NOVEL APPROACHES TO DIAGNOSIS AND THERAPY OF SEPSIS
Work in the lab aims at uncovering novel approaches to diagnose and treat sepsis and related inflammatory disorders. Sepsis is a life-threatening condition and the leading cause of death in intensive care units in highincome countries. The mainstay of decreasing sepsis-induced mortality and morbidity is based on two strategies: the prompt start of an effective antibiotic therapy and the reduction of the systemic inflammatory response syndrome (SIRS) that causes multiorgan failure and death. In fact, harmful stimuli, such as pathogens or dead cells, are detected by pattern-recognition receptors and trigger different downstream signalling cascades, leading to production of proinflammatory cytokines or type I interferons in immune cells. Among these receptors are the key components of the inflammasomes, cytosolic molecular platforms which oligomerize upon ligand binding and trigger caspase-1-dependent maturation and secretion of proinflammatory cytokines such as IL-1β. Many studies highlight the clinical relevance of inflammasome overactivation not only in the pathogenesis of infection diseases, including sepsis, but also in several congenital and acquired inflammatory disorders. Indeed, the tight control of inflammasome assembly and signalling is crucial because it must allow the immune system to initiate antimicrobial and inflammatory responses but it should avoid tissue damage due to excessive activation leading to chronic or systemic inflammatory diseases. However, despite an intense effort in these years, the molecular mechanism underlying inflammasome activation are still unclear. Although it is accepted that mitochondrial-mediated ROS production are involved, the integration of mitochondrial dysfunction, metabolic derangements and inflammasome activation along with their contribution to the pathogenesis of sepsis remain incompletely elucidated. Advances in understanding the immune response to sepsis will provide the opportunity to develop more effective therapies.
The main goal of our research is to characterize the role of a mitochondrial enzyme, monoamine oxidase, in inflammasome activation. The impact of leukocyte monoamine oxidase activity on tissue damage and local or systemic inflammation has been quite overlooked, and its role in sepsis is virtually unknown. Positive outcome of this study should provide the basis for repositioning of clinical-grade monoamine oxidase inhibitors as viable candidates in the treatment of sepsis. This enzyme is located in the outer mitochondrial membrane and catalyzes the oxidative deamination of neurotransmitters, i.e. catecholamines, and dietary amines, generating the corresponding aldehydes, ammonia and hydrogen peroxide. Monoamine oxidase physiologic role in the central nervous system is well-established: it terminates neurotransmitter signalling and, by doing this, it generates hydrogen peroxide that is however constantly removed by endogenous scavengers. On the contrary, in pathological conditions, the increased activity of the enzyme overcomes the cellular antioxidant defences, altering the redox homeostasis and eliciting deleterious effects.
We also plan to characterize the role of monoamine oxidase in immune cells of dystrophic muscles. Indeed, although muscular dystrophies are a family of inherited diseases affecting muscle cells, they are characterized by a massive inflammatory infiltrate in muscles. In Duchenne muscular dystrophy, for example, dystrophin deficiency leads to chronic membrane instability, cell death and continuous release of Toll-like receptor ligands, which overactivate the immune response (Rosenberg et al., 2015).
Selected PubblicationsSorato E, Menazza S, Zulian A, Sabatelli P, Gualandi F, Merlini L, Bonaldo P, Canton M, Bernardi P, Di Lisa F.. 2014. Monoamine oxidase inhibition prevents mitochondrial dysfunction and apoptosis in myoblasts from patients with collagen VI myopathies. Free Radic Biol Med, 10, 40-47.
Canton M, Menazza S, Sheeran F L, Polverino De Laureto P, Di Lisa F, And Pepe S . 2011. Oxidation of myofibrillar proteins in human heart failure. J Am Coll Cardiol, vol. 57 (3); p. 300-309, ISSN: 0735-1097
Menazza S, Blaauw B, Tiepolo T, Toniolo L, Braghetta P, Spolaore B, Reggiani C, Di Lisa F, Bonaldo P, Canton M. . 2010. Oxidative stress by monoamine oxidases is causally involved in myofiber damage in muscular dystrophy. Hum Mol Genet, vol. 19; p. 4207-4215
Caffieri S, Di Lisa F, Bolesani F, Facco M, Semenzato G, Dall'Acqua F, Canton M. . 2007. The mitochondrial effects of novel apoptogenic molecules generated by psoralen photolysis as a crucial mechanism in PUVA therapy. Blood , 109 (11), 4988-94.
Canton M, Skyschally A, Menabo R, Boengler K, Gres P, Schulz R, Haude M, Erbel R, Di Lisa F, Heusch G. . 2006. Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization. Eur Heart J , 27 (7), 875-81
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