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      Auxiliary activation of the complement system and its importance for the pathophysiology of clinical conditions

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          Activation and regulation of the cascade systems of the blood (the complement system, the coagulation/contact activation/kallikrein system, and the fibrinolytic system) occurs via activation of zymogen molecules to specific active proteolytic enzymes. Despite the fact that the generated proteases are all present together in the blood, under physiological conditions, the activity of the generated proteases is controlled by endogenous protease inhibitors. Consequently, there is remarkable little crosstalk between the different systems in the fluid phase. This concept review article aims at identifying and describing conditions where the strict system-related control is circumvented. These include clinical settings where massive amounts of proteolytic enzymes are released from tissues, e.g., during pancreatitis or post-traumatic tissue damage, resulting in consumption of the natural substrates of the specific proteases and the available protease inhibitor. Another example of cascade system dysregulation is disseminated intravascular coagulation, with canonical activation of all cascade systems of the blood, also leading to specific substrate and protease inhibitor elimination. The present review explains basic concepts in protease biochemistry of importance to understand clinical conditions with extensive protease activation.

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          Most cited references 140

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          Pathophysiology of polytrauma.

          Immediate and early trauma deaths are determined by primary brain injuries, or significant blood loss (haemorrhagic shock), while late mortality is caused by secondary brain injuries and host defence failure. First hits (hypoxia, hypotension, organ and soft tissue injuries, fractures), as well as second hits (e.g. ischaemia/reperfusion injuries, compartment syndromes, operative interventions, infections), induce a host defence response. This is characterized by local and systemic release of pro-inflammatory cytokines, arachidonic acid metabolites, proteins of the contact phase and coagulation systems, complement factors and acute phase proteins, as well as hormonal mediators: it is defined as systemic inflammatory response syndrome (SIRS), according to clinical parameters. However, in parallel, anti-inflammatory mediators are produced (compensatory anti-inflammatory response syndrome (CARS). An imbalance of these dual immune responses seems to be responsible for organ dysfunction and increased susceptibility to infections. Endothelial cell damage, accumulation of leukocytes, disseminated intravascular coagulation (DIC) and microcirculatory disturbances lead finally to apoptosis and necrosis of parenchymal cells, with the development of multiple organ dysfunction syndrome (MODS), or multiple organ failure (MOF). Whereas most clinical trials with anti-inflammatory, anti-coagulant, or antioxidant strategies failed, the implementation of pre- and in-hospital trauma protocols and the principle of damage control procedures have reduced post-traumatic complications. However, the development of immunomonitoring will help in the selection of patients at risk of post-traumatic complications and, thereby, the choice of the most appropriate treatment protocols for severely injured patients.
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            Human plasma proteinase inhibitors.

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              Evolutionary families of peptidases.

              The available amino acid sequences of peptidases have been examined, and the enzymes have been allocated to evolutionary families. Some of the families can be grouped together in 'clans' that show signs of distant relationship, but nevertheless, it appears that there may be as many as 60 evolutionary lines of peptidases with separate origins. Some of these contain members with quite diverse peptidase activities, and yet there are some striking examples of convergence. We suggest that the classification by families could be used as an extension of the current classification by catalytic type.

                Author and article information

                +46(0)70 942 3977 , Bo.Nilsson@igp.uu.se
                Semin Immunopathol
                Semin Immunopathol
                Seminars in Immunopathology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                12 September 2017
                12 September 2017
                : 40
                : 1
                : 87-102
                [1 ]GRID grid.410712.1, Institute of Clinical and Experimental Trauma-Immunology, , University Hospital Ulm, ; 89081 Ulm, Germany
                [2 ]ISNI 0000 0004 1936 9457, GRID grid.8993.b, Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, , Uppsala University, ; SE-751 85 Uppsala, Sweden
                [3 ]ISNI 0000 0001 2174 3522, GRID grid.8148.5, Linnæus Center of Biomaterials Chemistry, , Linnæus University, ; SE-391 82 Kalmar, Sweden
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funded by: Uppsala University
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                © Springer-Verlag GmbH Germany, part of Springer Nature 2018


                complement system, proteases, protease inhibitors, trauma


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