Rat Model Of Systemic Inflammation Research Articles

Neuromodulator hydrogen sulfide attenuates sickness behavior induced by lipopolysaccharide

Sickness behavior reflects a state of altered physiology and central nervous system function that occurs during systemic infection or inflammation, serving as an adaptive response to illness. This study aims to elucidate the role of hydrogen sulfide (H2S) in regulating sickness behavior and neuroinflammatory responses in a rat model of systemic inflammation. Adult male Wistar rats were treated with lipopolysaccharide (LPS) to induce sickness behavior. Intracerebroventricular (i.c.v.) pretreatments included aminooxyacetic acid (AOAA), an inhibitor of H2S synthesis, and sodium sulfide (NaHS), an H2S donor. Behavioral assays were conducted, along with the assessment of astrocyte activation, as indicated by GFAP expression in the hypothalamus. Pretreatment with NaHS mitigated LPS-induced behavioral changes, including hypophagia, social and exploratory deficits, without affecting peripheral cytokine levels, indicating a central modulatory effect. AOAA, conversely, accentuated certain behavioral responses, suggesting a complex role of endogenous H2S in sickness behavior. These findings were reinforced by a lack of effect on plasma interleukin levels but significant reduction in GFAP expression. Our findings support the central role of H2S in modulating neuroinflammation and sickness behavior, highlighting the therapeutic potential of targeting H2S signaling in neuroinflammatory conditions.

Autoregulation of blood flow drives early hypotension in a rat model of systemic inflammation induced by bacterial lipopolysaccharide.

Uncontrolled vasodilation is known to account for hypotension in the advanced stages of sepsis and other systemic inflammatory conditions, but the mechanisms of hypotension in earlier stages of such conditions are not clear. By monitoring hemodynamics with the highest temporal resolution in unanesthetized rats, in combination with ex-vivo assessment of vascular function, we found that early development of hypotension following injection of bacterial lipopolysaccharide is brought about by a fall in vascular resistance when arterioles are still fully responsive to vasoactive agents. This approach further uncovered that the early development of hypotension stabilized blood flow. We thus hypothesized that prioritization of the local mechanisms of blood flow regulation (tissue autoregulation) over the brain-driven mechanisms of pressure regulation (baroreflex) underscored the early development of hypotension in this model. Consistent with this hypothesis, an assessment of squared coherence and partial-directed coherence revealed that, at the onset of hypotension, the flow-pressure relationship was strengthened at frequencies (<0.2 Hz) known to be associated with autoregulation. The autoregulatory escape to phenylephrine-induced vasoconstriction, another proxy of autoregulation, was also strengthened in this phase. The competitive demand that drives prioritization of flow over pressure regulation could be edema-associated hypovolemia, as this became detectable at the onset of hypotension. Accordingly, blood transfusion aimed at preventing hypovolemia brought the autoregulation proxies back to normal and prevented the fall in vascular resistance. This novel hypothesis opens a new avenue of investigation into the mechanisms that can drive hypotension in systemic inflammation.

A leukotriene-dependent spleen-liver axis drives TNF production in systemic inflammation.

Production of the proinflammatory cytokine tumor necrosis factor (TNF) must be precisely regulated for effective host immunity without the induction of collateral tissue damage. Here, we showed that TNF production was driven by a spleen-liver axis in a rat model of systemic inflammation induced by bacterial lipopolysaccharide (LPS). Analysis of cytokine expression and secretion in combination with splenectomy and hepatectomy revealed that the spleen generated not only TNF but also factors that enhanced TNF production by the liver, the latter of which accounted for nearly half of the TNF secreted into the circulation. Using mass spectrometry-based lipidomics, we identified leukotriene B4 (LTB4) as a candidate blood-borne messenger in this spleen-liver axis. LTB4 was essential for spleen-liver communication in vivo, as well as for humoral signaling between splenic macrophages and Kupffer cells in vitro. LPS stimulated the splenic macrophages to secrete LTB4, which primed Kupffer cells to secrete more TNF in response to LPS in a manner dependent on LTB4 receptors. These findings provide a framework to understand how systemic inflammation can be regulated at the level of interorgan communication.

Application and Efficacy of Vitamin E-Bonded Polysulfone Membrane in Acute Blood Purification Therapy

Introduction: Acute blood purification therapy (BPT) has been evaluated in the context of intensive care for serious conditions related to systemic inflammation, but its mechanism and efficacy are not fully understood. Objective: This study examined the feasibility of using vitamin E-bonded polysulfone membranes (VEPS) for BPT in a LPS-induced rat model of systemic inflammation. Methods: To evaluate the efficacy of BPT with a VEPS membrane, polysulfone (PS) membranes conventionally used in intensive care were bonded with the antioxidant vitamin E and used in a rat model of lipopolysaccharide (LPS)-induced systemic inflammation. BPT using a PS membrane (PS group) or a VEPS membrane (VEPS group) was performed 6 h after administration of LPS. Extracorporeal circulation was established in normal rats as a control (sham group). Survival rates, histology of lung specimens, and levels of myeloperoxidase (MPO) and high mobility group box-1 (HMGB-1) were examined in each group. Results: Survival rates at 24 h after LPS administration were 100% in the VEPS group and 50% in the PS group. Pulmonary architecture was largely maintained and the level of infiltration of inflammatory cells remained moderate in the VEPS group. Levels of active MPO before and after BPT were significantly higher in the PS and VEPS groups than in the sham group, with no significant differences between the PS and VEPS groups. HMGB-1 levels were significantly elevated after BPT in the PS group. Conclusions: This study demonstrated that use of the VEPS membrane for BPT increased survival rate and reduced lung injury in a rat model of systemic inflammatory response syndrome (SIRS), suggesting the possible use of VEPS membranes in the treatment of serious conditions related to systemic inflammation.

Therapeutic effects of IkB kinase inhibitor during systemic inflammation

Animal models of inflammatory diseases support the idea that nuclear factor κB (NF-κB) activation plays a pathophysiological role and is widely implicated in multiple organ dysfunction (MOD). Indeed, the inhibition of the IκB kinase (IKK) complex, involved in the NF-κB pathway, can represent a promising approach to prevent MOD. The present work employed a rat model of systemic inflammation to investigate the preventive effects of Inhibitor of IKK complex (IKK16).In male Wistar rats, systemic inflammation was induced by a tail vein injection of lipopolysaccharides (LPS challenge; 12 mg/kg). Treatment with IKK16 (1 mg/kg body weight) was administered, by tail vein, 15 min post-LPS. Age- and sex-matched healthy rats and LPS rats without treatment were used as controls. At 24 h post-IKK16 treatment, serum enzyme levels indicative of liver, kidney, pancreas and muscle function were evaluated by biochemical analysis, and RT-PCR technique was used to analyze gene expression of pro-inflammatory cytokines. Hemodynamic parameters were also considered to assess the LPS-induced inflammation.IKK16 treatment yielded a strong therapeutic effect in preventing LPS-induced elevation of serological enzyme levels, attenuating hepatic, renal, pancreatic and muscular dysfunction after LPS challenge. Moreover, as expected, LPS promoted a significantly overexpression of TNF-α, IL-6 and IL-1β in the heart, kidney, and liver; which was diminished by IKK16 treatment.The present study provides convincing evidence that selective inhibition of the IκB kinase complex through the action of IKK16, plays a protective role against LPS-induced multiple organ dysfunction by reducing the acute inflammatory response induced by endotoxin exposure.

Cognitive deficits after systemic induction of inducible nitric oxide synthase

Nitric oxide acts as an important neurotransmitter as well as a sepsis mediator. During sepsis, high levels of nitric oxide, produced by the inducible form of the nitric oxide synthase (iNOS), may lead to disturbances concerning these conflicting roles and cause septic encephalopathy. To evaluate this theory, we aimed at first, to demonstrate cognitive dysfunction in a rat model based on systemic iNOS induction; second, to elucidate molecular mechanisms; and third, to prevent cognitive deficits in our sepsis model. We used a rat systemic inflammation model that is based on the induction of iNOS by heat-killed Corynebacterium parvum in different doses (30 or 60 mg kg). NO2/NO3 plasma levels were measured to prove iNOS induction. Cognitive performance was investigated. In brain tissue, NOS protein and NOS activity were determined. To prevent cognitive deficits, two groups of rats received L-N-(1-Iminoethyl)-lysine (L-NIL), a specific iNOS inhibitor in the drinking water. The rats[Combining Acute Accent] cognitive performance, that is, short-term memory as well as long-term memory was impaired in C. parvum rats with a peak at the third day after injection in the 60 mg kg group. At the same day, neuronal NOS (nNOS)-protein content in the prefrontal cortex was reduced in C. parvum rats. nNOS activity was also reduced in C. parvum rats. The cognitive deficit in short-term memory could be prevented by L-NIL. We demonstrate early, reversible cognitive deficits in a rat model of systemic inflammation with increased systemic iNOS activity. As systemic inhibition of iNOS activity prevented rats from the deficit in short-term memory, an involvement of systemic iNOS induction in this deficit is likely. Whether the reduced nNOS-protein expression and nNOS activity are connected to systemic iNOS induction, however, remains unclear.

RETRACTED: Continuous Hemodiafiltration Therapy Ameliorates LPS-Induced Systemic Inflammation in a Rat Model

Systemic inflammation can result in multiple organ dysfunction syndrome, a potentially life-threatening condition. Some reports suggest that continuous hemodiafiltration can effectively remove proinflammatory cytokines from circulation during systemic inflammation. In the present study, we investigated whether continuous hemodiafiltration therapy could prevent LPS-induced systemic inflammation and improve survival in a rat model. Male Wistar rats were injected with lipopolysaccharide (LPS; 7.5 mg/kg body weight), and 6 h later were treated with either single-pass hemofiltration (C group), continuous hemofiltration (CHF group), continuous hemodiafiltration (CHDF group), or mock filtration (Control group). We performed histologic examinations of lung and liver tissues, determined serum cytokine levels, and survival rates for each treatment group, and compared cytokine removal between CHF and CHDF therapies. Histologic examination revealed significant reduction in inflammation in lung and liver tissues harvested 24 h after CHDF compared with the Control group. Likewise, LPS-induced serum TNF-α and IL-6 levels decreased with continuous hemodiafiltration along with a significant improvement in survival. After 30 min of treatment, both CHF and CHDF removed significant amounts of TNF-α and IL-6 from the blood. However, serum cytokine levels measured before and after filtration were not significantly different. Continuous hemodiafiltration therapy lowered inflammatory cytokines and increased survival rates in a rat model of systemic inflammation. Therefore, continuous hemodiafiltration may be a potential therapy for use against various systemic inflammatory diseases.

ETS-GS, a New Anti-Oxidative Drug, Protects Against Lipopolysaccharide-Induced Acute Lung and Liver Injury

Sepsis is a major health threat that remains refractory to treatment. Impairment of normal cellular function due to oxidative stress is implicated in organ injury during systemic inflammatory responses. We investigated whether the new anti-oxidative drug, ETS-GS, could inhibit secretion of cytokines and mono-nitrogen oxides, thus reducing organ damage in a rat model of lipopolysaccharide-induced sepsis. Lipopolysaccharide was administered intravenously to male Wistar rats in order to establish a rat model of systemic inflammation. These rats were challenged with or without intravenous ETS-GS. Mouse macrophage RAW264.7 cells were stimulated with lipopolysaccharide, with or without simultaneous ETS-GS treatment, in order to elucidate the mechanism of action. Histologic examination revealed that ETS-GS markedly reduced lipopolysaccharide-induced interstitial edema and leukocytic infiltration in lung tissue, and lipopolysaccharide-induced bleeding and leukocytic infiltration in liver tissue harvested 12 h after treatment. Cytokine (interleukin-6 and tumor necrosis factor-α) secretion was strongly induced by lipopolysaccharide; this induction was similarly inhibited by ETS-GS treatment. Likewise, lipopolysaccharide-induced secretion of mono-nitrogen oxides was inhibited by ETS-GS. In the in vitro studies, ETS-GS administration inhibited IκB phosphorylation. ETS-GS blocked the lipopolysaccharide-induced inflammatory response and protected against acute lung and liver injury normally associated with endotoxemia in this rat model of systemic inflammation. Further, this protection may be mediated through the inhibition of nuclear factor κ-light-chain-enhancer of activated B cells activation. Our results suggest that ETS-GS is a potential therapeutic agent for sepsis.

Insulin Treatment of Diabetic Rats Reduces Cardiac Function in a Lipopolysaccharide-Induced Systemic Inflammation Model

Diabetes is a common comorbidity in patients with various medical conditions. Tight glucose control is known to improve systemic inflammation; however, whether it is effective in diabetic patients is unknown. The purpose of this study was to examine how strict glucose control affects systemic inflammation in diabetic patients. Male Wistar rats. We determined the effect of insulin therapy on cardiac function in a rat model of systemic inflammation. We administered lipopolysaccharide intravenously, with or without insulin, to streptozotocin-induced diabetic rats. After induction of systemic inflammation, we determined serum cytokine (IL-6 and TNFα) and nitrate/nitrite levels and measured cardiac function. Cytokine levels and cardiac function were significantly reduced in diabetic rats compared to non-diabetic rats. Moreover, insulin treatment was associated with higher cytokine levels and decreased cardiac function. In systemic inflammatory conditions, diabetes increases various proinflammatory mediators and inhibits cardiac function; insulin treatment exacerbates these effects. Thus, strict glucose control may not be desirable in diabetic patients with systemic inflammatory conditions.

Cepharanthine Exerts Anti-Inflammatory Effects Via NF-κB Inhibition in a LPS-Induced Rat Model of Systemic Inflammation

Systemic inflammatory response syndromes involving sepsis continue to have extremely high mortality rates. Inflammation is difficult to control when it spreads throughout the body and often progresses into multiple organ dysfunction, eventually leading to death. Cepharanthine (CE) is a plant alkaloid that possesses bioactive properties, with various known actions. In the present study, we investigated protective effects of CE in a lipopolysaccharide (LPS)-induced systemic inflammatory response model and examined underlying mechanisms. We intravenously administered LPS (7.5 mg/kg) to male Wistar rats after intraperitoneal injections of either physiologic saline (LPS group) or CE (10 mg/kg; CE + LPS group), or 2 h before intraperitoneal injection of CE (post-CE + LPS group). We then compared changes in serum cytokine and nitrogen oxide levels over time, and performed histologic examinations of the lungs and liver in each group. Using mouse macrophage RAW264.7 cells, we determined the effect of CE on LPS-induced cytokine secretion into the cell culture medium, as well as NF-κB activity. The increase in LPS-induced cytokine levels in rat serum was significantly inhibited by CE treatment; this effect was also seen in the post-CE + LPS group. In addition, we observed histologic improvements with CE co-treatment. In vitro, CE inhibited NF-κB activation by inhibiting the IKK pathway. These results suggest that CE exerts protective effects, at least in part, via NF-κB inhibition. CE may thus be a potential agent for treating systemic inflammatory response syndromes such as sepsis.

Systemic inflammation leads to resistance to atracurium without increasing membrane expression of acetylcholine receptors.

Systemic inflammation may be associated with resistance to nondepolarizing neuromuscular blocking drugs, the mechanisms of which are, however, uncharacterized. The authors therefore investigated the pharmacodynamics of atracurium and its relation to the expression of nicotinic acetylcholine receptors and alpha1 -acid glycoprotein in a rat model of systemic inflammation. To induce a systemic inflammation, male CD rats received 56 mg/kg corynebacterium parvum intravenously. On days 2, 4, 6, 8, 10, 12, 14, or 16 after infection, neuromuscular transmission was measured. The individual effective dose of atracurium was determined, followed by an atracurium infusion at a rate to establish a steady state neuromuscular block of 50%. Total and unbound plasma concentrations of atracurium for 50% paralysis were measured using high-performance liquid chromatography. Acetylcholine receptors were quantitated using 125I-alpha-bungarotoxin. alpha1 -Acid glycoprotein concentrations in the serum were measured using a competitive chemiluminescence immunoassay. The effective dose of atracurium was increased on days 4, 6, and 8. Total atracurium plasma concentrations at 50% neuromuscular paralysis were increased on days 4, 6, 8, and 10, with a peak at day 8 (8.0 +/- 1.3 micro g/ml) compared with control rats (4.23 +/- 0.82 micro g/ml). The alpha1 -acid glycoprotein concentrations were increased between days 2 and 10, with a peak on day 4 (6.52 +/- 1.45 mg/ml), and recovered to control values (0.61 +/- 0.33 mg/ml) on day 12. Unbound plasma concentrations of atracurium to achieve 50% depression, as well as the expression of acetylcholine receptors, did not differ between groups. Resistance to atracurium during corynebacterium parvum-induced systemic inflammation is due to increased drug binding to alpha1 -acid glycoprotein and is unrelated to changes in acetylcholine receptor expression.