Bactericidal/permeability increasing protein attenuates the myocardial inflammation/dysfunction that occurs with burn complicated by subsequent infection

2007 ◽  
Vol 103 (3) ◽  
pp. 948-958 ◽  
Author(s):  
Jureta W. Horton ◽  
David L. Maass ◽  
D. Jean White ◽  
Joseph P. Minei
Keyword(s):  
Contractile Function ◽  
Total Body Surface Area ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cytokine Secretion ◽  
Myocardial Inflammation ◽  
Susceptibility To Infection ◽  
Tnf Α ◽  
Total Body ◽  
T Values

Intubation and mechanical ventilation after burn contribute to pneumonia-related infection. Although postburn presence or absence of endotoxin has been described, inactivation of Toll-like receptor 4 signaling has been shown to improve postburn organ function, suggesting that LPS participates in burn-related susceptibility to infection. We hypothesized that bactericidal/permeability-increasing protein (rBPI) given postburn would attenuate myocardial inflammation/dysfunction associated with postburn septic challenge given 7 days postburn. Rats were given burn over 40% total body surface area, lactated Ringer 4 ml·kg−1·% burn−1; burns received either vehicle or rBPI, 1 mg·kg−1·h−1for 48 h postburn. Postburn day 7, subgroups of burns and shams were given intratracheal Klebsiella pneumoniae, 4 × 106CFU to produce burn complicated by sepsis; additional sham and burn subgroups received intratracheal vehicle to produce sham sepsis. Vehicle-treated groups: 1) sham burn + sham sepsis 2) sham burn + sepsis, 3) burn + sham sepsis, 4) burn + sepsis. rBPI-treated groups: 5) sham burn + sham sepsis, 6) sham burn + sepsis, 7) burn + sham sepsis, 8) burn + sepsis. Cardiomyocyte cytokine secretion and myocardial function were studied 24 h after septic challenge, postburn day 8. Pneumonia-related infection 8 days after vehicle-treated burn produced myocyte cytokine secretion (pg/ml), indicated by increased myocyte TNF-α, 549 ± 46; IL-1β, 50 ± 8; IL-6, 286 ± 3 levels compared with levels in sham myocytes (TNF-α, 88 ± 11; IL-1β, 7 ± 1; IL-6, 74 ± 10; P < 0.05). Contractile dysfunction was evident from lower left ventricular pressure ±dP/d t values in this group compared with sham. rBPI attenuated myocyte cytokine responses to septic challenge and improved contractile function, suggesting that burn-related mobilization of microbial-like products contribute to postburn susceptibility to infection.

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.

Hypertonic saline-dextran suppresses burn-related cytokine secretion by cardiomyocytes

2001 ◽  
Vol 280 (4) ◽  
pp. H1591-H1601 ◽  
Author(s):  
Jureta W. Horton ◽  
David L. Maass ◽  
Jean White ◽  
Billy Sanders
Keyword(s):  
Hypertonic Saline ◽  
Burn Injury ◽  
Contractile Function ◽  
Total Body Surface Area ◽  
Isotonic Saline ◽  
Cytokine Secretion ◽  
Cardiac Contraction ◽  
Burn Trauma ◽  
Lps Challenge ◽  
Tnf Α

Whereas hypertonic saline-dextran (HSD, 7.5% NaCl in 6% D70) improves cardiac contractile function after burn trauma, the mechanisms of HSD-related cardioprotection remain unclear. We recently showed that cardiomyocytes secrete tumor necrosis factor-α (TNF-α), a response that was enhanced by burn trauma. This study addressed the question: does HSD modulate cardiac contraction/relaxation by altering cardiomyocyte TNF-α secretion? Wistar-Furth rats (325 g) were given a burn injury over 40% of the total body surface area and were then randomized to receive a bolus of either isotonic saline or HSD (4 ml/kg, n = 14 rats/group). Sham burn rats were given either isotonic saline or HSD ( n = 14 rats/group) to provide appropriate controls for the two burn groups. Hearts were isolated 24 h postburn for either Langendorff perfusion ( n = 8 hearts/group) or to prepare cardiomyocytes ( n = 6 hearts/group). Myocytes were stimulated with lipopolysaccharide (LPS) (0, 10, 25, or 50 μg for 18 h) to measure cytokine secretion. Burn trauma increased myocyte TNF-α and interleukin-1β and -6 secretion, exacerbated cytokine response to LPS stimulus, and impaired cardiac contraction. HSD treatment of burns decreased cardiomyocyte cytokine secretion, decreased responsiveness to LPS challenge with regard to cytokine secretion, and improved ventricular function. These data suggest that HSD mediates cardioprotection after burn trauma, in part, by downregulating cardiomyocyte secretion of inflammatory cytokines.

scholarly journals Hypertonic saline dextran after burn injury decreases inflammatory cytokine responses to subsequent pneumonia-related sepsis

2006 ◽  
Vol 290 (4) ◽  
pp. H1642-H1650 ◽  
Author(s):  
Jureta W. Horton ◽  
David L. Maass ◽  
D. Jean White
Keyword(s):  
Hypertonic Saline ◽  
Burn Injury ◽  
Inflammatory Responses ◽  
Contractile Function ◽  
Total Body Surface Area ◽  
Isotonic Saline ◽  
Ringer Solution ◽  
Myocardial Inflammation ◽  
Adult Rats ◽  
Tnf Α

The present study examined the hypothesis that hypertonic saline dextran (HSD), given after an initial insult, attenuates exaggerated inflammation that occurs with a second insult. Adult rats ( n = 15 per group) were divided into groups 1 (sham burn), 2 [40% total body surface area burn + 4 ml/kg isotonic saline (IS) + 4 ml·kg−1·% burn−1 lactated Ringer solution (LR)], and 3 (burn + 4 ml/kg HSD + LR), all studied 24 h after burns. Groups 4 (sham burn), 5 (burn + IS + LR), and 6 (burns + HSD + LR) received intratracheal (IT) vehicle 7 days after burns; groups 7 (burn + IS + LR) and 8 (burn + HSD + LR) received IT Streptococcus pneumoniae (4 × 106 colony-forming units) 7 days after burn. Groups 4–8 were studied 8 days after burn and 24 h after IT septic challenge. When compared with sham burn, contractile defects occurred 24 h after burn in IS-treated but not HSD-treated burns. Cardiac inflammatory responses (pg/ml TNF-α) were evident with IS (170 ± 10) but not HSD (45 ± 5) treatment vs. sham treatment (80 ± 15). Pneumonia-related sepsis 8 days after IS-treated burns ( group 7) exacerbated TNF-α responses/contractile dysfunction vs. IS-treated burns in the absence of sepsis ( P < 0.05). Sepsis that occurred after HSD-treated burns ( group 8) had less myocyte TNF-α secretion/better contractile function than IS-treated burns given septic challenge ( group 7, P < 0.05). We conclude that an initial burn injury exacerbates myocardial inflammation/dysfunction occurring with a second insult; giving HSD after the initial insult attenuates myocardial inflammation/dysfunction associated with a second hit, suggesting that HSD reduces postinjury risk for infectious complications.

scholarly journals Selective TNF-α targeting with infliximab attenuates impaired oxygen metabolism and contractile function induced by an acute exposure to air particulate matter

2015 ◽  
Vol 309 (10) ◽  
pp. H1621-H1628 ◽  
Author(s):  
Timoteo Marchini ◽  
Verónica D'Annunzio ◽  
Mariela L. Paz ◽  
Lourdes Cáceres ◽  
Mariana Garcés ◽  
...  
Keyword(s):  
Particulate Matter ◽  
Saline Solution ◽  
Contractile Function ◽  
Left Ventricular ◽  
Acute Exposure ◽  
Control Group ◽  
Contractile Reserve ◽  
Mice Model ◽  
Cardiovascular Morbidity And Mortality ◽  
Tnf Α

Inflammation plays a central role in the onset and progression of cardiovascular diseases associated with the exposure to air pollution particulate matter (PM). The aim of this work was to analyze the cardioprotective effect of selective TNF-α targeting with a blocking anti-TNF-α antibody (infliximab) in an in vivo mice model of acute exposure to residual oil fly ash (ROFA). Female Swiss mice received an intraperitoneal injection of infliximab (10 mg/kg body wt) or saline solution, and were intranasally instilled with a ROFA suspension (1 mg/kg body wt). Control animals were instilled with saline solution and handled in parallel. After 3 h, heart O2 consumption was assessed by high-resolution respirometry in left ventricle tissue cubes and isolated mitochondria, and ventricular contractile reserve and lusitropic reserve were evaluated according to the Langendorff technique. ROFA instillation induced a significant decrease in tissue O2 consumption and active mitochondrial respiration by 32 and 31%, respectively, compared with the control group. While ventricular contractile state and isovolumic relaxation were not altered in ROFA-exposed mice, impaired contractile reserve and lusitropic reserve were observed in this group. Infliximab pretreatment significantly attenuated the decrease in heart O2 consumption and prevented the decrease in ventricular contractile and lusitropic reserve in ROFA-exposed mice. Moreover, infliximab-pretreated ROFA-exposed mice showed conserved left ventricular developed pressure and cardiac O2 consumption in response to a β-adrenergic stimulus with isoproterenol. These results provides direct evidence linking systemic inflammation and altered cardiac function following an acute exposure to PM and contribute to the understanding of PM-associated cardiovascular morbidity and mortality.

Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion

2005 ◽  
Vol 288 (1) ◽  
pp. H221-H226 ◽  
Author(s):  
Meijing Wang ◽  
Ben M. Tsai ◽  
Ajay Kher ◽  
Lauren B. Baker ◽  
G. Mathenge Wairiuko ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Functional Recovery ◽  
Caspase 3 ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Acute Ischemia ◽  
Caspase 1 ◽  
Tnf Α

Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function (left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-α, IL-1β, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-α, IL-1β, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor (flutamide) or depleting testosterone (castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.

Lipid peroxidation contributes to cardiac deficits after ischemia and reperfusion of the small bowel

1993 ◽  
Vol 264 (5) ◽  
pp. H1686-H1692 ◽  
Author(s):  
J. W. Horton ◽  
D. J. White
Keyword(s):  
Lipid Peroxidation ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Cardiac Contractile Function ◽  
Langendorff Preparation ◽  
Cardiac Contractile ◽  
Intestinal Ischemia Reperfusion

Our previous studies showed that intestinal ischemia-reperfusion (IR) impairs cardiac contractile function. The present study examined the contribution of oxygen free radicals and lipid peroxidation of cardiac cell membrane to cardiac dysfunction after intestinal IR in a rat model of superior mesenteric artery (SMA) occlusion (atraumatic clip for 20 min) and collateral arcade ligation. Controls were sham operated (group 1, n = 25). In group 2, 30 rats with SMA occlusion were killed 3-4 h after reperfusion without treatment. Aminosteroid (U-74389F), a pharmacological agent known to inhibit lipid peroxidation of membranes, was given 1 min before occlusion of the SMA (group 3, n = 19). All rats were killed 3-4 h after reperfusion of the ischemic intestine, and the hearts were harvested for in vitro assessment of cardiac function (Langendorff preparation). Cardiac contractile depression occurred in the untreated group as indicated by a fall in left ventricular pressure (from 76 +/- 3 to 64 +/- 3 mmHg, P = 0.01), maximum +dP/dt (from 1,830 +/- 60 to 1,577 +/- 64 mmHg/s, P = 0.05), and maximum -dP/dt (from 1,260 +/- 50 to 950 +/- 60 mmHg/s, P = 0.005). Lipid peroxidation of cardiac membranes occurred after untreated IR as indicated by the rise in cardiac malondialdehyde levels (MDA) (from 0.203 +/- 0.046 to 0.501 +/- 0.044 nM/mg protein, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of a coronary alpha 1-constriction on transmural left ventricular flow and contractile function

1992 ◽  
Vol 262 (4) ◽  
pp. H965-H972 ◽  
Author(s):  
P. A. Gwirtz ◽  
J. M. Dodd-O ◽  
H. F. Downey ◽  
H. J. Mass ◽  
B. A. Barron ◽  
...  
Keyword(s):  
Contractile Function ◽  
Stellate Ganglion ◽  
Systolic Pressure ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Maximal Rate ◽  
Circumflex Artery ◽  
Ventricular Systolic Pressure ◽  
Adrenergic Antagonist

Modulation of myocardial contractile function and perfusion by alpha 1-adrenergic receptors were examined in anesthetized dogs during left stellate ganglion stimulation. In 11 dogs, stellate stimulation significantly increased heart rate, mean arterial pressure, left ventricular systolic pressure, maximal rate of left ventricular pressure generation, segmental shortening and rate of shortening in anterior and posterior ventricular regions, and myocardial oxygen extraction. Myocardial lactate extraction decreased. The selective alpha 1-adrenergic antagonist prazosin (0.5 mg) injected into the circumflex artery during stellate stimulation caused significant additional increases in maximal rate of left ventricular pressure generation by 19 +/- 5% and in rate of shortening in posterior subendocardium by 20 +/- 6%. No changes were observed in posterior subepicardial or anterior subendocardial segmental contractile function. Myocardial oxygen and lactate extractions returned to their control values following prazosin injection. Regional left ventricular perfusion was measured using tracer microspheres in five additional dogs. Stellate stimulation increased subepicardial and subendocardial perfusion by 30%. Prazosin increased both subepicardial and subendocardial perfusion by an additional 36%. Stellate stimulation increased norepinephrine concentration in the coronary sinus, but no further increase was noted after blockage of alpha 1-receptors by prazosin. Thus, during sympathetic stimulation, an alpha 1-vasoconstriction existed uniformly across the left ventricular wall. However, blockade of this vasoconstriction was associated with an increase in contractile function only in the deeper muscle layers.

Hemorrhage-induced α-adrenergic signaling results in myocardial TNF-α expression and contractile dysfunction

2001 ◽  
Vol 281 (1) ◽  
pp. H84-H92 ◽  
Author(s):  
Rohan Shahani ◽  
Lazar V. Klein ◽  
John G. Marshall ◽  
Sherwin Nicholson ◽  
Barry B. Rubin ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
Neutralizing Antibody ◽  
Multiple Organ ◽  
Left Ventricular ◽  
Enzyme Linked Immunosorbent Assay ◽  
Adrenergic Blockade ◽  
Adrenergic Stimulation ◽  
Tnf Α ◽  
Factor Α

Hemorrhagic shock (HS), secondary to major blood loss, frequently precedes multiple organ dysfunction and is accompanied by a surge in circulating catecholamine levels. Expression of the cardiodepressant cytokine, tumor necrosis factor-α (TNF-α), has been observed in the heart after HS and resuscitation (HS/R) and α1-adrenergic blockade prevented translocation of the nuclear transcription factor, NF-κB, to the nucleus. We hypothesized that α1-adrenergic stimulation induces myocardial TNF-α expression, which results in depressed cardiac function after HS/R. The role of α1-adrenergic stimulation in myocardial TNF-α expression and depressed cardiac function after HS/R was assessed by treatment with the α1-adrenergic inhibitor, prazosin hydrochloride (1 mg/kg ip), for 1 h before the onset of hemorrhage. In addition, TNF-α was neutralized with a specific antibody (600 μl/kg iv) 5 min before hemorrhage. HS was induced by the withdrawal of blood to a mean blood pressure of 50 mmHg for 1 h. Contractile function was measured with the use of a Langendorff apparatus 2 h after the end of HS. HS/R led to significant decreases in left ventricular developed tension and in the maximal rate of pressure increase over time during both contraction and relaxation. Myocardial expression of TNF-α measured by enzyme-linked immunosorbent assay increased significantly after 30 min of hemorrhage and peaked after 60 min of HS and 45 min of resuscitation. Depression in cardiac function after HS/R was reversed by 85% in hearts from rats treated with a TNF-α neutralizing antibody and by 90% in hearts from rats treated with prazosin hydrochloride. We conclude that HS activates a α1-adrenergic pathway, resulting in TNF-α expression in the heart and depressed myocardial contractile function.

Dynorphin, naloxone, and overflow of norepinephrine during cardiac nerve stimulation in dogs

1992 ◽  
Vol 263 (1) ◽  
pp. H153-H161 ◽  
Author(s):  
H. Gu ◽  
B. A. Barron ◽  
J. F. Gaugl ◽  
J. L. Caffrey
Keyword(s):  
Nerve Stimulation ◽  
Myocardial Contractility ◽  
Contractile Function ◽  
Time Derivative ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Endogenous Opioids ◽  
Control Group ◽  
Cardiac Nerve ◽  
Mediated Effects

The effects of dynorphin-(1-9) and naloxone on norepinephrine (NE) overflow and myocardial contractility were determined during left cardiac nerve stimulation in the anesthetized dog. Stimulation-induced increases in NE overflow from the left ventricle were monitored during control conditions, during infusion of dynorphin-(1-9), during dynorphin plus naloxone, and after naloxone alone. Four electrical stimulations were applied for 1 min at 20-min intervals. Repeated left cardiac nerve stimulations (control group) reduced stimulated NE overflow 50-60% by 1 h. If stimulations were only conducted at 0 and 1 h, the decline in NE overflow was not observed. Intracoronary dynorphin (2 nmol.min-1.kg-1, 20 min) lowered the stimulation-induced increase in NE overflow further and reduced first time derivative of left ventricular pressure (dP/dt) and myocardial O2 consumption responses. Naloxone (100 micrograms/kg) prevented all of the dynorphin-mediated effects. When given alone, naloxone increased both NE overflow and left ventricular dP/dt during stimulation and prevented or significantly delayed the gradual decline in overflow observed in stimulated controls. A postjunctional effect of dynorphin was evaluated by comparing contractile responses to the intracoronary infusion of NE before and during dynorphin. Dynorphin did not alter contractile function at rest or during NE infusion. In summary, dynorphin-(1-9) depresses nerve stimulation-induced, cardiac NE overflow, and myocardial contractility in a naloxone-reversible fashion. Alone, naloxone appears to regulate stimulated NE overflow through a qualitatively different mechanism. Endogenous opioids may normally moderate myocardial function during cardiac nerve stimulation by regulating junctional NE concentrations through a combination of effects on NE release and/or its subsequent reuptake.

Abstract 12624: Blockade of Exosome Secretion Attenuates Inflammatory Cytokines, Mitigates Cardiac Dysfunction, and Reduces Mortality in Polymicrobial Sepsis

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Xiaohong Wang ◽  
Dongze Qin ◽  
Kobina Essandoh ◽  
Wei Huang ◽  
Liwang Yang ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Contractile Function ◽  
Cecal Ligation ◽  
Left Ventricular ◽  
Polymicrobial Sepsis ◽  
Raw 264.7 Cells ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Tnf Α

Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored. Methods and Results: C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p<0.01). Myocardial contractile function, assessed at 12h post-CLP using a SONOS-7500 echocardiography system, revealed that pre-injection of GW4869 significantly attenuated CLP-associated cardiac dysfunction, evidenced by an improved left ventricular ejection fraction (LVEF) and minor axis fractional shortening (LVFS), compared to DMSO controls (n=8-10, p<0.01). Myeloperoxidase (MPO) activity, a marker of myocardial inflammation, measured with a [[Unable to Display Character: &#64258;]]uorometric assay kit, also showed a significant reduction in GW4869-pre-treated mice, compared to DMSO-controls (n=5, p<0.01). Similarly, serum levels of inflammatory cytokines TNF-α and IL-1β triggered by CLP were reduced by 72% and 61%, respectively in GW4869-treated mice, compared with controls (n=6). Furthermore, we observed that 67% (n=9) of the DMSO controls, but only 20% in GW4869-treated mice (n=10) had died by 48h post-CLP. In vitro study confirmed that GW4869 limited the production of TNF-α and IL-1β in RAW 264.7 cells (a mouse macrophage cell line) challenged with endotoxin (LPS, 1μg/ml, 24 h). Conclusions: Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.

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