Role of fibrinogen in the attenuation of ischemia reperfusion and remote ischemic preconditioning / El papel del fibrinógeno en la atenuación de la isquemia-reperfusión y el preacondicionamiento isquémico remoto

Abstract Background: Ischemic reperfusion injury (IRI) is a common hazard involved in many human diseases, such as cerebral stroke, myocardial infarction, solid organ transplant dysfunction or failure, and vascular diseases. Understanding the molecular bases of this injury is essential for the prevention and control of these life-threatening conditions. Ischemic and remote ischemic preconditioning techniques (IPC and RIPC, respectively) have gained increasing importance in the clinical practice to protect against the IRI; however, the exact mechanisms of these techniques are not fully understood, which renders their clinical application query. Possible effectors: Nitric oxide (NO) has been reported by multiple studies to be an important mediator of the protective effects of those techniques. While the physiological concentrations of NO and fibrinogen (FB) are known to antagonize each other, the circulating levels of both effectors increase in response to RIPC. Hypothesis: While NO has potential anti-inflammatory effects, non-soluble fibrinogen (sFB) shows pro- inflammatory effects. However, the sFB may have the potential to act synergistically rather than antagonistically with NO toward the attenuation of the IRI. Conclusion: While increased FB is considered a risk factor for cardiovascular and inflammatory conditions that is also able to decrease the efflux of NO, and increase the NO oxidative metabolits and S- nitroglutathione, the increased sFB during the acute phase reaction might have other protective aspects that should be carefully investigated.

Resumen Antecedentes: La lesión por isquemia-reperfusión (LIR) es un riesgo común involucrado en muchas enfermedades humanas tales como derrame cerebral, infarto del miocardio, disfunción o falla de trasplante de órgano sólido, y enfermedades vasculares. Una comprensión de la base molecular de esta lesión es fundamental para la prevención y el control de estas enfermedades potencialmente mortales. Las técnicas de preacondicionamiento isquémico y preacondicionamiento isquémico remoto (PIR) han cobrado una creciente importancia en la práctica clínica para la protección contra la LIR, sin embargo, los mecanismos precisos de estas técnicas no se entienden plenamente, lo cual pone en duda su aplicación clínica. Posibles efectores: El óxido nítrico (ON) ha sido reportado por varios estudios como un importante mediador de los efectos protectores de estas técnicas. Si bien se sabe que las concentraciones fisiológicas del ON y fibrinógeno son antagónicas, los niveles circulantes de ambos efectores aumentan en respuesta al PIR. Hipótesis: Aunque el ON tiene posibles efectos anti-inflamatorios, el fibrinógeno insoluble muestra efectos proinflamatorios. Sin embargo, el fibrinógeno soluble puede tener el potencial de actuar de manera sinérgica en lugar de antagónica con el ON hacia la atenuación de la LIR. Conclusión: Aunque el fibrinógeno elevado se considera un factor de riesgo para las enfermedades cardiovasculares e inflamatorias, que también puede disminuir la descarga de ON y aumentar los niveles de metabolitos oxidantes del ON y de S-nitrosoglutatión, el aumento de fibrinógeno soluble durante la reacción de fase aguda puede tener otros aspectos protectores que deben ser cuidadosamente investigados.

Combined Ex Vivo Organ Perfusion and Mesenchymal Stem Cells Transplantation.

Background: The importance of solid organ transplants is increasing due to the increasing incidence of end-stage organ diseases. With the limitations facing the recruitment of the suitable grafts, ex vivo organ perfusion (EVOP) techniques have been developed to increase the graft acceptance rates and improve the clinical outcomes. Methodology: The role of mesenchymal stem cells (MSCs) in this regard is not limited to the regenerative ability. MSCs have proved their ability to effectively modulate the immune response and inflammation. Accordingly, the idea of the combined ex vivo organ perfusion and MSCs transplant came to focus. This manuscript reviews some points that should be considered, while applying this technique. Conclusion: The combined EVOP-MSCs is a therapeutic technique that should be soon applied in the practice of solid organ transplants. However, certain remarks should be considered on the pre-clinical levels before taking the studies further into the clinical levels. Although the present report will focus on the lung transplant, the ideas and the remarks are also to be considered for all other solid organ transplants, such as heart, liver and kidney.

Mesenchymal Stem Cells and Lung Transplantation: A Couple for a Perfect Relationship.

With the increased incidence of lung and other organ failure, organ transplantation becomes a frequent surgical intervention. Research is focused on improving the practice of lung and other organ transplantation in order to improve the clinical outcome and to decrease the incidence of post-operative complications. This manuscript represents the author's view of the possibility of improving the lung transplantation outcome through the co-transplantation of mesenchymal stem cells, and the expected positive effects of that application.

Ex Vivo Lung Perfusion and Transplant: State of the Art and View to the Future.

After the first clinical application of ex vivo lung perfusion in 2001, the technique has been used in many lung transplant centers worldwide. In addition, many modifications have been tested, leading to the development of various ex vivo lung perfusion systems and application protocols. Currently, the Lund protocol, the Toronto protocol, and Organ Care System Lung protocol are the clinically applied ex vivo lung perfusion protocols, based on the favorable results of the safety studies. Accordingly, the comparison among these EVLP systems and protocols should be an important research target, in order to provide the evidence based medical data that would recommend one protocol over the others. In this manuscript, the current experience with EVLP is reviewed and some molecular and clinical targets, that could be used to compare the various protocols of the technique, are introduced.

Could Ex Vivo Lung Perfusion Be a Platform to Decrease the Incidence of Chronic Lung Allograft Dysfunction?

The number of patients requiring lung transplantation is increasing, with a significant unmet demand for grafts. Ex vivo lung perfusion has been developed to increase graft recruitment. The major complications of lung transplantation include chronic allograft dysfunction (CLAD) whose cumulative incidence ranges from 43-80% within the first 5 years of transplantation. Many risk factors are listed for development of CLAD and almost all of those risk factors would involve activation of Toll-like receptors. This paper represents the author's overview regarding the development of CLAD as a complication of lung transplantation and the possible protective potential of ex vivo lung perfusion in this regard.