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

Abstract

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.

Local complement activation is associated with primary graft dysfunction after lung transplantation

“…Given that ECLS in itself is known to increase complement activation products ( 22 , 23 ), we analyzed their levels in subjects (from both cohorts) who received ECLS compared with those who did not. In the Penn cohort, the median sC4d levels were comparable (median, interquartile range [IQR, ng/mL]: 365, 201.2–624.8 in those who received ECLS, compared with 241.2: 111–590.1 in those who did not, P = 0.3) as were the median sC5b-9 levels (median, IQR, ng/mL: 499, 114–1027 in those who received ECLS, compared with 294, 60–960 in those who did not, P = 0.5).…”

Decrease in alpha-1 antiproteinase antitrypsin is observed in primary Sjogren’s syndrome condition

“…DNA methylation has been long proposed that is responsible for the stable maintenance of gene expression patterns [41,46]. Specifically, DNA methylation establishes a silent chromatin state by collaborating with proteins that modify nucleosomes [43]. Importantly, our results showed that DNA methylation was altered in serpinina1 gene encoding for alpha-1 antiproteinase antitrypsin.…”

“…Alpha-1 antiproteinase antitrypsin is widely distributed in body fluids, and its concentration is especially increased in acute inflammatory responses. Importantly, in intestinal epithelia, it is suggested that alpha-1 antiproteinase antitrypsin may be an important self-protective mechanism against various proteases such as the pancreatic proteolytic enzymes as well as and collagenase released from leucocytes [43]. As salivary and pancreatic glands secrete similar proteases and have similar structure involving acini and the ductal system, it could be suggested that alpha 1 antiproteinase antitrypsin could be part of the self-defence mechanism in salivary glands as well.…”

Innate networking: Thrombotic microangiopathy, the activation of coagulation and complement in the sensitized kidney transplant recipient

“…The primary ignition mechanism—whether complement or coagulation activation—at the site of antibody binding is not clear; however, once activated, complement and coagulation then engage in a complex set of interactions(54). TMA may be considered to be a consequence of this thromboinflammatory fire, and its severity potentially related to the combination of donor and recipient characteristics to both propel or inhibit the ensuing effects.…”