In response to severe tissue trauma, several "molecular danger" sensing and signaling pathways are activated, especially the complement and the apoptosis cascade. Although possible crossroads between both systems have been proposed, little is known about the underlying molecular interactions. In this study a new interaction interface is presented for C3a and C5a generation by the pro-apoptotic factor granzyme B. In vitro incubation of the central human complement components C3 and C5 with the serine protease granzyme B resulted in a concentration-dependent production of the anaphylatoxins C3a and C5a. The so generated anaphylatoxin C5a was chemotactic active for isolated human neutrophils. In a translational approach, intracellular granzyme B concentration in leukocytes was determined early after severe tissue trauma. In comparison to healthy volunteers, multiple injured patients (less than one hour after trauma, Injury Severity Score > 18, n = 5) presented a significant increase in granzmye B levels in neutrophils and lymphocytes. Thus, tissue trauma is associated with early activation of both, the complement and apoptosis system. The present data suggest a new form of interaction between the complement and the apoptosis system on the level of granzyme B that is capable to generate C3a and C5a independently of the established complement proteases.
"The amplification cascade then culminates in the association of C5b with C6, C7 and C8, which induces the polymerisation of 10–16 C9 molecules in order to assemble a transmembrane pore called the terminal ‘membrane attack complex’ (MAC), with subsequent lysis of the targeted pathogens or abnormal host cells as a result . Importantly, components of the blood clotting and fibrinolysis pathways, as well as other cell-derived serine proteases, can also directly cleave and activate C3 and C5 proteins, and thus initiate the formation of complement end products, independent of the C3 and C5 convertases, a process that is now referred to as the extrinsic pathway[32-34]. "
[Show abstract][Hide abstract] ABSTRACT: The complement system, a major component of the innate immune system, is becoming increasingly recognised as a key participant in physiology and disease. The awareness that immunological mediators support various aspects of both normal central nervous system (CNS) function and pathology has led to a renaissance of complement research in neuroscience. Various studies have revealed particularly novel findings on the wide-ranging involvement of complement in neural development, synapse elimination and maturation of neural networks, as well as the progression of pathology in a range of chronic neurodegenerative disorders, and more recently, neurotraumatic events, where rapid disruption of neuronal homeostasis potently triggers complement activation. The purpose of this review is to summarise recent findings on complement activation and acquired brain or spinal cord injury, i.e. ischaemic-reperfusion injury or stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), highlighting the potential for complement-targeted therapeutics to alleviate the devastating consequences of these neurological conditions.
Journal of Neuroinflammation 06/2012; 9(1):137. DOI:10.1186/1742-2094-9-137 · 5.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment guidelines and management principles of polytrauma patients are largely derived from experience, supplemented by the results of few clinical studies. Their clinical impact on survival outcome is rarely scientifically evaluated. Hence, research algorithms need to be developed which enable a rapid and profound reevaluation of the current treatment strategies in polytrauma care and which provide a solid basis for the assessment of future treatment options. Such new concepts might include a more individualized approach and a better identification of operative windows for early definitive care. Since polytrauma results in a complex physiological and immunological disorder, which is additionally influenced by multiple confounding variables, it is challenging to establish such novel algorithms by clinical research only. In this regard, the well defined parameters in valid basic science models can provide a solid base for evaluating current concepts and investigating future treatment options. Here we have analyzed the contribution of basic science to well-established concepts in polytrauma care, such as the management of trauma induced coagulopathy or the damage control orthopedics concept. Many of these ideas moved from previous basic science activities to clinical studies but in many cases the direct effects of basic science on clinical trials or even clinical management strategies often remain elusive. Nevertheless, the knowledge which is created on a daily basis by basic science studies acts as an invaluable data pool, which can be accessed and combined for the clinical researcher to develop and address clinically relevant questions, providing them with a comprehensive pool of information to carefully plan and conduct their clinical trials. This may then subsequently lead to the development of new management principles for polytrauma patients.
European Journal of Trauma and Emergency Surgery 06/2011; 38(3):231-239. DOI:10.1007/s00068-011-0159-5 · 0.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In response to severe tissue trauma several danger sensing and signalling cascades are activated, including the complement and the apoptosis systems. In polytrauma patients, both the early activation of the complement cascade with an excessive generation of the potent anaphylatoxin C5a and the induction of apoptosis have been shown to modulate the post-traumatic immune response. However, little is known about a direct interaction between the complement and apoptosis systems after severe tissue trauma. Therefore the focus of the present study was to elucidate the interplay between the central complement component C5 and the pro-apoptotic aspartic protease cathepsin D. In vivo, the cathepsin D plasma concentration of multiple injured patients was markedly increased when compared to healthy volunteers. In vitro incubation of C5 with cathepsin D resulted in a concentration- and time-dependent generation of C5a, which was inhibited by the aspartate protease inhibitor pepstatin A. Immunoblotting and sequencing analysis indicated that the C5 cleavage product represents the native form of human C5a, also exhibiting chemotactic activity for human neutrophils. In conclusion, these data show for the first time that cathepsin D is increased in plasma early after severe tissue injury. Furthermore, the results provide in vitro evidence of cleavage of C5 by an aspartic protease with subsequent generation of functional C5a, which represents a new path of complement activation.
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