Pathogenic role of complement in renal ischemia/reperfusion injury

The aim of the research described in this thesis was to study the role of complement in renal ischemia/reperfusion injury (IRI) and to delineate the contribution of the different complement pathways involved. So far, in human renal IRI, the activation pathways of complement by ischemic proximal tubular epithelial cells (PTEC) are still incompletely elucidated. In chapter 2 we therefore established an in vitro model to simulate IRI on human and mouse PTEC by culturing these cells under normoxic or hypoxic conditions and then investigated the subsequent effects on complement activation following reoxygenation (reperfusion). We specifically focused on the question which pathway(s) of complement activation are initiated by human and mouse PTEC after hypoxic stress. In chapter 3 we addressed the lack of evidence for involvement of complement in human IRI. We assessed the formation and release of C5b-9 during early reperfusion in clinical kidney transplantation in living donor, brain-dead donor, and cardiac dead donor kidney transplantation. Complement activation following I/R may take place in both tubular and vascular compartments. Therefore, we systematically measured terminal complement activation during early reperfusion in human kidney transplantation in both the tubular compartment by immunohistochemistry and the intravascular compartment by selective arteriovenous measurements over the transplanted kidney. In chapter 4 we studied whether C5b-9 could also be detected in urines of transplant recipients early after transplantation. In addition, we investigated the possibility whether in proteinuric urine, which is common following transplantation, C5b-9 might be generated independent of a renal contribution. Based on previous clinical studies that high serum levels of MBL were associated with inferior renal allograft survival following clinical transplantation, we examined in chapter 5 the role of MBL in the pathophysiology of renal IRI and explored the therapeutic targeting of MBL in a rat model of renal IRI. We identified an entirely novel role for MBL in mediating reperfusion-induced kidney injury following ischemia which is completely independent of complement activation. In chapter 6 we studied the mechanism by which MBL might mediate tubular injury following renal I/R. Vascular leakage results in exposure of tubular cells to MBL, which was shown to be the primary culprit of tubular injury. Recombinant human C1 inhibitor (rhC1INH) is a serine protease inhibitor that inhibits complement activation, reduces vascular permeability and interacts with MBL. In chapter 7 we therefore explored the therapeutic application of rhC1INH in renal IRI and studied whether rhC1INH is able to attenuated MBL-mediated kidney injury. In chapter 8 we investigated the impact of short- and long-term IRI on vascular integrity, pericytes and angiopoietin expression. Finally, in chapter 9 the findings presented in this thesis are critically discussed and the possible implications for kidney transplantation are presentedUBL - phd migration 201

Cardiac foetal reprogramming:a tool to exploit novel treatment targets for the failing heart

As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure

A distributed topology information system for optical networks based on the semantic web

The research networking community has embraced novel network architectures to provide e-Science applications with dedicated connections instead of shared links. IP and optical services converge in these new infrastructures to form hybrid networks. Lightpaths are the services offered to clients in the optical portion of the network. They are chosen because they guarantee the appropriate QoS in terms of bandwidth and latency. NDL-the Network Description Language-is a data model offering users and providers of lightpaths with a common ontology to describe topology information of hybrid optical networks. The strength of NDL is that it supports a wide range of applications, including pathfinding, visualisation and asset management, via the definition of a common data model to exchange network descriptions. Since NDL is based on the Semantic Web techniques, it is straightforward to relate NDL with application-specific ontologies. In this paper we present the current status of the NDL schemas and its use in several applications

Transition between Two Oscillation Modes

A model for the symmetric coupling of two self-oscillators is presented. The nonlinearities cause the system to vibrate in two modes of different symmetries. The transition between these two regimes of oscillation can occur by two different scenarios. This might model the release of vortices behind circular cylinders with a possible transition from a symmetric to an antisymmetric Benard-von Karman vortex street.Comment: 12 pages, 0 figure