Changes In Ischemia-reperfusion Injury Research Articles

Clinicopathological Analysis of Uterine Allografts Including Proposed Scoring of Ischemia Reperfusion Injury and T-cell–mediated Rejection—Dallas UtErus Transplant Study: A Pilot Study

Uterus transplantation (UTx) enables pregnancy in infertile women. This study describes the histopathological changes of ischemia reperfusion injury and mostly acute T-cell-mediated rejection (TCMR) in UTx and proposes modification toward a working formulation grading system with associated treatments. Protocol and indication biopsies from 11 living and 2 deceased donor UTx recipients were analyzed. Serving as a control were 49 age-matched nontransplanted uteri. All posttransplant histopathological specimens were evaluated in a blinded fashion by 3 pathologists. Response to treatment was assessed by follow-up biopsies. Serial serum donor-specific antibody (DSA) responses were also recorded. Changes attributed to ischemia reperfusion resolved within 2 wk of UTx in most of the patients. For TCMR grading, perivascular inflammation, focal capillary disruption, and interstitial hemorrhage were added to interface inflammation, intercellular edema, stromal inflammation, and epithelial apoptotic bodies. Of the 173 protocol biopsies, 98 were classified as negative for TCMR; 34 as indeterminate-borderline; 35 as mild; 3 as moderate; and 3 as severe, 1 of which occurred in a DSA-positive recipient and also showed microvascular injury. Corticosteroids successfully treated all moderate-to-severe TCMR episodes. Mild TCMR was treated by increasing existing baseline immunosuppression. Indeterminate-borderline episodes were not treated. Neither ischemia-reperfusion injury nor TCMR with DSA adversely affected embryo transfer. Relying on a modified histopathological grading system, we developed a treatment strategy resulting in resolution of TCMR and successful pregnancies.

Telluric acid ameliorates hepatic ischemia reperfusion-induced injury in rats: Involvement of TLR4, Nrf2, and PI3K/Akt signaling pathways

In past tellurium-based compounds had limited use, however, their therapeutic potential have been target of interest recently due to antioxidant and anti-inflammatory capabilities in experimental endotoxemia. Nevertheless, their potential hepatoprotective effect against ischemia reperfusion (IR) injury is still obscure. This study examined the possible hepatoprotective effect of telluric acid (TELL), one of tellurium-based compound, against the deteriorating effect hepatic IR injury in rats through directing toll like receptor-4 (TLR4) cascade, phosphoinositide 3-kinase(PI3K)/Akt axis, and nuclear erythroid-related factor-2 (Nrf-2) pathway as possible mechanisms contributed to TELL’s effect. Indeed, male Wistar rats were randomized into 3 groups: sham-operated, control IR and TELL (50 µg/kg). TELL was administrated once daily for seven consecutive days prior to the IR induction. Pretreatment with TELL attenuated hepatic IR injury as manifested by hampered plasma aminotransaminases and lactate dehydrogenase activities. Also, TELL opposed IR induced elevation in tissue expression/activity of high-mobility group box protein-1 (HMGB1), TLR4, myeloid differentiation primary-response protein 88 (MyD88), phospho-nuclear factor-kappa B p65 (p-NF-κB p65), phospho-mitogen activated protein kinasep38 (p-MAPKp38) and tumor necrosis factor-alpha (TNF-α). Moreover, TELL reduced the elevated thiobarbituric acid reactive substances along with increased both Nrf-2 and endothelial nitric oxide synthase (eNOS) protein expression, beside replenishment of hepatic reduced glutathione. In addition, TELL induced obvious upregulation of p-PI3K and p-Akt protein expressions together with restoration of histopathological changes in IR injury. In conclusion, TELL purveyed conceivable novel hepatoprotective mechanisms and attenuated events associated with acute hepatic injury via inhibition of TLR4 downstream axis and activation of Nrf-2 and PI3K/Akt signaling cascades. Thus, TELL may provide a novel therapeutic potential for complications of hepatic IR injury.

S-Adenosylmethionine attenuates bile duct early warm ischemia reperfusion injury after rat liver transplantation

Warm ischemia reperfusion injury (IRI) plays a key role in biliary complication, which is a substantial vulnerability of liver transplantation. The early pathophysiological changes of IRI are characterized by an excessive inflammatory response. S-Adenosylmethionine (SAM) is an important metabolic intermediate that modulates inflammatory reactions; however, its role in bile duct warm IRI is not known. In this study, male rats were treated with or without SAM (170 μmol/kg body weight) after orthotopic autologous liver transplantation. The histopathological observations showed that bile duct injury in the IRI group was more serious than in the SAM group. The alanine aminotransferase (ALT), alkaline phosphatase (ALP) and direct bilirubin (DBIL) levels in the serum of the IRI group were significantly increased compared to the SAM group (P < .05). Simultaneously, SAM effectively improved the survival of the transplant recipients. Furthermore, the H2O2 and malondialdehyde (MDA) of the IRI group were much higher compared to the SAM group (P < .05). The GSH/GSSG ratio in the SAM group was significantly increased by SAM treatment compared to the IRI group (P < .05). SAM administration significantly inhibited macrophage infiltration in liver and bile duct tissues, down-regulated TNF-α levels and up-regulated IL-10 expression in bile duct tissues compared to the IRI group (P < .05). The number of apoptotic biliary epithelial cells and caspase-3-positive cells in IRI rat livers were much higher compared to those in SAM-treated rats at 24 h after liver transplantation (P < .05). These data suggested that SAM protected bile ducts against warm IRI by suppressing oxidative stress, inflammatory reactions and apoptosis of biliary epithelial cells after liver transplantation.α

Global MicroRNA Expression Profiling of Mouse Livers following Ischemia-Reperfusion Injury at Different Stages.

Hepatic ischemia-reperfusion injury is a dynamic process consisting of two stages: ischemia and reperfusion, and triggers a cascade of physiological and biochemical events. Given the important role of microRNAs in regulating gene expression, we analyzed gene expression changes in mouse livers at sham control, ischemia stage, and reperfusion stage. We generated global expression profiles of microRNA and mRNA genes in mouse livers subjected to ischemia-reperfusion injury at the three stages, respectively. Comparison analysis showed that reperfusion injury had a distinct expression profile whereas the ischemia sample and the sham control were clustered together. Consistently, there are 69 differentially expressed microRNAs between the reperfusion sample and the sham control whereas 28 differentially expressed microRNAs between the ischemia sample and the sham control. We further identified two modes of microRNA expression changes in ischemia-reperfusion injury. Functional analysis of both the differentially expressed microRNAs in the two modes and their target mRNAs revealed that ischemia injury impaired mitochondrial function, nutrient consumption, and metabolism process. In contrast, reperfusion injury led to severe tissue inflammation that is predominantly an innate-immune response in the ischemia-reperfusion process. Our staged analysis of gene expression profiles provides new insights into regulatory mechanisms of microRNAs in mouse hepatic IR injury.

In Vivo Proton Magnetic Resonance Spectroscopy of Hepatic Ischemia/Reperfusion Injury in an Experimental Model

Hepatic ischemia/reperfusion injury (IRI) occurs during certain hepatobiliary surgeries, hemorrhagic shock, and veno-occlusive disease. Biochemical changes caused by hepatic IRI lead to hepatocellular remodeling, including cellular regeneration or irreversible apoptosis. This study aims to characterize and monitor the metabolic changes in hepatic IRI using proton magnetic resonance spectroscopy (¹H MRS). Sprague-Dawley rats (n = 8) were scanned with ¹H MRS using 5.0 × 5.0 × 5.0 mm³ voxel over a homogeneous liver parenchyma at 7 Tesla with a respiratory-gated point-resolved spectroscopy sequence at 1 day before, 6 hours, 1 day, and 1 week after 30 minutes total hepatic IRI. Signal integral ratios of choline-containing compounds (CCC), glycogen and glucose complex (Glyu), methylene proton ((-CH₂-)(n)), and methene proton (-CH=CH-) to lipid (integral sum of methyl proton (-CH₃), (-CH₂-)(n) and -CH=CH-) were quantified by areas under peaks longitudinally. The CCC-to-lipid and Glyu-to-lipid ratios at 6 hours after IRI were significantly higher than those at 1 day before, 1 day, and 1 week after injury. The (-CH₂-)(n)-to-lipid, and -CH=CH-to-lipid ratios showed no significant differences over different time points. Hepatocellular regeneration was observed at 6 hours after IRI in histology with immunohistochemical technique. Changes in CCC-to-lipid and Glyu-to-lipid ratios likely reflect the hepatocellular remodeling and impaired glucose utilization upon hepatic IRI, respectively. The experimental findings in the current study demonstrated that ¹H MRS is a valuable tool for characterizing either global or regional metabolic changes in liver noninvasively and longitudinally. Such capability has the potential to lead to early diagnosis and detection of impaired liver function.

University of Wisconsin solution for pulmonary preservation in a rat transplant model

University of Wisconsin and modified Euro-Collins solutions for pulmonary preservation were compared in a rat orthotopic left lung isotransplant model. Heart-lung blocks of donor rats were flushed with and preserved in one of the preservation solutions at 0 °C. After 6 or 12 hours of cold ischemia, the left lungs were transplanted into recipient rats and repcrfused for 1 hour. Pulmonary function was assessed by measuring oxygen and carbon dioxide tensions in arterial blood after removal of the right lung. Lipid peroxide concentrations were measured as thiobarbiturate acid-reactive substances. The ratios of wet to dry weight of grafts after ischemia and after reperfusion were calculated. Histologic changes of ischemia-reperfusion injury of the lung tissue were evaluated using a graded scale. Oxygen tension after 6 hours of preservation followed by reperfusion was significantly higher with University of Wisconsin solution (308.8 ± 81.1 mm Hg) than with Euro-Collins solution (50.8 ± 17.8 mm Hg; p < 0.001). Carbon dioxide tension in the University of Wisconsin solution group was also significantly lower than in the Euro-Collins solution group (28.2 ± 2.3 versus 46.0 ± 4.5 mm Hg; p < 0.05). Lipid peroxide concentration after 6 hours' preservation in University of Wisconsin solution was significantly lower (0.88 ± 0.07 μmol/g) than that in Euro-Collins solution (1.26 ± 0.12 μmol/g; p < 0.05). After 12 hours of preservation only lipid peroxide concentration with University of Wisconsin solution was significantly lower (1.30 ± 0.09 μmol/g) than with Euro-Collins solution (1.71 ± 0.15 μmol/g; p < 0.05). There were no differences in the other variables. We conclude that University of Wisconsin solution provides superior lung preservation than does Euro-Collins solution in this transplant model.