Sepsis-Induced Coagulation in the Baboon Lung Is Associated with Decreased Tissue Factor Pathway Inhibitor

Tang, Haiwang; Ivanciu, Lacramioara; Popescu, Narcis I.; Peer, G.; Hack, Erik; Lupu, Cristina; Taylor, Fletcher B.; Lupu, Florea

doi:10.2353/ajpath.2007.070104

Cited by 84 publications

(90 citation statements)

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“…Bacterial aggregates found in tissue lesions (ie, the bubo) undoubtedly contain even higher bacterial numbers, well within the concentration range (10 7 -10 9 cfu/mL) used in the present study to quantify TFPI inactivation. Tang et al recently reported decreased TFPI levels and increased TF-dependent coagulation in the lungs of septic baboons compared with healthy baboons, 54 which would be consistent with this premise. Other sepsis model studies have shown little decrease in TFPI activity under septic conditions.…”

Section: Discussionsupporting

confidence: 66%

Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins

Yun¹,

Cott

Tapping

et al. 2009

Blood

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The immune response to infection includes activation of the blood clotting system, leading to extravascular fibrin deposition to limit the spread of invasive microorganisms. Some bacteria have evolved mechanisms to counteract this host response. Pla, a member of the omptin family of Gram-negative bacterial proteases, promotes the invasiveness of the plague bacterium, Yersinia pestis, by activating plasminogen to plasmin to digest fibrin. We now show that the endogenous anticoagulant tissue factor pathway inhibitor (TFPI) is also highly sensitive to proteolysis by Pla and its orthologs OmpT in Escherichia coli and PgtE in Salmonella enterica serovar Typhimurium. Using gene deletions, we demonstrate that bacterial inactivation of TFPI requires omptin expression. TFPI inactivation is mediated by proteolysis since Western blot analysis showed that TFPI cleavage correlated with loss of anticoagulant function in clotting assays. Rates of TFPI inactivation were much higher than rates of plasminogen activation, indicating that TFPI is a better substrate for omptins. We hypothesize that TFPI has evolved sensitivity to proteolytic inactivation by bacterial omptins to potentiate procoagulant responses to bacterial infection. This may contribute to the hemostatic imbalance in disseminated intravascular coagulation and other coagulopathies accompanying severe sepsis. (Blood. 2009;113: 1139-1148) IntroductionAside from its role in minimizing blood loss, the clotting system is also an effector arm of the immune system that modulates release of inflammatory mediators and prevents the spread of invasive microorganisms through extravascular fibrin deposition. This "quarantine through coagulation" strategy is evolutionarily primitive, as evidenced by the sensitivity of the horseshoe crab clotting system to activation by bacterial endotoxin. 1 Indeed, fibrin deposition is one of the hallmarks of inflammation in humans, and the induration accompanying delayed-type hypersensitivity skin reactions is caused by extravascular fibrin deposition. 2 Inflammatory responses to infection include expression of tissue factor on activated monocytes as well as increased acute phase proteins like fibrinogen and PAI-I, which contribute to hypercoagulable states. 3 Some bacteria modulate the host coagulation system to evade immune responses or facilitate dissemination through extravascular tissues. For example, staphylocoagulase and streptokinase form complexes with prothrombin or plasminogen, converting them into prothrombotic (thrombin) or profibrinolytic (plasmin) enzymes. 4 Likewise, plasminogen activator (Pla), a member of the omptin family of bacterial proteases, promotes dissemination of the plague agent, Yersinia pestis, from subcutaneous sites to the lymphatic and circulatory systems. 5 Proteolytic activation of plasminogen by Pla is thought to facilitate Y pestis migration through tissue barriers, because plasmin degrades fibrin clots and extracellular matrix components, activates procollagenases, and inactivates collagenase inhibitors. [6...

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Section: Discussionsupporting

confidence: 66%

Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins

Yun¹,

Cott

Tapping

et al. 2009

Blood

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“…Notably, TFPI levels in plasma do not reflect the total amount of TFPI that may be relevant in vivo, since most TFPI is produced by endothelial cells [9]. Under certain (inflammatory) conditions TFPI expression is decreased, for example, during sepsis [10] which could likely increase the LP activation.…”

Section: Discussionmentioning

confidence: 99%

TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

et al. 2014

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The lectin pathway (LP) of complement has a protective function against invading pathogens. Recent studies have also shown that the LP plays an important role in ischemia/reperfusion (I/R)-injury. MBL-associated serine protease (MASP)-2 appears to be crucial in this process. The serpin C1-inhibitor is the major inhibitor of MASP-2. In addition, aprotinin, a Kunitz-type inhibitor, was shown to inhibit MASP-2 activity in vitro.In this study we investigated whether the Kunitz-type inhibitor tissue factor pathway inhibitor (TFPI) is also able to inhibit MASP-2. Ex vivo LP was induced and detected by C4-deposition on mannan-coated plates. The MASP-2 activity was measured in a fluid-phase chromogenic assay. rTFPI in the absence or presence of specific monoclonal antibodies was used to investigate which TFPI-domains contribute to MASP-2 inhibition. Here, we identify TFPI as a novel selective inhibitor of MASP-2, without affecting MASP-1 or the classical pathway proteases C1s and C1r. Kunitz-2 domain of TFPI is required for the inhibition of MASP-2. Considering the role of MASP-2 in complement-mediated I/R-injury, the inhibition of this protease by TFPI could be an interesting therapeutic approach to limit the tissue damage in conditions such as cerebral stroke, myocardial infarction or solid organ transplantation.Keywords: Complement-coagulation crosstalk r Complement inhibition r MASP-2 r TFPI Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe complement system comprises over 30 different plasma proteins. The complement system consists of three activation pathways, each differing in their recognition mechanism while Correspondence: Mischa P. Keizer e-mail: m.keizer@sanquin.nl converging in a common terminal pathway at the level of complement component 3 (C3). The antibody-dependent classical pathway (CP) initiates the complement system via the binding of C1q to antibodies. Binding to specific sugar motifs by mannan-binding lectins (MBLs) or one of the ficolins activates the lectin pathway (LP) by subsequent activation of the MBL-associated serine proteases (MASPs). The alternative pathway activates spontaneously on surfaces that lack complement regulatory proteins and acts as amplification route for the other two pathways.www.eji-journal.eu Eur. J. Immunol. 2015. 45: 544-550 Innate immunity 545Besides the LP role as first line of defense against invading pathogens, by opsonization and induction of an inflammatory response, recent studies have shown that the LP also plays a prominent role in ischemia/reperfusion (I/R) injury. MBL-deficiency appears to be protective in human myocardial infarction [1], gastrointestinal I/R injury [1], and stroke [2]. This detrimental role of the LP in I/R injury has been confirmed in mice by selectively targeting MASP-2. MASP-2 knockout mice were protected from both gastrointestinal and myocardial I/R injury [3]. Together, these data indicate an important role for MASP-2 in aggravating cell damage in ischemi...

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“…13 Animals were killed at T ϩ 24 hours and tissue specimens were removed from the lungs, kidney, adrenals, heart and spleen, snapfrozen in liquid nitrogen and stored at Ϫ80°C or fixed for microscopy. 14 The complement activation products C3a, C3b, and TCC and complement activity were measured as described. [15][16][17][18] Soluble thrombomodulin (sTM) was measured as described, 13 and P-selectin was measured using a monkey sP-selectin enzyme-linked immunosorbent assay (ELISA; Bender MedSystems).…”

Section: Methodsmentioning

confidence: 99%

Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis

Silasi‐Mansat

Zhu

Popescu

et al. 2010

Blood

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Severe sepsis leads to massive activation of coagulation and complement cascades that could contribute to multiple organ failure and death. To investigate the role of the complement and its crosstalk with the hemostatic system in the pathophysiology and therapeutics of sepsis, we have used a potent inhibitor (compstatin) administered early or late after Escherichia coli challenge in a baboon model of sepsis-induced multiple organ failure. Compstatin infusion inhibited sepsis-induced blood and tissue biomarkers of complement activation, reduced leucopenia and thrombocytopenia, and lowered the accumulation of macrophages and platelets in organs. Compstatin decreased the coagulopathic response by down-regulating tissue factor and PAI-1, diminished global blood coagulation markers (fibrinogen, fibrin-degradation products, APTT), and preserved the endothelial anticoagulant properties. Compstatin treatment also improved cardiac function and the biochemical markers of kidney and liver damage. Histologic analysis of vital organs collected from animals euthanized after 24 hours showed decreased microvascular thrombosis, improved vascular barrier function, and less leukocyte infiltration and cell death, all consistent with attenuated organ injury. We conclude that complement-coagulation interplay contributes to the progression of severe sepsis and blocking the harmful effects of complement activation products, especially during the organ failure stage of severe sepsis is a potentially important therapeutic strategy. (Blood. 2010;116(6):1002-1010) IntroductionSevere sepsis is a multistage, multifactorial, and life-threatening clinical syndrome that arises through the innate response to infection and can appear as a complication in conditions like trauma, cancer, and surgery. 1 Despite important strides made in understanding its pathophysiology, the sepsis-related mortality and morbidity rates still remain unacceptably high. Sepsis affects approximately 700 000 people and accounts for approximately 210 000 deaths per year 2 in the United States alone. In its most fulminant form, sepsis can produce cardiovascular collapse and death within hours. More common is the development of multiple organ failure (MOF) secondary to hypoperfusion and intravascular thrombosis. The MOF may run a protracted clinical course and eventually proves fatal in 30% to 40% of patients. The mechanisms responsible for the persistent and progressive organ failure are less understood. To examine this problem we have developed nonhuman primate models of Escherichia coli sepsis, which, depending on the bacterial dose, mimic the different pathophysiologic syndromes observed in clinical practice. 3 Challenge with 10 10 cfu/kg E coli (LD100) results in an explosive inflammatory and coagulopathic response leading to irreversible shock and death. The administration of a lower dose, 10 9 cfu/kg E coli (LD50), produces transient hypotension followed by MOF, which may progress and prove fatal in approximately 50% of the animals. The pathophysiology of the LD50 mo...

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Sepsis-Induced Coagulation in the Baboon Lung Is Associated with Decreased Tissue Factor Pathway Inhibitor

Cited by 84 publications

References 59 publications

Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins

Proteolytic inactivation of tissue factor pathway inhibitor by bacterial omptins

TFPI inhibits lectin pathway of complement activation by direct interaction with MASP‐2

Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis

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