Cardiovascular effects of nose-only water-pipe smoking exposure in mice

2013 ◽  
Vol 305 (5) ◽  
pp. H740-H746 ◽  
Author(s):  
Abderrahim Nemmar ◽  
Priya Yuvaraju ◽  
Sumaya Beegam ◽  
Annie John ◽  
Haider Raza ◽  
...  
Keyword(s):  
Middle Eastern ◽  
Plasma Concentrations ◽  
Cardiovascular Effects ◽  
Major Type ◽  
Water Pipe ◽  
Occlusion Time ◽  
Cardiac Inflammation ◽  
Smoking Exposure ◽  
Tnf Α

Water-pipe smoking (WPS) is a major type of smoking in Middle Eastern countries and is increasing in popularity in Western countries and is perceived as relatively safe. However, data on the adverse cardiovascular effects of WPS are scarce. Here, we assessed the cardiovascular effects of nose-only exposure to mainstream WPS generated by commercially available honey-flavored “moasel” tobacco in BALB/c mice. The duration of the session was 30 min/day for 1 mo. Control mice were exposed to air. WPS caused a significant increase of systolic blood pressure (SBP) in vivo (+13 mmHg) and plasma concentrations of IL-6 (+30%) but not that of TNF-α. Heart concentrations of IL-6 (+184%) and TNF-α (+54%) were significantly increased by WPS. Concentrations of ROS (+95%) and lipid peroxidation (+27%) were significantly increased, whereas those of GSH were decreased (−21%). WPS significantly shortened the thrombotic occlusion time in pial arterioles (−46%) and venules (40%). Plasma von Willebrand factor concentrations were significantly increased (+14%) by WPS. Erythrocyte numbers (+15%) and hematocrit (+17%) were significantly increased. Blood samples taken from mice exposed to WPS and exposed to ADP showed significant platelet aggregation compared with air-exposed mice. WPS caused a significant shortening of activated partial thromboplastin time (−45%) and prothrombin time (−13%). We conclude that 1-mo nose-only exposure to WPS increased SBP and caused cardiac inflammation, oxidative stress, and prothrombotic events. Our findings provide plausible elucidation that WPS is injurious to the cardiovascular system.

scholarly journals Short-Term Nose-Only Water-Pipe (Shisha) Smoking Exposure Accelerates Coagulation and Causes Cardiac Inflammation and Oxidative Stress in Mice

2015 ◽  
Vol 35 (2) ◽  
pp. 829-840 ◽  
Author(s):  
Abderrahim Nemmar ◽  
Priya Yuvaraju ◽  
Sumaya Beegam ◽  
Badreldin H Ali
Keyword(s):  
Oxidative Stress ◽  
Platelet Aggregation ◽  
Plasma Concentrations ◽  
Cardiovascular Effects ◽  
Water Pipe ◽  
Short Term ◽  
Cardiac Inflammation ◽  
Short Term Exposure ◽  
And Oxidative Stress

Background/Aim: Water-pipe smoking (WPS) has acquired worldwide popularity, and is disseminating particularly rapidly in Europe and North America. However, little is known about the short-term cardiovascular effects of WPS. Methods: Presently, we assessed the short-term cardiovascular effects of nose-only exposure to mainstream WPS in BALB/c mice for 30 min/day for 5 consecutive days. Control mice were exposed to air. At the end of the exposure period, several cardiovascular endpoints were measured. Results: WPS did not affect the number of leukocytes and the plasma concentrations of C-reactive protein, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6). Likewise, plasma levels of lipid peroxidation (LPO), reduced glutathione (GSH) and catalase were not affected by WPS. By contrast, WPS aggravated in vivo thrombosis by shortening the thrombotic occlusion time in pial arterioles and venules. The number of circulating platelets was reduced by WPS suggesting the occurrence of platelet aggregation in vivo. Elevated concentrations of fibrinogen and plasminogen activator inhibitor-1 were seen after the exposure to WPS. Blood samples taken from mice exposed to WPS and exposed to adenosine diphosphate showed more platelet aggregation. The heart concentrations of IL-6 and TNFα were augmented by WPS. Likewise, heart levels of LPO, reactive oxygen species and the antioxidants catalase and GSH were increased by WPS. However, the systolic blood pressure and heart rate were not affected by WPS. Conclusion: It can be concluded that short-term exposure to WPS exerts procoagulatory effects and induce cardiac inflammation and oxidative stress. At the time point investigated, there was no evidence for blood inflammation or oxidative stress.

scholarly journals Water-Pipe Smoke Exposure-Induced Circulatory Disturbances in Mice, and the Influence of Betaine Supplementation Thereon

2017 ◽  
Vol 41 (3) ◽  
pp. 1098-1112 ◽  
Author(s):  
Abderrahim Nemmar ◽  
Suhail Al-Salam ◽  
Sumaya Beegam ◽  
Priya Yuvaraju ◽  
Abderrahim Oulhaj ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Plasma Concentrations ◽  
Immunohistochemical Analysis ◽  
Plasminogen Activator Inhibitor ◽  
Water Pipe ◽  
Plasminogen Activator Inhibitor 1 ◽  
Factor Α ◽  
Air Control

Background/Aims: It has been shown, both experimentally and clinically, that water-pipe smoke (WPS) exposure adversely affects the cardiovascular system (CVS) through the generation of oxidative stress and inflammation. Betaine, a naturally occurring compound in common foods, has antioxidant and anti-inflammatory actions. However, its potential to mitigate the adverse effect of WPS on the CVS has never been reported before. This is the subject of this study in mice. Methods: Mice were exposed daily for 30 min to either normal air (control), or to WPS for two consecutive weeks. Betaine was administered daily by gavage at a dose of 10mg/kg, 1h before either air or WPS exposure. Results: Betaine mitigated the in vivo prothrombotic effect of WPS in pial arterioles and venules. Moreover, it reversed the WPS-induced decrease in circulating platelets. Likewise, betaine alleviated platelet aggregation in vitro, and the shortening of activated partial thromboplastin time and prothrombin time induced by WPS. Betaine reduced the increase of plasminogen activator inhibitor-1 and fibrinogen concentrations in plasma induced by WPS. Betaine also diminished the WPS-induced increase of plasma concentrations of interleukin 6 and tumor necrosis factor α, and attenuated the increase of lipid peroxidation and superoxide dismutase. Immunohistochemical analysis of the heart revealed an increase in the expression of inducible nitric oxide synthase and cytochrome C by cardiomyocytes of the WPS-exposed mice. These effects were averted by betaine. Conclusion: Our findings suggest that betaine treatment significantly mitigated WPS-induced hypercoagulability, and inflammation, as well as systemic and cardiac oxidative stress.

Abstract 88: Microrna-21* Controls Sepsis-induced Cardiac Dysfunction

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hui Wang ◽  
Yihua Bei ◽  
Jing Shi ◽  
Wei Sun ◽  
Hui Liu ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Cardiac Contractility ◽  
Cardiac Metabolism ◽  
Myocardial Inflammation ◽  
Chain Reactions ◽  
Cardiac Inflammation ◽  
Over Expression ◽  
Polymerase Chain Reactions ◽  
Tnf Α

Background: Sepsis-induced cardiac dysfunction is charactered by cardiac contractility dysfunction, myocardial inflammation and cardiac metabolism abnormal. Dysfunction of microRNAs (miRNAs, miRs) contributes to a variety of human diseases. However, their roles in sepsis-induced cardiac dysfunction are unclear. Methods and Results: Cardiac dysfunction was induced by E.coli lipopolysaccharide (LPS) administration in mice and 8 dysregulated miRNAs were identified by miRNA arrays. Among them, miR-21* was found to be increased most obviously as determined by quantitative reverse transcription polymerase chain reactions. Inhibition of miR-21* in vivo by antagomir attenuated the reduction of factional shortening (FS) and ejection fraction (EF) induced by LPS administration while forced over-expression of miR-21* in vivo by agomir accelerated LPS-induced cardiac dysfunction. Besides that, S100A8 and S100A9, two genes related to cardiac contractility were also found to be regulated in vivo by injection of miR-21* agomirs and antagomirs. Interestingly, cardiac inflammation indictors such as TNF-α and IL-6 and cardiac metabolism regulators including PPAR family, CD36, FATP, GLUT1, GLUT4, PDK4 were not changed by miR-21* in vivo. These data indicate that miR-21* controls sepsis-induced cardiac dysfunction by direct affecting cardiac contractility instead of cardiac inflammation and metabolism. SORBS2 was identified as a target gene of miR-21* and it was decreased by miR-21* agomir and increased by miR-21* antagomir in vivo. In consist with this, circulating levels of miR-21* were also increased in patients with sepsis compared with healthy controls. Conclusion: miR-21* controls sepsis-induced cardiac dysfunction by regulating SORBS2. Inhibition of miR-21* represents a novel therapeutic strategy for sepsis-induced cardiac dysfunction.

scholarly journals Short-term alpha- or gamma-delta-enriched tocopherol oil supplementation differentially affects the expression of proinflammatory mediators: selective impacts on characteristics of protein tyrosine nitration in vivo

2013 ◽  
Vol 3 (1) ◽  
pp. 6 ◽  
Author(s):  
Ted H. Elsasser ◽  
Stanislaw Kahl ◽  
Katie M. Lebold ◽  
Maret G. Traber ◽  
Jessica Shaffer ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Short Term ◽  
Proinflammatory Response ◽  
E Coli ◽  
Amyloid A ◽  
Proinflammatory Mediators ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor

While vitamin E has been used for decades in cattle diets, the principle form used traditionally is the synthetic α-isoform acetate or succinate and largely no data exist on the biological partitioning or functionality of the major naturally occurring γ- and δ-isoforms in cattle. Using tyrosine 3’-nitrated protein (pNT) as a biomarker of nitrosative cell stress, we sought to evaluate the effectiveness of short-term feeding supplementation of high content natural α-tocopherol (<em>α-T</em>, 96% α-isomer) compared to high content γ- and δ-enriched low α-content mixed tocopherol oils (<em>γ-T</em>, ~70% <em>γ-</em>, 20% δ-, &lt;5% α-isoform) to mitigate systemic and hepatic aspects of the proinflammatory response to endotoxin (LPS). Calves fed diets supplemented with <em>α-T</em>, <em>γ-T</em> for five days or no tocopherol supplement (<em>T0E</em>) were challenged with a low-level of LPS (0.25 μg/kg, iv, <em>E. coli </em>055:B5) sufficient to effect a liver nitration response. As fed,<em> α-T</em> or <em>γ-T</em> increased plasma and liver content of the respective tocopherols reflecting their relative abundance in the respective diets. Plasma or tissue mediators and biomarkers of the proinflammatory response [plasma concentrations of tumor necrosis factor-α (TNF-α, P&lt;0.001), nitrate+nitrite (NOx, P&lt;0.01), and serum amyloid A (SAA, P&lt;0.001)], and general liver content of pNT (P&lt;0.005) increased after LPS. LPS-mediated increases in TNF-α were not dif- ferent between diet treatments; both plasma NOx (P&lt;0.05) and generalized liver pNT (P&lt;0.03) responses were attenuated significantly in <em>α-T </em>and <em>γ-T versus T0E calves</em>. Plasma SAA was significantly decreased in γ-T calves at 24 h post-LPS relative to responses in <em>α-T</em> or <em>T0E </em>calves. The nitration of the mitochondrial proteins 24 h post-LPS was not only attenuated in <em>α-T</em> and <em>γ-T vs T0E</em>, but also the mitigating effect of <em>γ-T</em> on these specific nitration events was greater than that of <em>α-T </em>(P&lt;0.01). Results are consistent with the concept that short-term <em>α-T</em> or <em>γ-T</em> supplementation can effectively decrease proinflammatory liver pNT after LPS; some mitochondrial nitration targets may be better protected with prophylactic supplementation with γ-,δ-tocopherol enriched oil.

Role of interleukin-6 in cardiac inflammation and dysfunction after burn complicated by sepsis

2007 ◽  
Vol 292 (5) ◽  
pp. H2408-H2416 ◽  
Author(s):  
Hongchao Zhang ◽  
Huan-You Wang ◽  
Rhonda Bassel-Duby ◽  
David L. Maass ◽  
William E. Johnston ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Total Body Surface Area ◽  
Left Ventricular ◽  
Myocardial Inflammation ◽  
Contractile Dysfunction ◽  
Cardiac Inflammation ◽  
Tnf Α

To examine the role of myocardial interleukin-6 (IL-6) in myocardial inflammation and dysfunction after burn complicated by sepsis, we performed 40% total body surface area contact burn followed by late (7 days) Streptococcus pneumoniae pneumonia sepsis in wild-type (WT) mice, IL-6 knockout (IL-6 KO) mice, and transgenic mice overexpressing IL-6 in the myocardium (TG). Twenty-four hours after sepsis was induced, isolated cardiomyocytes were harvested and cultured in vitro, and supernatant concentrations of IL-6 and tumor necrosis factor (TNF)-α were measured. Cardiomyocyte intracellular calcium ([Ca2+]i) and sodium ([Na+]i) concentrations were also determined. Separate mice in each group underwent in vivo global hemodynamic and cardiac function assessment by cannulation of the carotid artery and insertion of a left ventricular pressure volume conductance catheter. Hearts from these mice were collected for histopathological assessment of inflammatory response, fibrosis, and apoptosis. In the WT group, there was an increase in cardiomyocyte TNF-α, [Ca2+]i, and [Na+]i after burn plus sepsis, along with cardiac contractile dysfunction, inflammation, and apoptosis. These changes were attenuated in the IL-6 KO group but accentuated in the TG group. We conclude myocardial IL-6 mediates cardiac inflammation and contractile dysfunction after burn plus sepsis.

scholarly journals Nicotine aggravates the brain postischemic inflammatory response

2011 ◽  
Vol 300 (4) ◽  
pp. H1518-H1529 ◽  
Author(s):  
Shayna T. Bradford ◽  
Svetlana M. Stamatovic ◽  
Raj S. Dondeti ◽  
Richard F. Keep ◽  
Anuska V. Andjelkovic
Keyword(s):  
Inflammatory Response ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Plasma Concentrations ◽  
Neurological Deficits ◽  
Cell Phenotype ◽  
Tnf Α ◽  
The Brain

A substantial body of evidence suggests that nicotine adversely affects cerebral blood flow and the blood-brain barrier and is a risk factor for stroke. The present study investigated the effect of nicotine on cerebrovascular endothelium under basal and ischemia/reperfusion injury under in vivo condition. Nicotine (2 mg/kg sc) was administered to mice over 14 days, which resulted in plasma nicotine levels of ∼100 ng/ml, reflecting plasma concentrations in average to heavy smokers. An analysis of the phenotype of isolated brain microvessels after nicotine exposure indicated higher expression of inflammatory mediators, cytokines (IL-1β, TNF-α, and IL-18), chemokines (CCL2 and CX3CL1), and adhesion molecules (ICAM-1, VCAM-1, and P-selectins), and this was accompanied by enhanced leukocyte infiltration into brain during ischemia/reperfusion ( P < 0.01). Nicotine had a profound effect on ischemia/reperfusion injury; i.e., increased brain infarct size ( P < 0.01), worse neurological deficits, and a higher mortality rate. These experiments illuminate, for the first time, how nicotine regulates brain endothelial cell phenotype and postischemic inflammatory response at the brain-vascular interface.

A Chemical APC Mimetic Protects Endothelium from Thromboinflammatory Injury

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3835-3835 ◽  
Author(s):  
Karen E.P. De Ceunynck ◽  
Christian G. Peters ◽  
Sharjeel A. Chaudhry ◽  
Abhishek Jain ◽  
Sarah J. Higgins ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Conflicts Of Interest ◽  
Anticoagulant Activity ◽  
Plasma Concentrations ◽  
Leukocyte Rolling ◽  
Protective Effects ◽  
Laser Injury ◽  
Tnf Α ◽  
Soluble E Selectin

Abstract Stimulation of protease-activated receptor 1 (PAR1) on endothelium by activated protein C (APC) is protective in animal models of inflammation and APC has been used clinically in sepsis and wound healing. Clinical use of APC in sepsis, however, was terminated as it was compromised by APC's anticoagulant activity, which is associated with bleeding and limits its dosing in patients. We used a small molecule approach to circumvent this problem. With support from the Molecular Libraries Program, we screened 302,457 compounds to identify small molecules that modulated PAR1-mediated platelet activation. One class of PAR1-targeted compounds, which we termed parmodulins, was found to act at the cytosolic face of PAR1, at the G-protein binding sites. When evaluated in endothelial cell cultures,parmodulin 1 (PM1) and parmodulin 2 (PM2) inhibited apoptosis induced by thrombin, TNF-α, or staurosporine, in a manner similar to APC. PAR1 knockdown using siRNA abolished these protective effects demonstrating that parmodulins elicit a cytoprotective pathway by acting through PAR1. To assess the mechanism of action of parmodulin cytoprotection, we first evaluated proximal signaling mechanisms. Parmodulins stimulated phosphorylation of PI3-kinase and Akt in endothelium. Inhibition of Gβγ blocked parmodulin-induced phosphorylation of Akt, indicating that parmodulins act at the cytosolic face of PAR1 by releasing Gβγ. Transcriptional profiling of over 30,000 genes and specific evaluation of NF-kB transcriptional activation showed that exposure to PM2 blocked TNF-α-induced transcriptional activation. In addition to interfering with inflammatory signaling, parmodulins also stimulated the upregulation of cytoprotective proteins such as stanniocalcin-1. Since our premise was that parmodulins could achieve cytoprotective effects without anticoagulant effects, we compared dose curves of APC versus PM2 in both apoptosis assays and standard clotting assays. APC prolonged the aPTT at concentrations lower than those required to achieve cytoprotection of the endothelium. The low APC concentration used in our study was similar to plasma concentrations measured in clinical studies. Hence, these data were consistent with the fact that clinical bleeding was observed at doses of APC used for sepsis. In contrast, despite inhibiting apoptosis as effectively as APC, PM2 had no effect on plasma aPTT at any concentration. Nonetheless, PM2 was able to inhibit LPS- and TNF-α-induced thrombin generation and FXa activation on endothelium owing to its cytoprotective effect. PM2 also prevented TNF-α-induced accumulation of platelets on endothelium in bioengineered microvessels. These data demonstrate that PM2 can reduce inflammation-induced endothelial pro-thrombotic phenotype even without directly inhibiting coagulation factors. To assess the endothelial protective effects of PM2 in vivo we evaluated leukocyte rolling in cremaster venules of mice. Infusion of PM2 significantly reduced surgery-induced leukocyte rolling flux compared to vehicle-treated mice. As selectins are critically involved in leukocyte rolling we monitored soluble E-selectin levels in LPS-induced inflammation. Treatment of mice with PM2 significantly reduced the LPS-induced release of soluble E-selectin. Previously, we demonstrated that PM2 blocks platelet accumulation in a mouse laser injury model of thrombus formation. We here show that infusion of PM2 also significantly reduces fibrin accumulation to 25% of control (p<0.001) at the site of laser injury. Together our data show that PM2 exerts endothelial-mediated anti-inflammatory, anti-coagulant and anti-thrombotic effects in vitro and in vivo. These results demonstrate that modulating PAR1 at the cytosolic face could represent an alternative approach to APC in the treatment of thromboinflammatory disorders like sepsis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Undaria pinnatifida Fucoidan-Rich Extract Induces Both Innate and Adaptive Immune Responses

2019 ◽  
Vol 14 (8) ◽  
pp. 1934578X1987372
Author(s):  
Hwan H. Lee ◽  
Yoo J. Cho ◽  
Daeung Yu ◽  
Donghwa Chung ◽  
Gun-Hee Kim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cd8 T Cells ◽  
Undaria Pinnatifida ◽  
Plasma Concentrations ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Tnf Α ◽  
Ifn Γ

Fucoidans are widely used as an ingredient of dietary supplements. We investigated the immune stimulatory activities of Undaria pinnatifida ( Alariaceae) fucoidan-rich extract (UPF-RE) in vitro as well as in vivo . In vitro, the extract stimulated Raw 264.7 cells to produce significant nitric oxide (NO) metabolites and cytokines (TNF-α, IL-1α, IL-1β, and IL-6). It also induced the proliferation of primary mouse splenocytes and the secretion of IL-4, which correlated with the phosphorylation of Extracellular-signal-regulated kinase (ERK) protein. In in vivo experiments, first, 50 mg/kg of 3 different types of UPF-RE, DSU02, DSU02L (low molecular weight, <3 kDa), and DSU02H (high molecular weight, >10 kDa), were orally administered to C57BL/6 mice. After 14 days, the frequencies of CD3+, CD4+, and CD8+ T cells and NK cells from each group were analyzed. Plasma concentrations of TNF-α and IFN-γ were determined. The frequencies of CD3+ and CD4+ showed a statistically significant increase in splenocytes isolated from the DSU02 and DSU02H groups. Also, there was significant production of TNF-α and IFN-γ from the DSU02 group. Second, 3 different concentrations of DSU02 (50, 100, and 150 mg/kg) were orally administered. After 14 days, the proliferative capacity of CD3+, CD4+, and CD8+ T cells was investigated, and the plasma concentrations of IgM and total IgG were determined. Plasma concentration of IgM from the DSU02 150 mg/kg group was statistically significantly higher compared with that from the other groups. We suggest that UPF-RE could be a good candidate for a natural immune stimulator to induce innate as well as adaptive immune responses.

Effects of chronic in-vivo treatments with protease-activated receptor 2 agonist on endothelium function and blood pressures in mice

2013 ◽  
Vol 91 (4) ◽  
pp. 295-305 ◽  
Author(s):  
Keon H. Hughes ◽  
Enoka P. Wijekoon ◽  
James E. Valcour ◽  
Elizabeth W. Chia ◽  
John J. McGuire
Keyword(s):  
Blood Pressure ◽  
Vascular Dysfunction ◽  
Plasma Concentrations ◽  
Mesenteric Arteries ◽  
Tnf Α ◽  
Endothelium Function ◽  
Factor Α ◽  
Isolated Arteries ◽  
Protease Activated Receptor 2

Short-term treatments with protease-activated receptor 2-activating peptides (PAR2-AP) induce endothelium-dependent vasodilation and decrease blood pressure. In this study, we tested the effect of chronic in-vivo treatment with PAR2-AP on the blood pressure and endothelium function of mice. Male PAR2 wild-type (WT) and par2-deficient (KO) mice received subcutaneous infusions of either saline, low (PAR2-LD), or high (PAR2-HD) doses of 2-furoyl-LIGRLO-amide for 1 or 2 weeks. In each treatment group, endothelium function was assessed in isolated arteries. Blood pressure, heart rate, and locomotor activity were recorded by radiotelemetry, and levels of tumour nercrosis factor α (TNF-α) and interkeukin 1β (IL-1β) were measured in plasma samples by ELISA. The relaxation of WT aortas and mesenteric arteries induced by PAR2-AP was decreased by PAR2-LD and PAR2-HD. In mesenteric arteries, PAR2-LD and PAR2-HD decreased the relaxation induced by acetylcholine, but not by nitroprusside; in aortas, PAR2-LD and PAR2-HD caused differential decreases in the relaxations induced by acetylcholine and nitroprusside. Only PAR2-HD lowered systolic arterial pressures in WT, when compared with all of the other groups. TNF-α and IL-1β plasma concentrations were not different among the groups. We conclude that the systolic blood pressure of unrestrained mice can be lowered by chronic in-vivo activation of PAR2; however, this effect is countered by receptor desensitization and the concomitant development of endothelium and vascular dysfunction.

scholarly journals Cytokine modulation by PX differently affects specific acute phase proteins during sepsis in rats

1998 ◽  
Vol 275 (5) ◽  
pp. R1412-R1419 ◽  
Author(s):  
Laure Voisin ◽  
Denis Breuillé ◽  
Benoît Ruot ◽  
Cécile Rallière ◽  
Fabienne Rambourdin ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Acute Phase ◽  
Acute Phase Proteins ◽  
Plasma Concentrations ◽  
Plasma Corticosterone ◽  
Mrna Levels ◽  
Cytokine Modulation ◽  
Tnf Α ◽  
Treatment Support

To explore the regulation of the acute phase response in vivo, the effects of pentoxifylline (PX) treatment (100 mg/kg ip 1 h before infection) were investigated in infected and pair-fed rats 2 and 6 days after an intravenous injection of live bacteria ( Escherichia coli). PX treatment prevented the increase in plasma tumor necrosis factor (TNF)-α (peak 1.5 h after the infection) and resulted in an 84 and 61% inhibition of plasma interleukin (IL)-1β and IL-6, respectively (peaks at 3 h). Plasma corticosterone kinetics were not modified by the treatment. Infection increased α1-acid glycoprotein (AGP), α2-macroglobulin (A2M), and fibrinogen plasma concentrations and decreased albumin levels. PX significantly reduced AGP plasma concentration as early as day 2 in infected animals but reduced A2M and fibrinogen plasma levels only at day 6. The treatment had no effect on the albumin plasma concentration. Hepatic AGP and fibrinogen mRNA levels increased in infected rats, whereas those of A2M were unchanged and those of albumin were decreased. Two days after infection, AGP and fibrinogen mRNA levels were reduced in treated infected animals. PX was ineffective in modifying those of A2M and albumin. These data demonstrate, in vivo, that different acute phase proteins are individually regulated in sepsis. The in vivo effects of PX treatment support the hypothesis that TNF-α plays an important role in the regulation of AGP production, whereas other factors seem to be involved in the regulation of A2M, fibrinogen, and albumin expression.

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