Reduced Mannose-Binding Lectin-Associated Serine Protease (MASP)-1 is Associated with Disturbed Coagulation in Septic Shock

2019 ◽  
Vol 119 (06) ◽  
pp. 952-961 ◽  
Author(s):  
Julie Brogaard Larsen ◽  
Mathies Appel Laursen ◽  
Christine Lodberg Hvas ◽  
Kim Michael Larsen ◽  
Steffen Thiel ◽  
...  
Keyword(s):  
Septic Shock ◽  
Complement System ◽  
Sofa Score ◽  
Thrombin Generation ◽  
Mannose Binding Lectin ◽  
Lectin Pathway ◽  
Complement Factor ◽  
Mannose Binding ◽  
The Complement System ◽  
Binding Lectin

Background Activation of the complement system is part of the dysregulated immune response in sepsis. The mannose-binding lectin-associated serine proteases (MASP)-1 and -2 activate the lectin pathway of the complement system. Besides, these proteins can activate coagulation in vitro. However, the role of the lectin pathway proteins in the development of sepsis-related disseminated intravascular coagulation (DIC) is only sparsely investigated. Aim This article investigates the association between lectin pathway proteins and coagulation disturbances in septic shock patients. Materials and Methods We included 36 septic shock patients from the intensive care unit, Aarhus University Hospital, Denmark. Blood samples were obtained within 24 hours after admission (day 1), and subsequently on day 2 and day 3. Plasma concentrations of mannose-binding lectin (MBL), H-ficolin, M-ficolin, CL-L1, CL-K1, MASP-1, -2 and -3, MBL-associated proteins of 19 and 44 kDa as well as complement factor C3dg were assessed. Standard coagulation parameters, thrombin generation, thrombin–anti-thrombin (TAT) complex and pro-thrombin fragment 1 + 2 were measured. Sequential Organ Failure Assessment (SOFA) score, DIC score and 30-day mortality were assessed. Results Reduced MASP-1 plasma concentration was associated with DIC score ≥5 (p = 0.02), impaired thrombin generation (p = 0.03) and lower plasma TAT complex levels (p = 0.03). No association was found between lectin pathway proteins and SOFA score or 30-day mortality. Conclusion Reduced MASP-1 concentrations were associated with impaired coagulation in septic shock patients. This indicates that increased MASP-1 activation and consumption is associated with the more severe coagulation disturbances in sepsis and points to a possible role for MASP-1 in sepsis-related DIC.

scholarly journals Changes in Mannose-Binding Lectin and Collectin Kidney 1 Levels in Sepsis Patients With and Without Disseminated Intravascular Coagulation

2019 ◽  
Vol 25 ◽  
pp. 107602961882118
Author(s):  
Mineji Hayakawa ◽  
Katsuki Ohtani ◽  
Nobutaka Wakamiya
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Complement System ◽  
Mannose Binding Lectin ◽  
Classical Type ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intravascular Coagulation ◽  
Icu Admission ◽  
Mannose Binding ◽  
The Complement System ◽  
Binding Lectin

In sepsis, systemic coagulation activation frequently causes disseminated intravascular coagulation (DIC), and the uncontrolled activation of the complement system can induce multiple organ dysfunction and poor prognosis. This study aimed to examine the association of DIC with levels of collectin kidney 1 (CL-K1), a novel collectin of the complement system, and mannose-binding lectin (MBL), a classical-type collectin in patients with sepsis. We collected blood samples prospectively from adult patients with sepsis admitted to the intensive care unit (ICU) from day 1 (admission) to day 5. The CL-K1 and MBL levels were measured by enzyme-linked immunosorbent assay, and DIC was diagnosed by using a scoring algorithm. The correlation of CL-K1 and MBL levels with other coagulation markers was analyzed. There were 37 patients with DIC (DIC group) and 15 without DIC (non-DIC group). Compared to the non-DIC group, the DIC group had more severe conditions and higher mortality. During the 5 days after ICU admission, plasma CL-K1 levels were similar between the groups, but plasma MBL levels were significantly lower in the DIC group. Plasma CL-K1 levels were weakly correlated with prothrombin time, activated partial thromboplastin time, and antithrombin levels; plasma MBL levels were weakly correlated with fibrin/fibrinogen degradation product levels and DIC score. In conclusion, during the first 5 days of ICU admission, plasma CL-K1 levels were similar between the DIC and non-DIC groups. However, plasma MBL levels were lower in the DIC group compared to the non-DIC group, and the significance of this difference grew gradually over time.

LPS-induced platelet response and rapid shock in mice: contribution of O-antigen region of LPS and involvement of the lectin pathway of the complement system

Blood ◽  
2002 ◽  
Vol 100 (9) ◽  
pp. 3233-3239 ◽  
Author(s):  
Lijuan Zhao ◽  
Yuko Ohtaki ◽  
Kouji Yamaguchi ◽  
Misao Matsushita ◽  
Teizo Fujita ◽  
...  
Keyword(s):  
Complement System ◽  
Serine Proteases ◽  
Lectin Pathway ◽  
Platelet Response ◽  
O Antigen ◽  
Mannose Binding ◽  
Anaphylactoid Shock ◽  
K 12 ◽  
The Complement System ◽  
Binding Lectin

AbstractIntravenous injection of a lipopolysaccharide (LPS) into mice induces a rapid accumulation of platelets in the lung and liver. When degradation of the accumulated platelets occurs, anaphylactoid shock follows rapidly, the severity of the shock paralleling the quantity of platelets accumulated in the lung. Here we examined the contributions made by LPS structure and the complement system to the platelet response to LPS. BALB/c mice were injected with an LPS fromEscherichia coli O8, O9, O111, or K-12, or from recombinant mutants of K-12. The O-regions of the O8 and O9 LPSs consist of a mannose homopolysaccharide (MHP), while that of O111 consists of a heteropolysaccharide (not including mannose), and K-12 LPS lacks an O-region. O111 LPS was devoid of the ability to induce the platelet response or shock, while the ability of K-12 LPS was weak. The 2 recombinant LPSs—each having an O-region (from O8 or O9) linked to K-12 LPS—exhibited activities similar to or stronger than those of their original LPSs. Mannose-binding lectin (MBL) complexed with MBL-associated serine proteases (MASPs) bound strongly to LPSs containing MHP and caused C4 activation. Moreover, the abilities of these LPSs to activate the complement system corresponded well with their abilities to induce the platelet response and rapid shock. These results suggest that the structure of the O-antigen region is important for the platelet response to LPS, and that activation of the lectin pathway of the complement system is involved in this response.

scholarly journals Essential role of Mannose-binding lectin-associated serine protease-1 in activation of the complement factor D

2009 ◽  
Vol 207 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Minoru Takahashi ◽  
Yumi Ishida ◽  
Daisuke Iwaki ◽  
Kazuko Kanno ◽  
Toshiyuki Suzuki ◽  
...  
Keyword(s):  
Serine Protease ◽  
Alternative Pathway ◽  
Active Form ◽  
Mannose Binding Lectin ◽  
Activation Mechanism ◽  
Lectin Pathway ◽  
Complement Factor ◽  
Mannose Binding ◽  
Activation Peptide ◽  
Binding Lectin

The complement system is an essential component of innate immunity, participating in the pathogenesis of inflammatory diseases and in host defense. In the lectin complement pathway, mannose-binding lectin (MBL) and ficolins act as recognition molecules, and MBL-associated serine protease (MASP) is a key enzyme; MASP-2 is responsible for the lectin pathway activation. The function of other serine proteases (MASP-1 and MASP-3) is still obscure. In this study, we generated a MASP-1– and MASP-3–deficient mouse model (Masp1/3−/−) and found that no activation of the alternative pathway was observed in Masp1/3−/− serum. Mass spectrometric analysis revealed that circulating complement factor D (Df) in Masp1/3−/− mice is a zymogen (pro-Df) with the activation peptide QPRGR at its N terminus. These results suggested that Masp1/3−/− mice failed to convert pro-Df to its active form, whereas it was generally accepted that the activation peptide of pro-Df is removed during its secretion and factor D constitutively exists in an active form in the circulation. Furthermore, recombinant MASP-1 converted pro-Df to the active form in vitro, although the activation mechanism of pro-Df by MASP-1 is still unclear. Thus, it is clear that MASP-1 is an essential protease of both the lectin and alternative complement pathways.

scholarly journals Relative Roles of Complement Factor 3 and Mannose-Binding Lectin in Host Defense against Infection

2005 ◽  
Vol 73 (12) ◽  
pp. 8188-8193 ◽  
Author(s):  
Kazue Takahashi ◽  
Lei Shi ◽  
Lakshmi D. Gowda ◽  
R. Alan B. Ezekowitz
Keyword(s):  
Host Defense ◽  
Mannose Binding Lectin ◽  
Lectin Pathway ◽  
Complement Factor ◽  
Wild Type ◽  
Gram Positive Bacteria ◽  
Mannose Binding Protein ◽  
Mannose Binding ◽  
Binding Lectin ◽  
Mbl Deficiency

ABSTRACT Staphylococcus aureus is a major cause of severe nosocomial and community-acquired infections. Phagocytes and humoral molecules, including complement, have been proposed to cooperate in host defense against gram-positive bacteria. Circumstantial evidence indicates a role for complement, but this has not been formally defined. Complement activation is initiated by the classical, alternative, or lectin pathway, with the latter requiring mannose-binding lectin (MBL, also known as mannose-binding protein). MBL is an oligomeric serum protein that recognizes carbohydrates decorating a broad range of infectious agents, including S. aureus. We previously reported that MBL null mice were highly susceptible to S. aureus infection, confirming that MBL plays a key role in first-line host defense. In this study, we evaluated the relative roles of C3 and MBL against S. aureus infection by generating MBL × C3 null mice to compare with C3 single null mice. C3 deficiency alone significantly reduced survival to 19% from 97% of wild-type mice (P < 0.0001). Surprisingly, an additional MBL deficiency reduced the survival further to 7% (P < 0.0001). However, the MBL deficiency alone had a smaller though significant effect on survival, which was 77% (P = 0.018 versus wild-type mice). These results confirm an essential function for complement in host resistance against S. aureus infection but also identify an MBL-dependent mechanism that is C3 independent.

Mannose-binding lectin genetics: from A to Z

2008 ◽  
Vol 36 (6) ◽  
pp. 1461-1466 ◽  
Author(s):  
Peter Garred
Keyword(s):  
Epidemiological Studies ◽  
Mannose Binding Lectin ◽  
Host Cells ◽  
Lectin Pathway ◽  
Mannose Binding ◽  
The Stability ◽  
Genetically Determined ◽  
Micro Organisms ◽  
Binding Lectin

MBL (mannose-binding lectin) is primarily a liver-derived collagen-like serum protein. It binds sugar structures on micro-organisms and on dying host cells and is one of the four known mediators that initiate activation of the complement system via the lectin pathway. Common variant alleles situated both in promoter and structural regions of the human MBL gene (MBL2) influence the stability and the serum concentration of the protein. Epidemiological studies have suggested that genetically determined variations in MBL serum concentrations influence the susceptibility to and the course of different types of infectious, autoimmune, neoplastic, metabolic and cardiovascular diseases, but this is still a subject under discussion. The fact that these genetic variations are very frequent, indicates a dual role of MBL. This overview summarizes the current molecular understanding of human MBL2 genetics.

scholarly journals ON VASCULAR STENOSIS, RESTENOSIS AND MANNOSE BINDING LECTIN

2016 ◽  
Vol 29 (1) ◽  
pp. 57-59 ◽  
Author(s):  
Barbara Stadler KAHLOW ◽  
Rodrigo Araldi NERY ◽  
Thelma L SKARE ◽  
Carmen Australia Paredes Marcondes RIBAS ◽  
Gabriela Piovezani Ramos ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Mannose Binding Lectin ◽  
Mannose Binding ◽  
Vascular Stenosis ◽  
Micro Organisms ◽  
The Complement System ◽  
Binding Lectin

Mannose binding lectin is a lectin instrumental in the innate immunity. It recognizes carbohydrate patterns found on the surface of a large number of pathogenic micro-organisms, activating the complement system. However, this protein seems to increase the tissue damage after ischemia. In this paper is reviewed some aspects of harmful role of the mannose binding lectin in ischemia/reperfusion injury.

scholarly journals A New Surface Plasmon Resonance Assay for In Vitro Screening of Mannose-Binding Lectin Inhibitors

2016 ◽  
Vol 21 (7) ◽  
pp. 749-757 ◽  
Author(s):  
Matteo Stravalaci ◽  
Daiana De Blasio ◽  
Franca Orsini ◽  
Carlo Perego ◽  
Alessandro Palmioli ◽  
...  
Keyword(s):  
Surface Plasmon Resonance ◽  
Surface Plasmon ◽  
Plasmon Resonance ◽  
Ischemia Reperfusion ◽  
Mannose Binding Lectin ◽  
Lectin Pathway ◽  
In Vitro Screening ◽  
Mannose Binding ◽  
Binding Lectin

Mannose-binding lectin (MBL) is a circulating protein that acts as a soluble pattern recognition molecule of the innate immunity. It binds to carbohydrate patterns on the surface of pathogens or of altered self-cells, with activation of the lectin pathway of the complement system. Recent evidence indicates that MBL contributes to the pathophysiology of ischemia-reperfusion injury and other conditions. Thus, MBL inhibitors offer promising therapeutic strategies, since they prevent the interaction of MBL with its target sugar arrays. We developed and characterized a novel assay based on surface plasmon resonance for in vitro screening of these compounds, which may be useful before the more expensive and time-consuming in vivo studies. The assay measures the inhibitor’s ability to interfere with the binding of murine MBL-A or MBL-C, or of human recombinant MBL, to mannose residues immobilized on the sensor chip surface. We have applied the assay to measure the IC50 of synthetic glycodendrimers, two of them with neuroprotective properties in animal models of MBL-mediated injuries.

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