Searching novel therapeutic targets for scleroderma: P2X7-receptor is UP-regulated and promotes a fibrogenic phenotype in systemic sclerosis fibroblasts

Objectives: Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways. Methods: Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca2+ fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated. Results: P2X7R expression and Ca2+ permeability induced by the selective P2X7R agonist 2'-3'-O-(4-benzoylbenzoyl)ATP (BzATP) weremarkedly higher in SSc than control fibroblasts. Moreover, increased aSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway. Conclusion: In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca2+-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc

Uso della tecnologia VSC-HVDC per l'adeguamento dei sistemi HVDC a commutazione naturale per la riaccensione di rete

In the present thesis, a method of adapting an existing LCC HVDC line to be used for network reconnection has been proposed. Natural-switching converters are unable to independently support a blackout network due to the need for a frequency reference to make the switching happen. The planned adjustment consisted in the use of an auxiliary forced switched converter with reduced power for the resumption of operation of the grid temporarily out of service. The auxiliary VSC converter, normally used in the station only for auxiliary services or at the most unused, comes into operation when the need to restart a network in a state of generalized failure has been detected. The conversion station on the other hand, connected to a healthy network, does not change compared to the normal operating logic; the natural switching converter therefore remains operational. The object of this work is to determine a minimum sizing power for the VSC converter that allows it to perform the black start task for the network in question. The adaptation of the HVDC connection through the use of VSC is an alternative to the implementation of synchronous compensators for black start operation of the connection. The possible use of synchronous rotary compensators, which can be found in the literature, involves a high cost, primarily for maintenance, as well as a considerable increase in the degree of complexity of the system. The general characteristics of HVDC systems will be briefly described, the operating principles of LCC and VSC converters and their main features will be analysed. Before going into the description of the simulation carried out, we will briefly discuss the main issues concerning the commissioning of a system affected by blackouts and the ignition procedures. The verification of the functionality of the proposed method has been carried out through Matlab-Simulink software. Simulink-Simscape models of HVDC (High Voltage Direct Current), VSC (Voltage Source Converter) and LCC (Line Commutated Converter) have been developed and implemented. The overall model, created using Simscape library components, was designed to simulate events and magnitudes of interest for electrical power systems. The model integrates an AC power grid in reboot after an event that caused it to be out of general service. The structure in simulation sees the network out of service composed of loads representing the users in the area and loads representing the auxiliaries of the thermal power plant also out of service connected via an HVDC connection to a second alternating network functioning. The will of the work is to be able to power the power plant out of service and then to carry out the parallel through the only power supplied by the HVDC. The inverter must also take charge of the frequency control so that the generator can follow the loading ramp undisturbed. The transient of the grid being restored will be analysed and the dynamics resulting from the parallel with the generator and the load balance between this and the station VSC will be analysed. The control mode of the converter on restart will be deliberately set for island operation. The AC mains side conversion station operating will see the natural switching converter active, dimensioned according to the nominal connection characteristics. For LCC the control mode will not be considered for two reasons. The first is the invariance of the behaviour with respect to normal operation as it is connected to the healthy AC mains; while the second reason is to be found in the fact that in the absence of the need for power flow reversals, the converter works with minimum valve ignition delay angle. For our purposes, this mode of operation is equivalent to that of a diode bridge. The latter will actually be implemented through Simscape models in order to verify the behavior of this to the VSC power requirements The simulation mode provides a planned sequence of reboot of the network in blackout. The network made up of passive consumers and the thermal power plant will be started exclusively through the energy supplied by the station converter, since it is assumed that there are no other connections to neighbouring networks except HVDC. The simulation foresees the presence of a long alternating line as a connection between the generation area and the converter. The central unit will be started by the converter, even if the correct starting sequence of the central unit auxiliaries is beyond the scope of the the thesis. In order to simulate the operation of power plant start up, appropriate loads inserted in the step network have been provided. Their network connections will be useful for evaluating the response of the heavy duty transient drive. The boiler feed water pump, on the other hand, has been modelled by means of a large asynchronous direct insertion motor without the aid of soft starters or drives. When the power plant is started up, the parallel between the converter and the thermal power plant will be made. After a certain period of time before conditions are restored, the generator ramps up to allow the converter to discharge its power reserve. A certain number of loads are then stepped in. During this phase the ability of the converter to take over the control was checked. The generator, on the other hand, did not significantly change the mechanical power output compared to the set load intake ramp. Once the restart sequence has been completed and the generator has reached a stable operating condition, the drive control logic should return to that in use during normal mains conditions. This means that the natural-switching converter on the mains side of the station that has just been switched back on and the VSC, which has supported the resumption of the mains from out of service, will come back into operation. Although this is indispensable for the restoration of normal operating conditions, it has not been analysed in this work, leaving this task to subsequent discussion