International journal of molecular medicine
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We recently demonstrated that the hepatic cytochrome P-450 (CYP) isoform 1A2 is downregulated in sepsis, which appears to play an important role in the inflammatory response and liver injury. However, the mechanism responsible for the decreased CYP1A2 remains unknown. Since the transcription factor aryl hydrocarbon receptor (AhR) regulates the expression of CYP1A2 and the disruption of the AhR gene causes liver injuries, we hypothesized that downregulation of AhR plays an important role in the reduced hepatic CYP1A2 during sepsis. ⋯ However, proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta decreased AhR and CYP1A2 expression. As AhR activates the specific gene expression by binding to the target genes, the translocation of AhR to the nucleus in sepsis would suggest that alterations at AhR binding sites may also contribute to the downregulated CYP1A2 expression in sepsis. Since AhR gene expression decreased earlier than the occurrence of depression of CYP1A2 (CYP1A2 decreased at 10-20 h post CLP), the decreased AhR may play an important role in downregulating hepatic CYP1A2 during the progression of sepsis.
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Though often lifesaving, mechanical ventilation itself bears the risk of lung damage [ventilator-induced lung injury (VILI)]. The underlying molecular mechanisms have not been fully elucidated, but stress-induced mediators seem to play an important role in biotrauma related to VILI. Our purpose was to evaluate an animal model of VILI that allows the observation of pathophysiologic changes along with parameters of biotrauma. ⋯ VILI also induced pulmonary heat shock protein-70 expression and the activity of matrix metalloproteinases. The animal model used enabled us to observe the effect of high-pressure ventilation on mortality, lung damage/function and biotrauma. Thus, by combining barotrauma with biotrauma, this animal model may be suitable for studying therapeutical approaches to VILI.
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Subarachnoid hemorrhage due to the rupture of a cerebral aneurysm is a life-threatening disease. Despite this, the detailed mechanisms underlying the initiation and progression of cerebral aneurysm are unclear. The relation of hypercholesterolemia and apolipoprotein E (ApoE) to cerebral aneurysm formation, has been unclear until now. ⋯ The mRNA expression of ApoE in arterial walls was not different between the controls and cerebral aneurysms. Owing to the deficiency of ApoE, mice presented marked hypercholesterolemia, but there was no difference in cerebral aneurysm formation. In the present study, we clarified that ApoE was not responsible for cerebral aneurysm formation.