Infusion of Pharmaceutical-Grade Natural Human C-Reactive Protein Is Not Proinflammatory in Healthy Adult Human Volunteers

Lane, Thirusha; Wassef, Nancy; Poole, Stephen; Mistry, Yogesh; Lachmann, HJ; Gillmore, Julian D.; Hawkins, Philip N.; Pepys, Mark B.

doi:10.1161/circresaha.114.302770

Cited by 66 publications

(60 citation statements)

References 33 publications

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“…30 In accordance with our previous data, the present findings do not indicate that pCRP possesses intrinsic proinflammatory potential, and CRP was not deposited outside areas of focal inflammation, which confirms the findings of a recent study in which pCRP infusions in healthy volunteers showed no proinflammatory effect. 31 The ability of CRP to mediate any inflammatory effects was dependent on a preexisting localized inflammatory microenvironment with PLA2-mediated membrane changes. In the clinical setting, this is reflected by the fact that levels of circulating pCRP rise 6 to 12 hours after the inflammatory insult.…”

Section: Discussionmentioning

confidence: 99%

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

et al. 2014

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Recent animal work has suggested that injection of human pCRP can increase myocardial infarct size in a rat myocardial Background-The relevance of the dissociation of circulating pentameric C-reactive protein (pCRP) to its monomeric subunits (mCRP) is poorly understood. We investigated the role of conformational C-reactive protein changes in vivo. Methods and Results-We identified mCRP in inflamed human striated muscle, human atherosclerotic plaque, and infarcted myocardium (rat and human) and its colocalization with inflammatory cells, which suggests a general causal role of mCRP in inflammation. This was confirmed in rat intravital microscopy of lipopolysaccharide-induced cremasteric muscle inflammation. Intravenous pCRP administration significantly enhanced leukocyte rolling, adhesion, and transmigration via localized dissociation to mCRP in inflamed but not noninflamed cremaster muscle. This was confirmed in a rat model of myocardial infarction. Mechanistically, this process was dependent on exposure of lysophosphatidylcholine on activated cell membranes, which is generated after phospholipase A2 activation. These membrane changes could be visualized intravitally on endothelial cells, as could the colocalized mCRP generation. Blocking of phospholipase A2 abrogated C-reactive protein dissociation and thereby blunted the proinflammatory effects of C-reactive protein.Identifying the dissociation process as a therapeutic target, we stabilized pCRP using 1,6-bis(phosphocholine)-hexane, which prevented dissociation in vitro and in vivo and consequently inhibited the generation and proinflammatory activity of mCRP; notably, it also inhibited mCRP deposition and inflammation in rat myocardial infarction. Conclusions-These results provide in vivo evidence for a novel mechanism that localizes and aggravates inflammation via phospholipase A2-dependent dissociation of circulating pCRP to mCRP. mCRP is proposed as a pathogenic factor in atherosclerosis and myocardial infarction. Most importantly, the inhibition of pCRP dissociation represents a promising, novel anti-inflammatory therapeutic strategy. (Circulation. 2014;130:35-50.)

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Section: Discussionmentioning

confidence: 99%

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

et al. 2014

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“…In contrast, Mendelian randomisation studies showed that mild lifelong upregulation of CRP has no impact on HbA 1c , HOMA-IR or incident type 2 diabetes [28]. The recent finding that infusion of pharmaceutical-grade, endotoxin-free human CRP had no significant clinical or proinflammatory effects, at least in healthy adults [29], also supports the view that elevated hsCRP levels may be considered a risk marker or indicator rather than a genuine risk factor.…”

Section: Associations Between Immunological Variables and Deterioratimentioning

confidence: 98%

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study

et al. 2015

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Aims/hypothesis The role of biomarkers of subclinical inflammation in the early deterioration of glycaemia before type 2 diabetes is largely unknown. We hypothesised that increased levels of circulating proinflammatory biomarkers and decreased circulating adiponectin would be associated with 7 year increases of HbA 1c in non-diabetic individuals. Methods This study was based on individuals who participated in the prospective Cooperative Health Research in the Region of Augsburg (KORA) S4 survey (1999)(2000)(2001) and the 7 year follow-up KORA F4 (2006-2008) survey. Individuals with type 2 diabetes at baseline or with a diagnosis of diabetes in the period between both surveys were excluded, which left a sample of 850 men and women. Multivariable linear regression analyses were performed to assess associations among baseline values of leucocyte count and levels of acute-phase proteins (high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA] and fibrinogen), IL-6 and adiponectin with changes in HbA 1c between baseline and follow-up. Results A high leucocyte count and high hsCRP, SAA and IL-6 levels were positively associated with changes in HbA 1c after adjusting for age, sex, lifestyle factors and baseline HbA 1c . In contrast, the adiponectin level was inversely associated with changes in HbA 1c (p value between <0.0001 and 0.020). The associations of leucocyte count and levels of hsCRP and SAA with HbA 1c changes remained significant after additional adjustment for waist circumference and circulating lipids at baseline and for the 7 year change in waist circumference (p value between 0.004 and 0.045).Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3679-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users. Conclusions/interpretation An elevated leucocyte count and elevated hsCRP and SAA were associated with early deterioration of glycaemia before the diagnosis of type 2 diabetes. These associations were largely independent of baseline abdominal adiposity and increases in waist circumference.

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“…36 However, as discussed earlier, it has been proven to be a sensitive and independent marker of chronic inflammation in patients with cardiovascular diseases. 37 Taken together, this would suggest that an inflammation-dependent increase of CRP levels-in contrast to genetically determined elevated levels of CRP-is a prognostic marker for cardiovascular disease risk.…”

Section: Downloaded Frommentioning

confidence: 96%

Combined Effects of Inflammatory Status and Carotid Atherosclerosis

Mayer

Binder

Wagner

et al. 2016

Stroke

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Background and Purpose— Inflammatory responses play a key role in atherogenesis. The aim of this study was to assess the prognostic value of hsCRP (high-sensitivity C-reactive protein) and to evaluate whether degree of carotid stenosis and serum levels of hsCRP jointly predict long-term mortality in asymptomatic patients with carotid atherosclerosis. Methods— One thousand sixty-five patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. Results— During a median of 11.81 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. The risk of all-cause and cardiovascular mortality significantly increased in patients with elevated serum levels of hsCRP (the adjusted hazard ratio for cardiovascular mortality per increase of 1 mg/dL of hsCRP levels was 1.47; P <0.001). Patients with a high degree of carotid stenosis and increased hsCRP levels were particularly at risk of adverse outcome. Patients with carotid narrowing over 50% and hsCRP levels >0.29 mg/dL (=median) had nearly twice as high a risk of cardiovascular mortality compared with patients with carotid stenosis of <50% and hsCRP levels <0.29 mg/dL (adjusted hazard ratio 1.89; P <0.001). Improvement in risk stratification with combined assessment of carotid stenosis and hsCRP was confirmed by an improvement of the continuous net reclassification improvement with 18% for all-cause mortality and 15% for cardiovascular mortality compared with the degree of carotid stenosis alone ( P <0.01). Conclusions— Measurement of hsCRP in combination with ultrasound investigations of the carotid arteries at a single time point provides additional prognostic information for patients with asymptomatic carotid atherosclerosis.

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Infusion of Pharmaceutical-Grade Natural Human C-Reactive Protein Is Not Proinflammatory in Healthy Adult Human Volunteers

Cited by 66 publications

References 33 publications

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

Dissociation of Pentameric to Monomeric C-Reactive Protein Localizes and Aggravates Inflammation

Association of subclinical inflammation with deterioration of glycaemia before the diagnosis of type 2 diabetes: the KORA S4/F4 study

Combined Effects of Inflammatory Status and Carotid Atherosclerosis

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