Hepatic Plasma Proteins. Mechanisms of Function and Regulation

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Contents

  1. Navigation menu
  2. Blood function and composition
  3. Metabolic Functions of the Liver
  4. Liver immunology and its role in inflammation and homeostasis
  5. References

Kupffer cell-monocyte communication is essential for initiating murine liver progenitor cell-mediated liver regeneration. Hepatology ; 62 : — Toll-like receptor-induced innate immune responses in non-parenchymal liver cells are cell type-specific. Immunology ; : — Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice.

Hepatology ; 57 : — Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol ; 10 : — Immunosuppressive functions of hepatic myeloid-derived suppressor cells of normal mice and in a murine model of chronic hepatitis B virus. Clin Exp Immunol ; : — Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med ; 21 : — Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol ; 9 : — Bacteria in the bloodstream are trapped in the liver and killed by immigrating neutrophils.

Distinct subpopulations of gamma delta T cells are present in normal and tumor-bearing human liver. Clin Immunol ; : 56— NKT cells from normal and tumor-bearing human livers are phenotypically and functionally distinct from murine NKT cells. Blood ; : — Liver: an organ with predominant innate immunity. Hepatology ; 47 : — Natural killer activity of human liver-derived lymphocytes in various liver diseases. Hepatology ; 14 : — Liver grafts contain a unique subset of natural killer cells that are transferred into the recipient after liver transplantation. Liver Transpl ; 16 : — Nat Immunol ; 16 : 85— Characterization, quantification, and localization of passenger T lymphocytes and NK cells in human liver before transplantation.

Transpl Int ; 8 : — The liver eliminates T cells undergoing antigen-triggered apoptosis in vivo. Immunity ; 1 : — Molecular characterization of B cell clonal expansions in the liver of chronically hepatitis C virus-infected patients. J Immunol ; : 21— J Hepatol ; 38 : — Differential expression of lymphoid and myeloid markers on differentiating hematopoietic stem cells in normal and tumor-bearing adult human liver. In vitro evidence for the presence of hematopoietic stem cells in the adult human liver.

Hepatology ; 29 : — Presence of hematopoietic stem cells in the adult liver.

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Nat Med ; 2 : — Characterizing the lymphopoietic kinetics and features of hematopoietic progenitors contained in the adult murine liver in vivo. PLoS One ; 8 : e Jenne CN, Kubes P. Immune surveillance by the liver. Nat Immunol ; 14 : — Seki E, Brenner D. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology ; 48 : — Liver-primed memory T cells generated under noninflammatory conditions provide anti-infectious immunity. Cell Rep ; 3 : — Lab Invest ; 87 : — Ex vivo analysis of resident hepatic pro-inflammatory CD1d-reactive T cells and hepatocyte surface CD1d expression in hepatitis C.

J Viral Hepat ; 20 : — Changes in hepatic immunoregulatory cytokines in patients with metastatic colorectal carcinoma: implications for hepatic anti-tumour immunity. Cytokine ; 35 : — Clin Exp Immunol ; : 94— The activation state of human intrahepatic lymphocytes. Nature ; : — Cholesterol, inflammation and innate immunity. Nat Rev Immunol ; 15 : — Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology ; 52 : — Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells.

Hepatology ; 54 : — Filipe A, McLauchlan J.

Blood function and composition

Hepatitis C virus and lipid droplets: finding a niche. Trends Mol Med ; 21 : 34— Hepatocyte metabolic signalling pathways and regulation of hepatitis B virus expression. Liver Int ; 31 : — Immunometabolism governs dendritic cell and macrophage function. J Exp Med ; : 15— Hypoxia inducible factors in liver disease and hepatocellular carcinoma: current understanding and future directions.

J Hepatol ; 61 : — Living in the liver: hepatic infections. Nat Rev Immunol ; 12 : — Immune tolerance in liver disease. Hepatology ; 60 : — Induction of immunological tolerance by porcine liver allografts. Lerut J, Sanchez-Fueyo A.

Metabolic Functions of the Liver

An appraisal of tolerance in liver transplantation. Am J Transplant ; 6 : — Comparison of renal allograft outcomes in combined liver-kidney transplantation versus subsequent kidney transplantation in liver transplant recipients: analysis of UNOS database. Transplantation ; 82 : — J Hepatol ; 22 : — Kupffer cell prostaglandin-E2 production is amplified during hepatic regeneration. J Exp Med ; : 19— IL down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules.

Liver inflammation abrogates immunological tolerance induced by Kupffer cells. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin.

Liver immunology and its role in inflammation and homeostasis

Human liver dendritic cells promote T cell hyporesponsiveness. Interleukin secretion differentiates dendritic cells from human liver and skin. Am J Pathol ; : — Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion. Hepatology ; 45 : — Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells.

J Hepatol ; 49 : — Hepatic stellate cells function as regulatory bystanders. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. J Clin Invest ; : — Bidirectional transendothelial migration of monocytes across hepatic sinusoidal endothelium shapes monocyte differentiation and regulates the balance between immunity and tolerance in liver. Hepatology ; 63 : — Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function.

J Exp Med ; : — Moshage H. Cytokines and the hepatic acute phase response. J Pathol ; : — Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med ; : — Hepatocytes: a key cell type for innate immunity. Cell Mol Immunol e-pub ahead of print 21 December ; doi Novel mechanism of C-reactive protein for enhancing mouse liver innate immunity.

References

Hepatology ; 49 : — Interaction of the angiostatin kringle domain K4 with integrin receptor Mac-1 down-regulates transcriptional factor NF-kB, whereby attenuates NF-kB-related expression of neutrophil-derived tissue factor Chavakis et al. The kringle domain K5 has been found to restrict the neutrophil chemotactic activity Perri et al. Obviously, impaired fibrinolysis looses this anti-inflammatory action.

The formation of fibrin deposition is a direct consequence of increased thrombin production. A pro-inflammatory action of thrombin is realized by two interdependent ways: i by direct promotion of hypercoagulation accompanied by the pro-inflammatory effects described above; ii by stimulation of vascular and blood-borne cells and their further involvement in the inflammatory response.

Being a powerful signal molecule, thrombin interacts specifically with PAR-1, PAR-2, or PAR-3 and activates the signaling pathways in endothelial cells, platelets, mononuclear cells, and fibroblasts. Thrombin is a key protease-agonist, which controls the platelet involvement in the formation of thrombi by stimulation of platelet aggregation, granule secretion, and additional recruitment in the inflammatory process.

In an in vitro endothelial-cell-monolayer model, thrombin was shown to affect PARmediated signalling in a concentration-dependent manner. When activated protein C occupies PAR-1, thrombin can realise disruptive effects through activation of PAR-4; this effect requires a higher concentration of thrombin Bae et al.

Upon binding to thrombomodulin, thrombin inverts its coagulant and inflammatory functions into anticoagulant and anti-inflammatory ones. TM competes effectively with procoagulant substrates fibrinogen, V, VIII, and PARs for the same exosite-1 of thrombin but inhibits activation of the coagulation cascades. APC, in addition to its anticoagulant function, acts as a pleiotropic agent with anti-inflammatory, profibrinolytic, and cytoprotective effects.

After its activation, APC dissociates from the thrombin-TM complex and comes into plasma, where it acts as anticoagulant and profibrinolytic agent, or binds to cell membrane EPCR and regulates intracellular inflammatory pathways. APC is now considered as a signaling molecule that possesses an ability to selectively regulate cytokine production during the inflammatory response. At the same time, APC does not affect neutrophil respiratory bursts, phagocytic activity, and expression of monocyte adhesion molecules Stephenson et al.

In fact, APC does not seem to suppress the innate defensive mechanisms. As a consequence, the action of inflammatory cytokines and oxidative agents sharply reduce the efficiency of TM in PC activation and promote pro-inflammatory efficiency of thrombin. Prolonged activation of inflammatory cells promotes the production of large amounts of inflammatory mediators by downstream-cells affecting not only via an autocrine mechanism, but also in a paracrine manner.

The duration and amplitude of a cytokine-mediated systemic inflammation signal, upon reaching the liver, determine the probable pattern of HSPPs additionally produced during the acute inflammatory response. The HSPP level is known to be up-regulated by various pro-inflammatory cytokines similarly to other acute phase proteins, i. Activated protein C, that breaks thrombus generation through regulation of both coagulation and fibrinolysis apparently is not additionally expressed during the acute-host response.

There is some evidence that cytokine-dependent down-regulation of protein C synthesis occurs Yamamoto et al. In case, lowering of the plasma protein C level is observed in some diseases, which are attended with inflammation Danese et al. Another fact, which is a stronger proof, is that cytokines decrease the capacity of the endothelium to activate protein C precursor in activated protein C because they are able to down-regulate the amount of endothelial membrane-bound thrombomodulin Esmon, Alternatively, some authors hypothesize that plasma pool of precursor PC can rapidly decline because of enhanced APC consumption after counteracting with plasma inhibitors Danese et al.

It is obvious, that in pathological states, the relative proportions of HSPPs significantly vary depending on either driving or suppression of their production by inflammation. Changes in the plasma protein ratio can lead to disproportion between procoagulant and anticoagulant patterns under different pathophysiological conditions. Activated proteases are rapidly cleared from circulation and this determines only a crude assessment of their production.

Unlike CRP type-1 acute phase protein up-regulated by synergistic action of IL-6 and IL-1beta, most hemostatic proteases type-2 acute phase proteins require IL-6 alone for maximal induction of their synthesis Trautwein et al. IL-6 is a key effector that effectively promotes the coagulation pathway, not only by up-regulation of expression ofsome procoagulant factors such as TF, fibrinogen, and factor VIII but also by down-regulation of synthesis of some anticoagulants such as antithrombin and protein S Hou et al. Under transcriptional control by the cytokine IL-6, their circulating levels increase via cooperative up-regulation of the corresponding gene promoter activity.

Two macroglobulin promoters, e. ILdependent regulatory machine is a good example for demonstration how the overall expression of a single plasma protease gene can be controlled by the inflammatory signal that begins in the extracellular milieu and terminates at separate sites on the promoter region of the gene. The transcriptional and post-transcriptional regulation of the fibrinolytic system by inflammatory signals was recently reviewed in detail Medcalf, Simultaneously acting cytokines can exert additive, inhibitory, or synergistic effects on the HSPP production.

These cytokines are able to control gene expression independently or in combination with IL-6 Yamamoto et al. Various environmental factors and individual features of the patient including age, body mass index, levels of plasma triglycerides and atherosclerotic transformation of the vessel wall influence the cytokine-regulated levels of HSPP.

These additional influences modify local or systemic inflammatory responses depending on the host phenotype Lowry, Marked alterations in the plasma HSPP levelsfollowing an acute-phase stimulus are determined not only by transcriptional regulation but also by post-transcriptional and post-translational mechanisms. Despite the HSPPs are largely regulated by transcriptional control, they still strongly require the post-transcriptional regulation including co-translational and post-translational modification to confer their optimal functionality.

They should form the disulfide bonds to get native conformation as well as should be carboxylated, hydroxylated, phosphorylated, sulfated or glycosylated to achieve a specific function. In particular, the main coagulation factors II, VII, IX, X and protein C all are the vitamin K-dependent proteins are processed through further post-translational modification to become biologically active.

Before secretion, they undergo oxidative maturation that leads to binding of the appropriate pairs of cystein residues. The disulfide bonds are formed in the rough endoplasmic reticulum, since this process requires an oxidative environment. These functional groups are well-known as playing an important role in protein folding by stabilizing the tertiary and quaternary structure.

Furthermore, disulfide bonds can be responsible for intra- and intermolecular reorganization or even proteins aggregation. In addition to carboxylation and formation of disulfide bonds, a series of post-translational modifications occurs to attach N- or O-linked glycans to secreted proteins Table 2. Several N-linked glycosylation sites are well-known to be an attributive feature of HSPPs, which are glycoproteins. N-glycosylation has been recently discovered to be a crucial event in the regulation of the glycoprotein structure and function.

Via promotion or inhibition of intra- and intermolecular binding, glycans can regulate protein folding, cell adhesion and aggregation.

Glycosylation can also modulate the activity of plasma membrane receptors at the surface of the vascular endothelial cells, platelets, and leukocytes influencing in such a way intracellular signal transduction systems, which are responsible for homeostasis in circulation Skropeta, There are available data, suggesting that glycosylation is higher in proteins synthesized during the acute-phase responses. Human hemostatic proteins, coagulation factor IX and protein C, which both are the vitamin K-dependent proteins synthesized and secreted by hepatocytes, vary extensively in their glycosylation levels.

Coagulant factor IX has two N-glycosylation sites and is characterised by significantly more heterogeneity of N-glycan structures than anticoagulant protein C. Desialylation of PC and factor IX was shown to result in a two-threefold increase in the anticoagulant activity of protein C and in a loss of the coagulant activity of factor IX Gil et al. Alterations in the glycosylation pattern have been suggested to be specific in certain diseases An et al.

Nevertheless, it remains unclear whether inflammation signals control processing of coagulation proenzymes or not. Well-documentedinflammation impact on glycosylation of classic APPs allows researchers to suggest such a control. Experiments with glycoprotein deglycosylation showed that the removal of distinct glycan or total deglycosylation usually leads to remarkable reduction of the protein binding and enzymatic activity. However, at least two examples have been recently elucidated Skropeta, , wherethe enzyme activity increased upon deglycosylation of HSPPs.

In particular, removal of the two of four existing glycosylation sites in the human protein C molecule resulted in a two—threefold increase in the anticoagulant activity of APC due to an enhanced affinity of thrombin, the natural activator of PC. Interestingly, two fibrinolytic proteins, tPA and its specific substrate, Pg, interact more or less effectively depending on the peculiarities of attached glycans.

Plasminogen also exists in two glycoforms; type 1 has both N- and O-linked glycans, while type 2 has only an O-linked glycan. The combination of type II tPA with type 2 plasminogen induced a twofold more intense conversion of plasminogen to plasmin compared to interaction of more heavily glycosylated type I tPA with type 1 Pg. Changes in the microheterogenity and unique structure of glycans are now known to be ensued from folding of the glycoprotein early form during post-translation processing in the secretory pathway. Glycosylation is an enzymatic process regulated by distinct glycosyltransferases in the endoplasmic reticulum, which modulate unfolded glycoproteins prior to trafficking to the Golgi apparatus.

Unexpectedly, one experiment demonstrated that an alterated O-glycosylation pathway affects the N-glycosylated coagulation proteins in NAcTdeficient mice. In particular, the deficiency of a polypeptide GalNAc transferase ppGalNAcT contributed to shifting of O-glycan repertoire by other glycosyltransferases, as well as affected blood coagulation resulting in prolongation of the activated partial thromboplastin time, APTT, and bleeding time. Additionally, alterations in the degree of branching and of levels of sialylation, fucosylation, and mannosylation can dramatically change the glycoprotein turnover.

Blood Plasma Proteins (Types & Functions) - Albumin, Globulin, Fibrinogen - Bhushan Science

Although our information about glycan-mediated pathophysiological mechanisms is still very limited, their impact on the enzyme secretion, stability, and activity and on molecular trafficking and clearance allows researchers to suggest that glycosylation plays a special role in the phenotypical variability of hemostatic and inflammatory proteins in circulation.

Apparently, the acute-phase response generates a characteristic protein profile by alteration of synthesis, secretion, and clearance of protein reflected in their final concentrations. The actual level of plasma proteins under pathological conditions is also determined by changes in their stability, post-secretion proteolysis, functional activity, and accessibility for interaction. Marked alterations in the plasma protein levels are probably paralleled by modifications of their disulphide bonds.

The role of disulfides in regulation of the functional activity of HSPPs was subjected to intense research. A direct influence of inflammatory conditions on the structure or functions of plasma proteins is an intriguing question. Recently, we demonstrated that the concentration of DTNBA-active polypeptides produced in the course of the reaction of plasma and serum proteins with 5,5'-dithiobis 2-nitrobenzoic acid , was noticeable increased in patients with stable angina pectoris compared to healthy subjects.

In vitro blood coagulation was accompanied by a six-fold drop of the SS-containing components and 2,5-fold elevation of SH-containing polypeptides in patients, whereas mild changes were documented in control subjects. In addition, positive correlation of the plasma level of SH-containing polypeptides with concentrations of CRP and low-density lipoproteins was observed. Based on our findings, we can speculate that hypercoagulation in sclerotized vessels can enhance inflammation by promoting the development of oxidative stress.

Activated, and thereby, partially degraded HSPPs, after their more open conformation has been obtained, can exhibit earlier buried disulphide bridges, which can serve as pro-oxidant derivates during thiol-disulfide exchange Patalakh et al. It is interesting that tPA converted Pg into Pm more effectively on the surface of non-clottable partially reduced Fg rather than on untreated Fg Procyk et al. These data confirm the statement on the ability of disrupted disulfide bonds to modulate the functional activity of major HSPPs via conformational changes.

Newly obtained data suggest that particular SS-bonds are involved in regulation of HSPP functions via reduction or oxidation. We hypothesized that at least one common sensitive element in the protein structures of the plasma pattern might facilitate the adequate integrated response of the hemostasis system to an inflammatory impact. Redox-mediated signals, which are generated in plasma during inflammation, might control hemostasis pathways via such a sensitive element in protein structures.

And vice versa , exposed disulfide bonds through one-electron reduction can generate active intermediates transmitting pro-inflammatory or pro-oxidant extracellular signals to cell receptors and, thus, can induce production of more APPs and HSPPs, especially via the MAPK-mediated pathway Forman et al. For example, vascular endothelial cells represent an almost exclusive source of such a fibrinolytic component, as tPA produced by the endothelium in both physiological and pathophysiological states.

Another fibrinolytic component, PAI-1, has additional sites of synthesis, such as vascular endothelial cells, leukocytes, adipocytes, and platelets, but this occurs predominantly after their activation at inflammatory foci. Synthesis of protein C, which mainly occurs in the liver, was also identified in the kidneys, lungs, brain, and male reproductive tissue.

Therefore, a systemic or local inflammatory signal is able to recruit more than one cells source of HSPP. Aggregated platelets, activated leukocytes, and cells presented in the vascular wall release cytokines thereby altering local HSPP secretion. Impairment of total HSPP production because of disorders of the liver functions during systemic inflammation can be accompanied by increased protein consumption or by a decrease in the hepatic clearance for individual proteins.

In contrast, increased consumption is the main reason for suppression of the plasma level of such enzymatically active proteases, as APC, thrombin, Pm, and tPA. In turn, depletion of the pool of proteases results in ineffective consumption and clearance of their substrates.


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Respectively, the half-life time of involved factors is shortened or prolonged. It is obvious that the plasma levels of naturally active e. The above-mentioned regulatory mechanisms can affect significantly the HSPP kinetic profile with either a rise or a decline of their plasma levels. According to the study of Jern and colleagues Jern et al. These authors also suggested that the local endothelial release rate, rather than the systemic plasma level of t-PA, determines the plasma fibrinolytic potential destined to clot digestion in situ. The assay-measured plasma concentration of tPA insufficiently displays this local discrete increment.

Such a pro-inflammatory milieu facilitates the recruitment of additional platelet and inflammatory cells encouraging generate and amplify inflammation signals. Tissue plasminogen activator is secreted from the intracellular storage compartment after stimulation of PARs on the surface of endothelial cells. There are two pathways involved in tPA secretion from endothelial cells, constitutive and regulated secretion. Rates of the constitutive tPA release is differentiated markedly by the genotype; however, genetic variation most likely is not reflected in the circulating plasma t-PA levels.

Shear stress can modulate the cytokine effects by enhancing t-PA secretion and attenuating the PAI-1 release Kawai et al. Probably, the recovery of the tPA plasma pool in proportion to excessive consumption by PAI-1 is rapid but transient, since the augmented local tPA secretion is limited by the rate of its synthesis.

Because of the fact that the tPA-PAI-1 complex is usually cleared at a lower rate than free tPA, this can lead to the appearance of a disproportion between the antigen and activity values.

Nevertheless, it was demonstrated that vitronectin, a pro-inflammatory protein, enhances the reactivity of PAI-1 with APC about times Rezaie, We believe that these changes are a manifestation of reduction of the blood fibrinolytic potential. Using a regression analytical procedure, we simulated a potential profibrinolytic effect of endogenous PC as association of its plasma level with PAI-1 attenuation. Some evidence do exist that the plasma levels of PC are associated with the systemic inflammatory response to trauma, infection, resuscitated cardiac arrest, non-stable angina pectoris , etc.

It seems that most cardio-vascular diseases during their severe inflammation stage are complicated by a transient PC deficiency. The nature of this failure is not completely clear. We suppose that the PAI-1 inhibitory activity is involved into PC plasma pool depletion during acute inflammation. It seems that phenotypic PC alterations reflect different aspects of the APC turnover, up-regulated by inflammation stimuli. It seems that conversion of PC into APC, forced by the increasing thrombin production, can lead to rapid consumption of PC since APC undergoes action of the abundant amount of serine protease inhibitors, accumulated in the blood during the acute-phase response.

Activated platelets additionally produce PAI-1 during coagulation and thrombus formation. Particularly due to vitronectin activation PAI-1 should contribute significantly to the acquired protein C deficiency. As a result, further generation of activated protein C will be disturbed. Alternatively, some authors hypothesize that plasma pool of precursor PC can rapidly decline because of enhanced APC consumption after counteracting with plasma inhibitors Danese et al.

It is obvious, that in pathological states, the relative proportions of HSPPs significantly vary depending on either driving or suppression of their production by inflammation. Changes in the plasma protein ratio can lead to disproportion between procoagulant and anticoagulant patterns under different pathophysiological conditions. Activated proteases are rapidly cleared from circulation and this determines only a crude assessment of their production.

Unlike CRP type-1 acute phase protein up-regulated by synergistic action of IL-6 and IL-1beta, most hemostatic proteases type-2 acute phase proteins require IL-6 alone for maximal induction of their synthesis Trautwein et al. IL-6 is a key effector that effectively promotes the coagulation pathway, not only by up-regulation of expression ofsome procoagulant factors such as TF, fibrinogen, and factor VIII but also by down-regulation of synthesis of some anticoagulants such as antithrombin and protein S Hou et al.

Under transcriptional control by the cytokine IL-6, their circulating levels increase via cooperative up-regulation of the corresponding gene promoter activity. Two macroglobulin promoters, e. ILdependent regulatory machine is a good example for demonstration how the overall expression of a single plasma protease gene can be controlled by the inflammatory signal that begins in the extracellular milieu and terminates at separate sites on the promoter region of the gene.

The transcriptional and post-transcriptional regulation of the fibrinolytic system by inflammatory signals was recently reviewed in detail Medcalf, Simultaneously acting cytokines can exert additive, inhibitory, or synergistic effects on the HSPP production. These cytokines are able to control gene expression independently or in combination with IL-6 Yamamoto et al. Various environmental factors and individual features of the patient including age, body mass index, levels of plasma triglycerides and atherosclerotic transformation of the vessel wall influence the cytokine-regulated levels of HSPP.

These additional influences modify local or systemic inflammatory responses depending on the host phenotype Lowry, Marked alterations in the plasma HSPP levelsfollowing an acute-phase stimulus are determined not only by transcriptional regulation but also by post-transcriptional and post-translational mechanisms. Despite the HSPPs are largely regulated by transcriptional control, they still strongly require the post-transcriptional regulation including co-translational and post-translational modification to confer their optimal functionality.

They should form the disulfide bonds to get native conformation as well as should be carboxylated, hydroxylated, phosphorylated, sulfated or glycosylated to achieve a specific function. In particular, the main coagulation factors II, VII, IX, X and protein C all are the vitamin K-dependent proteins are processed through further post-translational modification to become biologically active.

Before secretion, they undergo oxidative maturation that leads to binding of the appropriate pairs of cystein residues. The disulfide bonds are formed in the rough endoplasmic reticulum, since this process requires an oxidative environment. These functional groups are well-known as playing an important role in protein folding by stabilizing the tertiary and quaternary structure. Furthermore, disulfide bonds can be responsible for intra- and intermolecular reorganization or even proteins aggregation.

In addition to carboxylation and formation of disulfide bonds, a series of post-translational modifications occurs to attach N- or O-linked glycans to secreted proteins Table 2. Several N-linked glycosylation sites are well-known to be an attributive feature of HSPPs, which are glycoproteins. N-glycosylation has been recently discovered to be a crucial event in the regulation of the glycoprotein structure and function.

Via promotion or inhibition of intra- and intermolecular binding, glycans can regulate protein folding, cell adhesion and aggregation. Glycosylation can also modulate the activity of plasma membrane receptors at the surface of the vascular endothelial cells, platelets, and leukocytes influencing in such a way intracellular signal transduction systems, which are responsible for homeostasis in circulation Skropeta, There are available data, suggesting that glycosylation is higher in proteins synthesized during the acute-phase responses.

Human hemostatic proteins, coagulation factor IX and protein C, which both are the vitamin K-dependent proteins synthesized and secreted by hepatocytes, vary extensively in their glycosylation levels. Coagulant factor IX has two N-glycosylation sites and is characterised by significantly more heterogeneity of N-glycan structures than anticoagulant protein C. Desialylation of PC and factor IX was shown to result in a two-threefold increase in the anticoagulant activity of protein C and in a loss of the coagulant activity of factor IX Gil et al.

Alterations in the glycosylation pattern have been suggested to be specific in certain diseases An et al. Nevertheless, it remains unclear whether inflammation signals control processing of coagulation proenzymes or not. Well-documentedinflammation impact on glycosylation of classic APPs allows researchers to suggest such a control.

Experiments with glycoprotein deglycosylation showed that the removal of distinct glycan or total deglycosylation usually leads to remarkable reduction of the protein binding and enzymatic activity. However, at least two examples have been recently elucidated Skropeta, , wherethe enzyme activity increased upon deglycosylation of HSPPs. In particular, removal of the two of four existing glycosylation sites in the human protein C molecule resulted in a two—threefold increase in the anticoagulant activity of APC due to an enhanced affinity of thrombin, the natural activator of PC.

Interestingly, two fibrinolytic proteins, tPA and its specific substrate, Pg, interact more or less effectively depending on the peculiarities of attached glycans. Plasminogen also exists in two glycoforms; type 1 has both N- and O-linked glycans, while type 2 has only an O-linked glycan. The combination of type II tPA with type 2 plasminogen induced a twofold more intense conversion of plasminogen to plasmin compared to interaction of more heavily glycosylated type I tPA with type 1 Pg.

Changes in the microheterogenity and unique structure of glycans are now known to be ensued from folding of the glycoprotein early form during post-translation processing in the secretory pathway. Glycosylation is an enzymatic process regulated by distinct glycosyltransferases in the endoplasmic reticulum, which modulate unfolded glycoproteins prior to trafficking to the Golgi apparatus.

Unexpectedly, one experiment demonstrated that an alterated O-glycosylation pathway affects the N-glycosylated coagulation proteins in NAcTdeficient mice. In particular, the deficiency of a polypeptide GalNAc transferase ppGalNAcT contributed to shifting of O-glycan repertoire by other glycosyltransferases, as well as affected blood coagulation resulting in prolongation of the activated partial thromboplastin time, APTT, and bleeding time.

Additionally, alterations in the degree of branching and of levels of sialylation, fucosylation, and mannosylation can dramatically change the glycoprotein turnover. Although our information about glycan-mediated pathophysiological mechanisms is still very limited, their impact on the enzyme secretion, stability, and activity and on molecular trafficking and clearance allows researchers to suggest that glycosylation plays a special role in the phenotypical variability of hemostatic and inflammatory proteins in circulation.

Apparently, the acute-phase response generates a characteristic protein profile by alteration of synthesis, secretion, and clearance of protein reflected in their final concentrations. The actual level of plasma proteins under pathological conditions is also determined by changes in their stability, post-secretion proteolysis, functional activity, and accessibility for interaction.

Marked alterations in the plasma protein levels are probably paralleled by modifications of their disulphide bonds. The role of disulfides in regulation of the functional activity of HSPPs was subjected to intense research. A direct influence of inflammatory conditions on the structure or functions of plasma proteins is an intriguing question.

Recently, we demonstrated that the concentration of DTNBA-active polypeptides produced in the course of the reaction of plasma and serum proteins with 5,5'-dithiobis 2-nitrobenzoic acid , was noticeable increased in patients with stable angina pectoris compared to healthy subjects. In vitro blood coagulation was accompanied by a six-fold drop of the SS-containing components and 2,5-fold elevation of SH-containing polypeptides in patients, whereas mild changes were documented in control subjects. In addition, positive correlation of the plasma level of SH-containing polypeptides with concentrations of CRP and low-density lipoproteins was observed.

Based on our findings, we can speculate that hypercoagulation in sclerotized vessels can enhance inflammation by promoting the development of oxidative stress. Activated, and thereby, partially degraded HSPPs, after their more open conformation has been obtained, can exhibit earlier buried disulphide bridges, which can serve as pro-oxidant derivates during thiol-disulfide exchange Patalakh et al.

It is interesting that tPA converted Pg into Pm more effectively on the surface of non-clottable partially reduced Fg rather than on untreated Fg Procyk et al. These data confirm the statement on the ability of disrupted disulfide bonds to modulate the functional activity of major HSPPs via conformational changes. Newly obtained data suggest that particular SS-bonds are involved in regulation of HSPP functions via reduction or oxidation. We hypothesized that at least one common sensitive element in the protein structures of the plasma pattern might facilitate the adequate integrated response of the hemostasis system to an inflammatory impact.

Redox-mediated signals, which are generated in plasma during inflammation, might control hemostasis pathways via such a sensitive element in protein structures. And vice versa , exposed disulfide bonds through one-electron reduction can generate active intermediates transmitting pro-inflammatory or pro-oxidant extracellular signals to cell receptors and, thus, can induce production of more APPs and HSPPs, especially via the MAPK-mediated pathway Forman et al. For example, vascular endothelial cells represent an almost exclusive source of such a fibrinolytic component, as tPA produced by the endothelium in both physiological and pathophysiological states.

Another fibrinolytic component, PAI-1, has additional sites of synthesis, such as vascular endothelial cells, leukocytes, adipocytes, and platelets, but this occurs predominantly after their activation at inflammatory foci. Synthesis of protein C, which mainly occurs in the liver, was also identified in the kidneys, lungs, brain, and male reproductive tissue. Therefore, a systemic or local inflammatory signal is able to recruit more than one cells source of HSPP. Aggregated platelets, activated leukocytes, and cells presented in the vascular wall release cytokines thereby altering local HSPP secretion.

Impairment of total HSPP production because of disorders of the liver functions during systemic inflammation can be accompanied by increased protein consumption or by a decrease in the hepatic clearance for individual proteins. In contrast, increased consumption is the main reason for suppression of the plasma level of such enzymatically active proteases, as APC, thrombin, Pm, and tPA. In turn, depletion of the pool of proteases results in ineffective consumption and clearance of their substrates. Respectively, the half-life time of involved factors is shortened or prolonged. It is obvious that the plasma levels of naturally active e.

The above-mentioned regulatory mechanisms can affect significantly the HSPP kinetic profile with either a rise or a decline of their plasma levels. According to the study of Jern and colleagues Jern et al. These authors also suggested that the local endothelial release rate, rather than the systemic plasma level of t-PA, determines the plasma fibrinolytic potential destined to clot digestion in situ. The assay-measured plasma concentration of tPA insufficiently displays this local discrete increment.

Such a pro-inflammatory milieu facilitates the recruitment of additional platelet and inflammatory cells encouraging generate and amplify inflammation signals. Tissue plasminogen activator is secreted from the intracellular storage compartment after stimulation of PARs on the surface of endothelial cells. There are two pathways involved in tPA secretion from endothelial cells, constitutive and regulated secretion. Rates of the constitutive tPA release is differentiated markedly by the genotype; however, genetic variation most likely is not reflected in the circulating plasma t-PA levels.

Shear stress can modulate the cytokine effects by enhancing t-PA secretion and attenuating the PAI-1 release Kawai et al. Probably, the recovery of the tPA plasma pool in proportion to excessive consumption by PAI-1 is rapid but transient, since the augmented local tPA secretion is limited by the rate of its synthesis. Because of the fact that the tPA-PAI-1 complex is usually cleared at a lower rate than free tPA, this can lead to the appearance of a disproportion between the antigen and activity values. Nevertheless, it was demonstrated that vitronectin, a pro-inflammatory protein, enhances the reactivity of PAI-1 with APC about times Rezaie, We believe that these changes are a manifestation of reduction of the blood fibrinolytic potential.

Using a regression analytical procedure, we simulated a potential profibrinolytic effect of endogenous PC as association of its plasma level with PAI-1 attenuation. Some evidence do exist that the plasma levels of PC are associated with the systemic inflammatory response to trauma, infection, resuscitated cardiac arrest, non-stable angina pectoris , etc. It seems that most cardio-vascular diseases during their severe inflammation stage are complicated by a transient PC deficiency.

The nature of this failure is not completely clear. We suppose that the PAI-1 inhibitory activity is involved into PC plasma pool depletion during acute inflammation. It seems that phenotypic PC alterations reflect different aspects of the APC turnover, up-regulated by inflammation stimuli. It seems that conversion of PC into APC, forced by the increasing thrombin production, can lead to rapid consumption of PC since APC undergoes action of the abundant amount of serine protease inhibitors, accumulated in the blood during the acute-phase response.

Activated platelets additionally produce PAI-1 during coagulation and thrombus formation. Particularly due to vitronectin activation PAI-1 should contribute significantly to the acquired protein C deficiency. As a result, further generation of activated protein C will be disturbed. As a result APC loses its crucial role in the regulation of hemostasis and inflammation.

While coagulation and inflammation are escalated, anticoagulant and fibrinolytic blood potentials are dropped. The described progression of events might provoke inflammatory and thrombogenic diseases in a manner we illustrate in figure 3. Recent advances in our understanding of the nature of critical factors, linking hypercoagulation with both acute and chronic inflammation are rather promising. Nevertheless, we only can propose some speculations predicting the balance disruption between procoagulant and anticoagulant components under conditions of abnormal hemostasis, as well as consequences of their ratio abnormality on inflammation duration.

A transient deficiency or acute inactivation of common hemostatic soluble plasma proteins, affecting hemostasis and inflammation by a mutual regulatory mechanism, was suggested as a key pathogenic factor of such life-threatening complications. Post-translational HSPPs modifications reviewed here could be considered as crucial phenomenon impacted by the inflammatory process.

Apparently, inflammation-associated variations in the structure and function of hemostatic proteins can influence their catalytic efficiency and measurable plasma levels. These changes should be taken into account in indication of pathological hemostasis. The recent knowledge on regulatory crosstalk between hemostatic system components and the inflammatory system allows discovering new therapeutic targets to be developed. This new approach could not only change the traditional paradigm of clotting factor substitution therapy, but also anti-inflammatory therapies. Activated protein C is expected to be an attractive therapeutic target with prominent anticoagulant, profibrinolytic, and anti-inflammatory properties, which can simultaneously regulate both inflammation and coagulation.

Nevertheless, the results of several clinical trials with recombinant APC or modified rAPC were found to be rather disappointing. Indeed, the peculiarities of the protein structure, attributed to regulatory components with pleiotropic action such as APC, may play a pivotal role in providing clinical benefit of designed protein variants.

To understand and to reconstruct perturbed functions of this machinery should be a prominent goal for both basic and clinical research studies. The author is thankful to Professor Stanislaw A. Kudinov, Dept. The author would like also thank Professor Francisco Veas for advice and for critically reading the manuscript.

Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Help us write another book on this subject and reach those readers. Login to your personal dashboard for more detailed statistics on your publications. Edited by Francisco Veas. Shannon Orr, Linda H.