Abstract 2673: C-reactive Protein Increases The Severity Of Stroke Outcome In Mice

C-reactive protein (CRP) is an acute-phase reactant that is elevated in a variety of chronic inflammatory conditions including obesity and autoimmune disorders. Elevated CRP is associated with greater incidence and severity of stroke. However, it is unknown whether CRP directly impacts the severity of stroke outcome. We previously demonstrated that CRP antagonizes endothelial NO synthase (eNOS) by attenuating eNOS serine 1176 phosphorylation via the activation of SHIP-1 in endothelium, which blunts signaling downstream of PI3 kinase. Furthermore, we have shown that modulation of the eNOS serine 1176 phosphorylation site affects vascular reactivity and determines stroke size in vivo. We therefore hypothesize that CRP increases stroke vulnerability in vivo by altering the phosphorylation state of eNOS. To test our hypothesis, we subjected wild-type (WT) and CRP transgenic mice (TG-CRP), which have modest elevations in CRP, to a stroke model of temporal focal ischemia with subsequent reperfusion. Mean blood pressure measured acutely from the common carotid artery under aerrane anesthesia (30 % oxygen, 70% nitrous oxide and 1.5% aerrane) was similar in TG-CRP mice (96 ± 8 mmHg, Mean ± SD, n=6) and WT mice (93 ± 9 mmHg, n=14). Using Laser Doppler flowmetry, we monitored cerebral blood flow (CBF) above the middle cerebral artery (MCA) during 30 minutes of MCA occlusion (MCAO) provoked by a filament and during the first 30 minutes of subsequent reperfusion. Although there was a directional trend, in TG-CRP mice CBF reperfusion after 30 minutes (55 ± 34 %, n=5) was not different from WT mice (80 ± 16 %, n=5, P=0.28). However, the TG-CRP mice demonstrated markedly larger infarct volumes as compared with WT mice after 30 minutes of MCAO and 48 hours of reperfusion (100 ± 26 mm3 in TG-CRP vs. 51 ± 21 mm3 in WT, n=5/group, p< 0.03). Neurological deficit after 48 hours of reperfusion was also worse in TG-CRP mice (3.0 points) as compared with WT mice (1.8 point). These findings indicate that CRP increases the severity of stroke outcome in a mouse model of cerebral reperfusion. As such, future therapies aimed at CRP or its mechanism of action in stroke may potentially prevent or improve the stroke outcomes in patients with chronic inflammatory conditions such as obesity.

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Abstract 277: Elevated C-Reactive Protein Contributes to Preeclampsia via Kinin Signaling Pathways

Hypertension ◽

10.1161/hyp.62.suppl_1.a277 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Nicholas Parchim ◽

Wei Wang ◽

Takayuki Iriyama ◽

Chen Liu ◽

Athar H Siddiqui ◽

...

Keyword(s):

Acute Phase Reactant ◽

Receptor Activation ◽

C Reactive Protein ◽

Direct Role ◽

Human Trophoblast ◽

Reactive Protein ◽

Induced Hypertension ◽

Pregnant Mice

Preeclampsia (PE) is a serious pregnancy disease characterized by hypertension and proteinuria. Despite intensive research efforts, the underlying cause of PE remains a mystery. PE is, however, associated with abnormalities of the immune system. Here we report that the levels of C-reactive protein (CRP), an important acute phase reactant, were significantly elevated in the plasma of human with PE at the third trimester. Next, we found that CRP protein levels in the placentas of PE patients were also significantly increased compared to controls. In an effort to determine the exact role of elevated CRP in PE, we infused CRP into pregnant mice. We found that injection of CRP into pregnant mice induced hypertension (170 mmHg mean systolic vs. 125 mmHg mean systolic control; p<0.05) and proteinuria (25 mg/ug vs 12 mg/ug vehicle; p<0.05), indicating the direct role of CRP in PE. CRP is known to bind with phosphocholine on damaged cell membranes. Recent studies identified that neurokinin B (NKB), a placental enriched neuropeptide and known pathogenic molecule for PE, is phosphocholinated. This posttranslational modification increases its stability and enhances NKB-mediated receptor activation. These findings raise an intriguing hypothesis that CRP may bind with NKB coupled to NK3R activation and contribute to PE. To test this hypothesis, we conducted a pulldown assay, and we found that CRP bound with NKB. Next, using a cellular invasion assay, we revealed that CRP decreased invasion of human trophoblast cells (0.7 to 0.07 invasion index, p<0.05), while treatment with an NK3R selective antagonist, SB222200, ameliorated this shallow invasion. Finally, we provided in vivo evidence that inhibition of NK3R by SB222200 or knockdown of NK3R by specific siRNA in a potent nanoparticle delivery system significantly reduced CRP-induced hypertension and proteinuria in pregnant mice (170 mmHg mean systolic CRP-injected vs. 130 mmHg mean systolic siRNA NK3R; p<0.05 and proteinuria 25 mg/ug vs. 15 mg/ug; p<0.05). Overall, our findings demonstrate that elevated CRP contributes to PE and NKB/NK3R is a novel mechanism underlying CRP-mediated shallow invasion and disease development. These studies suggest novel pathogenic biomarkers and innovative therapeutic targets for PE.

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C-Reactive Protein as a Predictor for Early Intervention in Patients with Ureteric Calculus- A Prospective Study

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2020/45408.14128 ◽

2020 ◽

Author(s):

Narendra Pai ◽

Rajeev Thekke Puthalath ◽

Chethan Thotahalli Krishna ◽

Suraj Hegde ◽

Amit Kumar

Keyword(s):

Early Intervention ◽

Acute Phase Reactant ◽

C Reactive Protein ◽

Reactive Protein ◽

Ureteric Calculus ◽

Inflammatory Conditions ◽

The Social ◽

Spontaneous Expulsion ◽

Almost All ◽

A Prospective Study

Introduction: Inflammation of ureteric wall may impede the passage of calculus which reduces the chances of spontaneous expulsion. C-Reactive Protein (CRP) being an acute phase reactant elevates in almost all inflammatory conditions. Aim: To determine whether CRP levels can predict the need for early intervention in symptomatic ureteric calculus. Materials and Methods: The sample was estimated to be 140 patients over the age of 18 years during the study duration of six months. Ureteric calculus measuring 5-10 mm were subjected to Medical Expulsion Therapy (MET) (Silodosin 8 mg at night). CRP levels were estimated on day 1 and day 7 from the presentation. CRP less than 6 mg/L was considered normal, represented as ‘negative’ in the present study; more than or equal to 6 mg/L was taken as ‘positive’. Patients who demonstrated rising/elevated CRP were considered for early endoscopic/surgical intervention. Data was analysed by Statistical Package for the Social Sciences (SPSS) v19.00. Results: Out of the 140 patients, 56 patients had positive CRP on day 7, of which only nine patients had expelled the stone at the end of two weeks (16.07%). Out of 84 negative CRP group patients, 56 showed evidence of spontaneous calculus expulsion within one week and 18 patients at the end of two weeks and 10 patients did not demonstrate spontaneous expulsion at the end of two weeks and required intervention. The present study showed a statistically significant correlation between the positive CRP levels and the rates of spontaneous expulsion of ureteric calculus (p=0.0001). Conclusion: CRP can be used as a predictor for an early intervention of symptomatic ureteric calculus.

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Human C-Reactive Protein Is Protective against Fatal Salmonella enterica Serovar Typhimurium Infection in Transgenic Mice

Infection and Immunity ◽

10.1128/iai.68.10.5652-5656.2000 ◽

2000 ◽

Vol 68 (10) ◽

pp. 5652-5656 ◽

Cited By ~ 74

Author(s):

Alexander J. Szalai ◽

J. L. VanCott ◽

Jerry R. McGhee ◽

John E. Volanakis ◽

William H. Benjamin

Keyword(s):

Host Defense ◽

Salmonella Enterica ◽

C Reactive Protein ◽

Humoral Immune ◽

Reactive Protein ◽

Inflammatory Conditions ◽

Lethal Infection ◽

Serum Titer ◽

Serovar Typhimurium

ABSTRACT C-reactive protein (CRP) is an acute-phase protein with a well-known association with infection and other inflammatory conditions. We have shown that expression of human CRP by CRP transgenic (CRPtg) mice is protective against lethal infection byStreptococcus pneumoniae, an effect likely mediated by CRP's ability to bind to this gram-positive pathogen. In the present study we tested whether CRPtg mice are resistant to infection withSalmonella enterica serovar Typhimurium, a gram-negative pathogen that causes the murine equivalent of typhoid fever. CRPtg mice experimentally infected with a virulent Typhimurium strain lived longer and had significantly lower mortality than their non-tg littermates. The greater resistance of CRPtg mice could be attributed to significantly increased early (0 to 4 h) blood clearance of salmonellae and significantly decreased numbers of bacteria in the liver and spleen on day 7 postinfection. In addition, 14 days after infection with an avirulent Salmonella strain, the serum titer of anti-Salmonella immunoglobulin G antibodies was higher in CRPtg than non-tg mice. This study provides unequivocal evidence that CRP plays an important role in vivo in host defense against salmonellae during the early stages of infection. In addition, as the beneficial effect of CRP includes enhancement of the host's humoral immune response, CRP may also contribute indirectly to host defense during later stages of infection.

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Inhibition of C5a des Arg-induced neutrophil alveolitis in transgenic mice expressing C-reactive protein

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1994.266.6.l649 ◽

1994 ◽

Vol 266 (6) ◽

pp. L649-L654 ◽

Cited By ~ 2

Author(s):

R. M. Heuertz ◽

D. Xia ◽

D. Samols ◽

R. O. Webster

Keyword(s):

Transgenic Mice ◽

Elevated Serum ◽

Neutrophil Infiltration ◽

Serum Levels ◽

Lavage Fluid ◽

Acute Phase Reactant ◽

C Reactive Protein ◽

Reactive Protein

C-reactive protein (CRP) is the classic acute phase reactant in man with serum levels elevated up to 1,000-fold after the onset of inflammation. CRP inhibits chemotaxis of complement (C5a)-stimulated neutrophils in vitro and rabbits with elevated serum CRP levels exhibit diminished neutrophil infiltration and vascular permeability in a model of C5a-induced alveolitis. To specifically evaluate the effect of CRP on C5a-induced neutrophil inflammation in vivo, experiments were performed in transgenic mice capable of expressing rabbit CRP in an inducible fashion. After direct instillation of a known inflammatory agent (C5a des Arg) into the airways, transgenic mice with high plasma levels of CRP showed significantly diminished infiltration of neutrophils into bronchoalveolar lavage fluid (BALF) and a significant reduction of BALF total protein levels compared with normal mice. These data indicate that CRP can diminish lung injury by a reduction in neutrophil influx and protein leakage into alveoli following complement-induced inflammation.

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Anti-TNF-α Treatment Reduces the Baseline Procoagulant Imbalance of Patients With Inflammatory Bowel Diseases

Inflammatory Bowel Diseases ◽

10.1093/ibd/izaa351 ◽

2021 ◽

Author(s):

Armando Tripodi ◽

Luisa Spina ◽

Laura Francesca Pisani ◽

Lidia Padovan ◽

Flaminia Cavallaro ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Coagulation Factors ◽

Infliximab Treatment ◽

C Reactive Protein ◽

Reactive Protein ◽

Thrombosis Risk ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Factor Α

Abstract Background Inflammatory bowel diseases (IBD) are characterized by an increased thrombosis risk of uncertain etiology. Coagulation derangement arising from inflammation may be a triggering factor. We hypothesized that strong inflammation inhibitors (eg, anti-tumor necrosis factor-α drugs) may affect coagulation. Methods Forty patients with IBD were compared with 57 control patients for coagulation factors and endogenous thrombin potential (ETP), the latter being the most sensitive marker of in vivo pro- and anticoagulation balance. We measured ETP in the presence and absence of thrombomodulin (the physiologic protein C [PC] activator). Coagulation at different timepoints was also assessed for 28 of these patients during infliximab treatment. Results The median ETP (nM thrombin × minutes) and range (minimum-maximum) were each higher in patients at baseline than in control patients in both the absence (2120 [1611-3041] vs 1865 [1270-2337]) and the presence (1453 [464-2522] vs 831 [104-1741]) of thrombomodulin. The ETP ratio (with/without thrombomodulin) was high at baseline (0.73 [0.21-0.90] vs 0.45 [0.07-0.85]). The ETP and ETP ratio declined during treatment and were significantly lower at the end than at baseline. Factor (F) VIII and fibrinogen, which were high at baseline, decreased during treatment and at the end were significantly lower than at baseline. The FVIII/PC ratio, which was high in patients at baseline, declined during treatment and at the end was lower than at baseline. C-reactive protein recorded at the end of treatment was lower than at baseline. Conclusions Patients with IBD have a procoagulant imbalance as shown by increased ETP at baseline. The ETP decreases during treatment with infliximab, which is related to decreased FVIII and FVIII/PC ratio. This effect is also related to the improvement of inflammation as shown by decreased fibrinogen and C-reactive protein.

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Association Between Antidepressants And C – Reactive Protein Among Adults With Inflammatory Conditions – A Population-Based Study

Value in Health ◽

10.1016/j.jval.2014.03.337 ◽

2014 ◽

Vol 17 (3) ◽

pp. A57

Author(s):

R. Garg ◽

X. Pan ◽

U. Sambamoorthi

Keyword(s):

Population Based ◽

C Reactive Protein ◽

Population Based Study ◽

Reactive Protein ◽

Inflammatory Conditions

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Influence of apolipoprotein E genotype and dietary α-tocopherol on redox status and C-reactive protein levels in apolipoprotein E3 and E4 targeted replacement mice

British Journal Of Nutrition ◽

10.1017/s000711450788634x ◽

2008 ◽

Vol 100 (1) ◽

pp. 44-53 ◽

Cited By ~ 10

Author(s):

Laia Jofre-Monseny ◽

Patricia Huebbe ◽

Inken Stange ◽

Christine Boesch-Saadatmandi ◽

Jan Frank ◽

...

Keyword(s):

Apoe Genotype ◽

Positive Association ◽

Thiobarbituric Acid ◽

Redox Status ◽

C Reactive Protein ◽

Cvd Risk ◽

Reactive Protein ◽

Antioxidant Defence System

The molecular basis of the positive association between apoE4 genotype and CVD remains unclear. There is direct in vitro evidence indicating that apoE4 is a poorer antioxidant relative to the apoE3 isoform, with some indirect in vivo evidence also available. Therefore it was hypothesised that apoE4 carriers may benefit from α-tocopherol (α-Toc) supplementation. Targeted replacement mice expressing the human apoE3 and apoE4 were fed with a diet poor (0 mg/kg diet) or rich (200 mg/kg diet) in α-Toc for 12 weeks. Neither apoE genotype nor dietary α-Toc exerted any effects on the antioxidant defence system, including glutathione, catalase, superoxide dismutase, glutathione peroxidase and glutathione reductase activities. In addition, no differences were observed in mitogen-induced lymphocyte proliferation. α-Toc concentrations were modestly higher in plasma and lower in tissues of apoE4 compared with apoE3 mice, with the greatest differences evident in the lung, suggesting that an apoE4 genotype may reduce α-Toc delivery to tissues. A tendency towards increased plasma F2-isoprostanes in apoE4 mice was observed, while liver thiobarbituric acid-reactive substances did not differ between apoE3 and apoE4 mice. In addition, C-reactive protein (CRP) concentrations were reduced in apoE4 mice indicating that this positive effect on CRP may in part negate the increased CVD risk associated with an apoE4 genotype.

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C-reactive protein and inflammation: conformational changes affect function

Biological Chemistry ◽

10.1515/hsz-2015-0149 ◽

2015 ◽

Vol 396 (11) ◽

pp. 1181-1197 ◽

Cited By ~ 95

Author(s):

Yi Wu ◽

Lawrence A. Potempa ◽

Driss El Kebir ◽

János G. Filep

Keyword(s):

Endothelial Cells ◽

Inflammatory Response ◽

Host Defense ◽

Conformational Changes ◽

Acute Phase Reactant ◽

Dependent Manner ◽

C Reactive Protein ◽

Inflammatory Microenvironment ◽

Reactive Protein ◽

Phase Reactant

Abstract The prototypic acute-phase reactant C-reactive protein (CRP) has long been recognized as a useful marker and gauge of inflammation. CRP also plays an important role in host defense against invading pathogens as well as in inflammation. CRP consists of five identical subunits arranged as a cyclic pentamer. CRP exists in at least two conformationally distinct forms, i.e. native pentameric CRP (pCRP) and modified/monomeric CRP (mCRP). These isoforms bind to distinct receptors and lipid rafts, and exhibit distinct functional properties. Dissociation of pCRP into its subunits occurs within the inflammatory microenvironment and newly formed mCRP may then contribute to localizing the inflammatory response. Accumulating evidence indicates that pCRP possesses both pro- and anti-inflammatory actions in a context-dependent manner, whereas mCRP exerts potent pro-inflammatory actions on endothelial cells, endothelial progenitor cells, leukocytes and platelets, and thus may amplify inflammation. Here, we review recent advances that may explain how conformational changes in CRP contribute to shaping the inflammatory response and discuss CRP isomers as potential therapeutic targets to dampen inflammation.

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Mouse C-reactive protein. Generation of cDNA clones, structural analysis, and induction of mRNA during inflammation

Biochemical Journal ◽

10.1042/bj2660283 ◽

1990 ◽

Vol 266 (1) ◽

pp. 283-290 ◽

Cited By ~ 55

Author(s):

A S Whitehead ◽

K Zahedi ◽

M Rits ◽

R F Mortensen ◽

J M Lelias

Keyword(s):

Acute Phase ◽

Acute Phase Reactant ◽

Untranslated Regions ◽

Leader Peptide ◽

Cdna Clones ◽

C Reactive Protein ◽

Reactive Protein ◽

Phase Reactant ◽

Inflammatory Stimuli ◽

A Minor

A full-length C-reactive protein (CRP) cDNA clone has been isolated from a CBA/J-strain-mouse acute-phase liver library. The 1614-nucleotide cDNA specifies mRNA 5′ and 3′ untranslated regions of 81 and 858 bases respectively that flank 675 bases encoding mouse pre-CRP. The derived amino acid sequence predicts a 19-residue leader peptide followed by a 206-residue mature mouse CRP that shows considerable sequence identity with both human and rabbit CRP. Northern-blot analysis of mouse liver CRP mRNA concentrations after inflammatory stimuli and comparison with hepatic induction of mRNA for the major mouse acute-phase protein serum amyloid P component established that CRP, a major acute-phase reactant in human and rabbit, is a minor acute-phase reactant in mouse. The size and organization of the mouse CRP mRNA 5′ and 3′ untranslated regions are significantly different from those of human and rabbit CRP mRNA and may have implications for its anomalous minimal induction during acute inflammation.

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