Inhibition of BRD4 Reduces Neutrophil Activation and Adhesion to the Vascular Endothelium Following Ischemia Reperfusion Injury (original) (raw)
Related papers
The interaction between ischemia–reperfusion and immune responses in the kidney
Journal of Molecular Medicine, 2009
Kidney ischemia-reperfusion injury (IRI) engages both the innate and adaptive immune responses. Cellular mediators of immunity, such as dendritic cells, neutrophils, macrophages, natural killer T, T, and B cells, contribute to the pathogenesis of renal injury after IRI. Postischemic kidneys express increased levels of adhesion molecules on endothelial cells and toll-like receptors on tubular epithelial cells. Soluble components of the immune system, such as complement activation proteins and cytokines, also participate in injury/repair of postischemic kidneys. Experimental studies on the immune response in kidney IRI have resulted in better understanding of the mechanisms underlying IRI and led to the discovery of novel therapeutic and diagnostic targets.
Innate Immune Response in Kidney Ischemia/Reperfusion Injury: Potential Target for Therapy
Journal of Immunology Research
Acute kidney injury caused by ischemia and subsequent reperfusion is associated with a high rate of mortality and morbidity. Ischemia/reperfusion injury in kidney transplantation causes delayed graft function and is associated with more frequent episodes of acute rejection and progression to chronic allograft nephropathy. Alloantigen-independent inflammation is an important process, participating in pathogenesis of injurious response, caused by ischemia and reperfusion. This innate immune response is characterized by the activity of classical cells belonging to the immune system, such as neutrophils, macrophages, dendritic cells, lymphocytes, and also tubular epithelial cells and endothelial cells. These immune cells not only participate in inflammation after ischemia exerting detrimental influence but also play a protective role in the healing response from ischemia/reperfusion injury. Delineating of complex mechanisms of their actions could be fruitful in future prevention and tre...
Renal Ischemia-Reperfusion Injury Molecular Mechanisms and Therapeutic Targets
Minia Journal of Medical Research
Ischemia/reperfusion injury (IRI) is caused by a rapid transient reduction in blood flow to a specific organ. IRI is typically accompanied by a strong inflammatory and oxidative stress response to hypoxia and reperfusion, which disrupts organ function. AKI caused by renal IRI contributes to a high morbidity and death rate in a variety of injuries. Although the pathophysiology of IRI is not fully understood, numerous key pathways leading to renal failure have been identified. The production of reactive oxygen species (ROS) during the reperfusion phase of the ischemic kidney and subsequent re-oxygenation begins a cascade of detrimental cellular reactions that leads to inflammation, cell death, and acute kidney failure. Greater knowledge of the cellular pathophysiological mechanisms causing kidney damage may lead to the development of more focused treatments to prevent and treat the damage. We discuss several significant possible mechanisms and treatment methods in renal IRI in this study.
Biological modulation of renal ischemia-reperfusion injury
Current opinion in organ transplantation, 2010
Biological modulation of renal ischemia-reperfusion injury holds the potential to reduce the incidence of early graft dysfunction and to safely expand the donor pool with kidneys that have suffered prolonged ischemic injury before organ recovery. In the current review, we will discuss clinical studies that compare kidney transplant recipients with and without early graft dysfunction in order to elucidate the pathophysiology of ischemic acute allograft injury. We will specifically review the mechanisms leading to depression of the glomerular filtration rate and activation of the innate immune system in response to tissue injury. We conclude that the pathophysiology of delayed graft function after kidney transplantation is complex and shares broad similarity with rodent models of ischemic acute kidney injury. Given the lack of specific therapies to prevent delayed graft function in transplant recipients, comprehensive efforts should be initiated to translate the promising findings obt...
Journal of the American Society of Nephrology : JASN, 2015
Monocytes and kidney-resident macrophages are considered to be involved in the pathogenesis of renal ischemia-reperfusion injury (IRI). Several subsets of monocytes and macrophages are localized in the injured tissue, but the pathologic roles of these cells are not fully understood. Here, we show that CD169(+) monocytes and macrophages have a critical role in preventing excessive inflammation in IRI by downregulating intercellular adhesion molecule-1 (ICAM-1) expression on vascular endothelial cells. Mice depleted of CD169(+) cells showed enhanced endothelial ICAM-1 expression and developed irreversible renal damage associated with infiltration of a large number of neutrophils. The perivascular localization of CD169(+) monocytes and macrophages indicated direct interaction with blood vessels, and coculture experiments showed that the direct interaction of CD169(+) cell-depleted peripheral blood leukocytes augments the expression levels of ICAM-1 on endothelial cells. Notably, the tr...
Brabykinin B1 Receptor Antagonism Is Beneficial in Renal Ischemia-Reperfusion Injury
2008
Previously we have demonstrated that bradykinin B1 receptor deficient mice (B1KO) were protected against renal ischemia and reperfusion injury (IRI). Here, we aimed to analyze the effect of B1 antagonism on renal IRI and to study whether B1R knockout or antagonism could modulate the renal expression of pro and anti-inflammatory molecules. To this end, mice were subjected to 45 minutes ischemia and reperfused at 4, 24, 48 and 120 hours. Wild-type mice were treated intraperitoneally with antagonists of either B1 (R-954, 200 mg/kg) or B2 receptor (HOE140, 200 mg/kg) 30 minutes prior to ischemia. Blood samples were collected to ascertain serum creatinine level, and kidneys were harvested for gene transcript analyses by real-time PCR. Herein, B1R antagonism (R-954) was able to decrease serum creatinine levels, whereas B2R antagonism had no effect. The protection seen under B1R deletion or antagonism was associated with an increased expression of GATA-3, IL-4 and IL-10 and a decreased T-bet and IL-1b transcription. Moreover, treatment with R-954 resulted in lower MCP-1, and higher HO-1 expression. Our results demonstrated that bradykinin B1R antagonism is beneficial in renal IRI.
Proceedings of the National Academy of Sciences, 2000
Neutrophil migration protects the body against foreign invasion. Sequestration and activation of neutrophils, however, require stringent regulation because they may also cause tissue damage by the release of lysosomal enzymes and reactive oxygen species. The activity of various chemoattractants [e.g., leukotriene B4 (LTB4), interleukin-8, and complements] has been documented by in vitro assays, whereas in vivo data have been limited mostly to histology.
PLoS ONE, 2014
Disruption of the renal endothelial integrity is pivotal for the development of a vascular leak, tissue edema and consequently acute kidney injury. Kidney ischemia amplifies endothelial activation and up-regulation of pro-inflammatory mechanisms. After restoring a sufficient blood flow, the kidney is damaged through complex pathomechanisms that are classically referred to as ischemia and reperfusion injury, where the disruption of the inter-endothelial connections seems to be a crucial step in this pathomechanism. Focusing on the molecular cell-cell interaction, the fibrinopeptide Bb 15-42 prevents vascular leakage by stabilizing these inter-endothelial junctions. The peptide associates with vascular endothelialcadherin, thus preventing early kidney dysfunction by preserving blood perfusion efficacy, edema formation and thus organ dysfunction. We intended to demonstrate the early therapeutic benefit of intravenously administered Bb 15-42 in a mouse model of renal ischemia and reperfusion. After 30 minutes of ischemia, the fibrinopeptide Bb 15-42 was administered intravenously before reperfusion was commenced for 1 and 3 hours. We show that Bb 15-42 alleviates early functional and morphological kidney damage as soon as 1 h and 3 h after ischemia and reperfusion. Mice treated with Bb 15-42 displayed a significantly reduced loss of VE-cadherin, indicating a conserved endothelial barrier leading to less neutrophil infiltration which in turn resulted in significantly reduced structural renal damage. The significant reduction in tissue and serum neutrophil gelatinase-associated lipocalin levels reinforced our findings. Moreover, renal perfusion analysis by color duplex sonography revealed that Bb 15-42 treatment preserved resistive indices and even improved blood velocity. Our data demonstrate the efficacy of early therapeutic intervention using the fibrinopeptide Bb 15-42 in the treatment of acute kidney injury resulting from ischemia and reperfusion. In this context Bb 15-42 may act as a potent renoprotective agent by preserving the endothelial and vascular integrity.