Translational and Mechanistic Study about Beta-1-Adrenergic Receptor Modulation on Neutrophils as a Therapy against Ischemia/Reperfusion Injury
[EN] Acute myocardial infarction and ischemic stroke are the two most frequent life-threatening presentations of atherosclerosis. These two conditions are the leading causes of morbidity and mortality worldwide. In both cases, the main determinant of poor outcome is the extent of irreversible injury...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/355217 |
| Acceso en línea: | http://hdl.handle.net/10261/355217 |
| Access Level: | acceso abierto |
| Palabra clave: | Isquemia/reperfusion Receptores adrenérgicos beta1, beta-bloqueantes http://metadata.un.org/sdg/3 Ensure healthy lives and promote well-being for all at all ages |
| Sumario: | [EN] Acute myocardial infarction and ischemic stroke are the two most frequent life-threatening presentations of atherosclerosis. These two conditions are the leading causes of morbidity and mortality worldwide. In both cases, the main determinant of poor outcome is the extent of irreversible injury. The mainstay treatment of acute myocardial infarction and ischemic stroke is timely reperfusion of the occluded artery to restore blood flow. However, despite being essential for tissue salvage, evidence shows that reperfusion itself triggers a set of potentially deleterious events that paradoxically contribute to final infarct size. From the different mechanisms involved in reperfusion-related injury, microvascular obstruction and acute inflammatory response play a central role. The beta-1-selective blocker metoprolol has been demonstrated to reduce myocardial infarct size through its inhibitory effect on neutrophils. Based on the cardioprotective effect of metoprolol injection, among other effects (e.g. antiarrhythmic effect); current clinical practice guidelines recommend early intravenous administration of beta-blockers to patients with an ongoing acute myocardial infarction. While different beta-blockers exist (with clear pharmacological differences among them), given the lack of comparative studies, clinical practice guidelines do not recommend on over another. While the adjuvant pharmacological treatment to reperfusion is well developed for acute myocardial infarction, treatment of stroke is currently restricted to reperfusion without coadjuvant therapies. Within this thesis, the biological effects of the different clinically available intravenous beta-blockers on different acute conditions have been tested. This work presents evidence that metoprolol has a particular action on neutrophils during exacerbated inflammation (acute myocardial infarction, peritonitis and acute lung injury) that affords a cardioprotection not provided by other beta-blockers, such as atenolol or propranolol. Besides, herein it is shown how these effects attributed to metoprolol are translated into protection in other different and complex pathological scenarios, in which neutrophils are shown to play a key role, such as ischemic stroke or acute respiratory distress syndrome. Although larger clinical studies are needed to confirm these results, the identification of metoprolol’s mechanism of action through neutrophil stunning has broadened the potential of an old drug as a therapeutic strategy against prevalent diseases for which adjuvant strategies are thoroughly limited (e.g. ischemic stroke and acute respiratory distress syndrome). Likewise, this work contributes to highlight the relevance of drug repurposing, as a highly efficient, time saving, low-cost and minimum risk of failure strategy, so as to speed up the slow development of a molecule from bench to market. Noteworthy, this thesis includes the execution of a clinical study in patients with severe COVID-19 (a condition characterized by acute respiratory distress syndrome with massive lung inflammatory response). The contribution of basic and translational research to the fight against this terrible pandemic is a role model of how science is vital in our society. |
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