The Protective Role of Protein C in Endotoxin-Induced Shock.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1748-1748
Author(s):  
Angelina J. Lay ◽  
Deborah Donahue ◽  
Meng-Ju Tsai ◽  
Francis J. Castellino
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Organ Damage ◽  
Protective Role ◽  
Survival Outcome ◽  
Disease Pathogenesis ◽  
Lps Challenge ◽  
First Time ◽  
Excessive Inflammatory Response

Abstract The serine protease, activated Protein C (aPC) plays an important role in the maintenance of vascular hemostasis. Besides its ability to regulate coagulation and fibrinolysis, aPC also possesses antiinflammatory and antiapoptotic properties. Severe depletion of plasma PC and aPC contributes to sepsis pathogenesis. Although treatment with recombinant aPC benefits a subset of patients with severe sepsis, mechanisms by which aPC improves survival in these patients remain largely unknown. Using mice genetically predisposed to a severe PC deficiency, we initiated studies to further elucidate the mechanistic relationships between very low endogenous PC levels and inflammatory disease pathogenesis. Here, we show for the first time, that novel genetic dosing of PC strongly correlates with survival outcome following endotoxin (LPS) challenge in mice. Our findings provide evidence that very low endogenous levels of PC predispose mice to early onset of disseminated intravascular coagulation, thrombocytopenia, hypotensive shock, organ damage, and reduced survival after LPS challenge. Furthermore, an excessive inflammatory response is observed in very low-PC mice, but is greatly reduced in WT cohorts. Administration of recombinant human aPC to low-PC mice significantly prevents endotoxin-induced hypotensive shock and prolongs survival. This study highlights the importance of host endogenous levels of PC in predicting survival outcome following a severe acute inflammatory challenge.

scholarly journals Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency

Blood ◽  
2006 ◽  
Vol 109 (5) ◽  
pp. 1984-1991 ◽  
Author(s):  
Angelina J. Lay ◽  
Deborah Donahue ◽  
Meng-Ju Tsai ◽  
Francis J. Castellino
Keyword(s):  
Protein C ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Activated Protein C ◽  
Organ Damage ◽  
Protein C Deficiency ◽  
Lps Challenge ◽  
Neonatal Lethality ◽  
First Time ◽  
Important Marker

Abstract The anticoagulant, activated protein C (aPC), possesses antithrombotic, profibrinolytic, anti-inflammatory, and antiapoptotic properties, and the level of this protein is an important marker of acute inflammatory responses. Although infusion of aPC improves survival in a subset of patients with severe sepsis, evidence as to how aPC decreases mortality in these cases is limited. Because a total deficiency of PC shows complete neonatal lethality, no animal model currently exists to address the mechanistic relationships between very low endogenous aPC levels and inflammatory diseases. Here, we show for the first time that novel genetic dosing of PC strongly correlates with survival outcomes following endotoxin (LPS) challenge in mice. The data provide evidence that very low endogenous levels of PC predispose mice to early-onset disseminated intravascular coagulation, thrombocytopenia, hypotension, organ damage, and reduced survival after LPS challenge. Furthermore, evidence of an exacerbated inflammatory response is observed in very low PC mice but is greatly reduced in wild-type cohorts. Reconstitution of low-PC mice with recombinant human aPC improves hypotension and extends survival after LPS challenge. This study directly links host endogenous levels of PC with various coagulation, inflammation, and hemodynamic end points following a severe acute inflammatory challenge.

Protective role of activated protein C in lung and airway remodeling

2004 ◽  
Vol 32 (Supplement) ◽  
pp. S262-S265 ◽  
Author(s):  
Koji Suzuki ◽  
Esteban Cesar Gabazza ◽  
Tatsuya Hayashi ◽  
Haruhiko Kamada ◽  
Yukihiko Adachi ◽  
...  
Keyword(s):  
Protein C ◽  
Airway Remodeling ◽  
Activated Protein C ◽  
Protective Role

Sepsis and the Role of Activated Protein C

2004 ◽  
Vol 24 (6) ◽  
pp. 40-45
Author(s):  
Janice Tazbir
Keyword(s):  
Protein C ◽  
Activated Protein C

scholarly journals C4b-binding protein exacerbates the host response to Escherichia coli

Blood ◽  
1991 ◽  
Vol 78 (2) ◽  
pp. 357-363 ◽  
Author(s):  
F Taylor ◽  
A Chang ◽  
G Ferrell ◽  
T Mather ◽  
R Catlett ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Acute Phase ◽  
Protein C ◽  
Activated Protein C ◽  
Protein S ◽  
Organ Damage ◽  
Vascular Damage ◽  
E Coli ◽  
Infusion Group ◽  
Sublethal Concentrations

Abstract Activated protein C is a plasma anticoagulant. For activated protein C to function as an anticoagulant, it must form a complex with protein S. Protein S anticoagulant activity is neutralized by formation of a reversible complex with C4b binding protein (C4bBP). C4bBP is an acute- phase plasma protein. When C4bBP levels increase, mass action forces the level of free protein S to decrease, giving rise to an acquired functional protein S deficiency. It has been proposed that these elevated C4bBP levels and the resultant acquired deficiency of protein S that occurs in inflammation could contribute to a hypercoagulable state. An experimental model to test this hypothesis was suggested by our previous studies that demonstrated that inhibition of protein C activation rendered baboons hypercoagulable in response to sublethal Escherichia coli infusion (J Clin Invest 79:918, 1987). We have extended these studies to examine the effect of inhibition of protein S activity with C4bBP in the host (baboon) response to infusion of sublethal concentrations of E coli organisms. Five sets of animals were studied: (1) those challenged with sublethal concentrations of E coli alone (0.4 x 10(10)/kg); (2) those supplemented only with C4bBP (20 mg/kg); (3) those challenged with the same level of E coli but supplemented with C4bBP (20 mg/kg); (4) those challenged with sublethal E coli and supplemented with C4bBP (20 mg/kg) and sufficient protein S (2.3 mg/kg) to fill the protein S binding sites on C4bBP; and (5) those challenged with lethal concentrations of E coli. Sublethal E coli infusion (group 1 animals) caused only an acute-phase response with no consumption of fibrinogen, detectable organ damage, or detectable tumor necrosis factor (TNF) in the plasma. C4bBP infusion (group 2 animals) resulted in no significant physiologic changes, no detectable plasma TNF, and little change in fibrinogen level. The group 3 animals, receiving both sublethal E coli and C4bBP, exhibited rapid consumption of fibrinogen, systemic organ damage, and detectable circulating TNF ultimately leading to death. The overall response of this group was very similar to the response of the group 5 animals receiving an LD100 dose of E coli. The group 4 animals, which were treated exactly as above except that C4bBP was supplemented with a slight excess of protein S, responded essentially like those that received sublethal E coli alone. These studies suggest that the elevation of C4bBP during an inflammatory response can contribute to fibrinogen consumption and vascular damage. This vascular damage may be associated with enhanced elaboration of cytokines like TNF.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Differential Activation of Fetal Hofbauer Cells in Primigravidas Is Associated with Decreased Birth Weight in Symptomatic Placental Malaria

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Stephanie L. Gaw ◽  
Bethann S. Hromatka ◽  
Sadiki Ngeleza ◽  
Sirirak Buarpung ◽  
Nida Ozarslan ◽  
...  
Keyword(s):  
Birth Weight ◽  
Placental Malaria ◽  
Perinatal Outcomes ◽  
Protective Role ◽  
Cross Sectional ◽  
Macrophage Response ◽  
Hofbauer Cells ◽  
Infant Birth ◽  
First Time

Background. Placental malaria is a leading global cause of low birth weight neonates, especially in first-time mothers. To better understand the role of innate immunity in placental malaria, we investigated the relationships between histopathological markers of placental malaria, fetal and maternal macrophage responses, and perinatal outcomes in a cross-sectional case control study of pregnant women presenting with symptomatic malaria at the time of delivery. Results. Primigravidas showed increased hemozoin deposition in placental villi (p=0.02), syncytiotrophoblasts (p=0.01), and fetal Hofbauer cells (p=0.01). The percentage of hemozoin-positive villi negatively correlated with infant birth weight (regression coefficient [b] = -0.03 kg decrease in birth weight per % increase in hemozoin-positive villi, p=0.035). Malaria-infected placentas showed a twofold increase in Hofbauer cells (p<0.001) and maternal macrophages (p<0.001). Placental malaria was associated with a threefold increase in the percentage of M2 maternal macrophages (19.2% vs 6.4%, p=0.01). Primigravidas showed a significant decrease in the Hofbauer cell M2-percentage in placental malaria (92.7% vs. 97.0%, p=0.04), which was predictive of infant birth weight (b=0.08 kg increase in birth weight per % increase in M2 Hofbauer cells, p=0.001). There was no association between maternal macrophage response and infant birth weights. Conclusions. Placentas with malarial infection had increased numbers of fetal Hofbauer cells in the villous stroma and maternal macrophages in the intervillous space. In primigravidas, decreased anti-inflammatory M2-type Hofbauer cells were predictive of lower birth weight. M2-type maternal macrophages were increased in placental malaria, but there was no association with gravidity or birth weight. These results suggested a protective role of M2 Hofbauer cells in fetal growth restriction.

scholarly journals Physical Activity Prevents Cartilage Degradation: A Metabolomics Study Pinpoints the Involvement of Vitamin B6

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1374 ◽  
Author(s):  
Deiana ◽  
Malerba ◽  
Dalle Carbonare ◽  
Cheri ◽  
Patuzzo ◽  
...  
Keyword(s):  
Physical Activity ◽  
Vitamin B6 ◽  
Cartilage Degradation ◽  
Protective Role ◽  
Before And After ◽  
Metabolomics Study ◽  
Cartilage Cells ◽  
First Time ◽  
Chondrosarcoma Cell Line

Osteoarthritis (OA) is predominantly characterized by the progressive degradation of articular cartilage, the connective tissue produced by chondrocytes, due to an imbalance between anabolic and catabolic processes. In addition, physical activity (PA) is recognized as an important tool for counteracting OA. To evaluate PA effects on the chondrocyte lineage, we analyzed the expression of SOX9, COL2A1, and COMP in circulating progenitor cells following a half marathon (HM) performance. Therefore, we studied in-depth the involvement of metabolites affecting chondrocyte lineage, and we compared the metabolomic profile associated with PA by analyzing runners’ sera before and after HM performance. Interestingly, this study highlighted that metabolites involved in vitamin B6 salvage, such as pyridoxal 5’-phosphate and pyridoxamine 5’-phosphate, were highly modulated. To evaluate the effects of vitamin B6 in cartilage cells, we treated differentiated mesenchymal stem cells and the SW1353 chondrosarcoma cell line with vitamin B6 in the presence of IL1β, the inflammatory cytokine involved in OA. Our study describes, for the first time, the modulation of the vitamin B6 salvage pathway following PA and suggests a protective role of PA in OA through modulation of this pathway.

scholarly journals Upregulation of Mitochondrial Redox Sensitive Proteins in LPS-Treated Stefin B-Deficient Macrophages

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1476 ◽  
Author(s):  
Mojca Trstenjak Prebanda ◽  
Janja Završnik ◽  
Boris Turk ◽  
Nataša Kopitar Jerala
Keyword(s):  
Redox Homeostasis ◽  
Redox Status ◽  
Protective Role ◽  
Protein Levels ◽  
Lps Challenge ◽  
Pyrin Domain ◽  
Cysteine Cathepsins ◽  
Peroxiredoxin 3 ◽  
Superoxide Dismutase 2

Stefin B (cystatin B) is an intracellular inhibitor of cysteine cathepsins and mutations in the stefin B gene, resulting in the development of Unverricht–Lundborg disease, which is a form of myoclonic epilepsy. It was suggested that a key mechanism behind stefin B-mediated disease progression was impaired redox homeostasis. Stefin B-deficient mice were found more sensitive to lipopolysaccharide (LPS)-induced sepsis as a consequence of increased expression of caspase-11 and Nucleotide-binding oligomerization domain, Leucine rich Repeat and Pyrin domain containing (NLRP nflammasome activation and higher levels of mitochondrial reactive oxygen species (ROS). In the present study, we investigated if LPS-triggered oxidative stress affected the protein levels and redox status of redox sensitive proteins—thioredoxin, peroxiredoxins, and superoxide dismutases in macrophages and spleens of LPS-injected mice. LPS challenge was found to result in a marked elevation in mitochondrial peroxiredoxin 3 (Prx3), sulfiredoxin, and superoxide dismutase 2 (Sod2) in stefin B-deficient macrophages and spleens. We determined that sulfiredoxin is targeted to mitochondria after LPS challenge. In conclusion, the upregulation of mitochondrial redox-sensitive proteins Prx3 and Sod2 in stefin B-deficient cells implies a protective role of stefin B in mitochondrial function.

scholarly journals Role of coagulation pathways and treatment with activated protein C in hyperoxic lung injury

Thorax ◽  
2009 ◽  
Vol 64 (2) ◽  
pp. 114-120 ◽  
Author(s):  
M R Looney ◽  
C T Esmon ◽  
M A Matthay
Keyword(s):  
Lung Injury ◽  
Protein C ◽  
Activated Protein C ◽  
Hyperoxic Lung Injury
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