compared with only 75% for inflammatory measures. Our findings present the power of circulation cholinesterase measurements as useful early diagnostic tools for the occurrence of stroke. Importantly, these were considerably more distinctive than the inflammatory biomarkers, albeit closely associated with them, which may open new venues for stroke diagnosis and treatment.