Induction of Heme Oxygenase-1 Can Halt and Even Reverse Renal Tubule-Interstitial Fibrosis

Background: The tubule-interstitial fibrosis is the hallmark of progressive renal disease and is strongly associated with inflammation of this compartment. Heme-oxygenase-1 (HO-1) is a cytoprotective molecule that has been shown to be beneficial in various models of renal injury. However, the role of HO-1 in reversing an established renal scar has not yet been addressed. Aim: We explored the ability of HO-1 to halt and reverse the establishment of fibrosis in an experimental model of chronic renal disease. Methods: Sprague-Dawley male rats were subjected to unilateral ureteral obstruction (UUO) and divided into two groups: non-treated and Hemin-treated. To study the prevention of fibrosis, animals were pre-treated with Hemin at days -2 and -1 prior to UUO. To investigate whether HO-1 could reverse established fibrosis, Hemin therapy was given at days 6 and 7 post-surgery. After 7 and/or 14 days, animals were sacrificed and blood, urine and kidney tissue samples were collected for analyses. Renal function was determined by assessing the serum creatinine, inulin clearance, proteinuria/creatininuria ratio and extent of albuminuria. Arterial blood pressure was measured and fibrosis was quantified by Picrosirius staining. Gene and protein expression of pro-inflammatory and pro-fibrotic molecules, as well as HO-1 were performed. Results: Pre-treatment with Hemin upregulated HO-1 expression and significantly reduced proteinuria, albuminuria, inflammation and pro-fibrotic protein and gene expressions in animals subjected to UUO. Interestingly, the delayed treatment with Hemin was also able to reduce renal dysfunction and to decrease the expression of pro-inflammatory molecules, all in association with significantly reduced levels of fibrosis-related molecules and collagen deposition. Finally, TGF-beta protein production was significantly lower in Hemin-treated animals. Conclusion: Treatment with Hemin was able both to prevent the progression of fibrosis and to reverse an established renal scar. Modulation of inflammation appears to be the major mechanism behind HO-1 cytoprotection.Fundacao de Amparo Pesquisa do Estado de Sao Paulo-FAPESP[07/07139-3]Coordenaco de Aperfeioamento de Pessoal de Nivel Superior-CAPESInstituto Nacional de Ciencia e Tecnologia de Complexos Fluidos (INCT)Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNP

Early hematoma retraction in intracerebral hemorrhage is uncommon and does not predict outcome.

BACKGROUND:Clot retraction in intracerebral hemorrhage (ICH) has been described and postulated to be related to effective hemostasis and perihematoma edema (PHE) formation. The incidence and quantitative extent of hematoma retraction (HR) is unknown. Our aim was to determine the incidence of HR between baseline and time of admission. We also tested the hypothesis that patients with HR had higher PHE volume and good prognosis. METHODS:This was a retrospective single-centre study in which serial planimetric volume measurements of the total hematoma volume (parenchymal (IPH) and intraventricular (IVH)) and PHE were performed in ICH patients with baseline non-contrast computed tomography (CT) completed within 6 hours of onset and follow-up CT 24 (±12) hours from symptom onset. HR was defined as a decrease in volume of >3ml or >15%, and hematoma expansion (HE) as an increase of >6ml or >30%. All other patients were categorized as stable hematoma (HS). Good outcome was defined as modified Rankin Scale (mRS) 0-2 at 90 days. RESULTS:A total of 136 patients (mean age = 69.3±13.39 years, 58.1% male) were included. Median (interquartile range) baseline total hematoma volume was 14.96 (7.80, 31.88) ml. HR >3ml and >15% occurred in 6 (4.4%) and 8 (5.9%) patients, respectively. Neither definition of HR was associated with follow-up PHE (p>0.297) or good outcome (p>0.249). IVH was the only independent predictor of HR (p<0.0241). CONCLUSIONS:Early HR is rare and associated with IVH, but not with PHE or clinical outcome. There was no relationship between HR, PHE, and patient prognosis. Therefore, HR is unlikely to be a useful endpoint in clinical ICH studies

Quantitative susceptibility mapping for following intracranial hemorrhage

Purpose: To follow the evolution of intracranial hemorrhage (ICH) by using quantitative susceptibility mapping (QSM).Materials and Methods: Thirty-six patients with ICH confirmed at CT were enrolled to follow ICH evolution on day 2, 7, and 30 after symptom onset between August 2013 and April 2017. QSM was reconstructed from MRI gradient-echo phase images acquired at 1.5 T or 3.0 T. ICH regions were manually drawn on two-dimensional sections of co-registered CT and MR images independently by two raters. The ICH areas and mean values were compared between CT and MRI by using Bland-Altman plots and Pearson correlation. QSM time evolution of ICH was assessed by using paired t tests and was compared with conventional T2-weighted fluid-attenuated inversion recovery, or T1-weighted or T2*-weighted magnitude intensities.Results: Significant reductions in ICH susceptibility were found between day 2 and day 7 (

Prolonged therapeutic hypothermia does not adversely impact neuroplasticity after global ischemia in rats

Hypothermia improves clinical outcome after cardiac arrest in adults. Animal data show that a day or more of cooling optimally reduces edema and tissue injury after cerebral ischemia, especially after longer intervention delays. Lengthy treatments, however, may inhibit repair processes (e.g., synaptogenesis). Thus, we evaluated whether unilateral brain hypothermia (33°C) affects neuroplasticity in the rat 2-vessel occlusion model. In the first experiment, we cooled starting 1 hour after ischemia for 2, 4, or 7 days. Another group was cooled for 2 days starting 48 hours after ischemia. One group remained normothermic throughout. All hypothermia treatments started 1 hour after ischemia equally reduced hippocampal CA1 injury in the cooled hemisphere compared with the normothermic side and the normothermic group. Cooling only on days 3 and 4 was not beneficial. Importantly, no treatment influenced neurogenesis (Ki67/Doublecortin (DCX) staining), synapse formation (synaptophysin), or brain-derived neurotropic factor (BDNF) immunohistochemistry. A second experiment confirmed that BDNF levels (ELISA) were equivalent in normothermic and 7-day cooled rats. Last, we measured zinc (Zn), which is important in plasticity, with X-ray fluorescence imaging in normothermic and 7-day cooled rats. Hypothermia did not alter the postischemic distribution of Zn within the hippocampus. In summary, cooling significantly mitigates injury without compromising neuroplasticity. © 2012 ISCBFM All rights reserved