C-peptide, a novel inhibitor of lung inflammation following hemorrhagic shock

C-peptide is a 31-amino acid peptide cleaved from proinsulin during insulin synthesis. Initially thought to be inert, C-peptide may modulate the inflammatory response in the setting of endotoxemia and ischemia reperfusion. However, the spectrum of its biological effects is unclear. We hypothesized that exogenous administration of C-peptide would modulate pro- and anti-inflammatory signaling pathways and thereby attenuate lung inflammation in an in vivo model of hemorrhagic shock. Hemorrhagic shock was induced in male Wistar rats (aged 3–4 mo) by withdrawing blood to a mean arterial pressure of 50 mmHg. At 3 h after hemorrhage, rats were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, animals received C-peptide (280 nmol/kg) or vehicle parenterally. Animals were euthanized at 1 and 3 h after resuscitation. C-peptide administration at resuscitation following hemorrhagic shock ameliorated hypotension and blunted the systemic inflammatory response by reducing plasma levels of IL-1, IL-6, macrophage inflammatory protein-1α, and cytokine-induced neutrophil chemoattractant-1. This was associated with a reduction in lung neutrophil infiltration and plasma levels of receptor for advanced glycation end products. Mechanistically, C-peptide treatment was associated with reduced expression of proinflammatory transcription factors activator protein-1 and NF-κB and activation of the anti-inflammatory transcription factor peroxisome proliferator-activated receptor-γ. Our data suggest that C-peptide ameliorates the inflammatory response and lung inflammation following hemorrhagic shock. These effects may be modulated by altering the balance between pro- and anti-inflammatory signaling in the lung.

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Focal intra-colon cooling reduces organ injury and systemic inflammation after REBOA management of lethal hemorrhage in rats

Scientific Reports ◽

10.1038/s41598-021-93064-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Awadhesh K. Arya ◽

Kurt Hu ◽

Lalita Subedi ◽

Tieluo Li ◽

Bingren Hu

Keyword(s):

Inflammatory Response ◽

Inflammatory Cytokines ◽

Troponin I ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Balloon Catheter ◽

Organ Injury ◽

Upper Body ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractResuscitative endovascular balloon occlusion of the aorta (REBOA) is a lifesaving maneuver for the management of lethal torso hemorrhage. However, its prolonged use leads to distal organ ischemia–reperfusion injury (IRI) and systemic inflammatory response syndrome (SIRS). The objective of this study is to investigate the blood-based biomarkers of IRI and SIRS and the efficacy of direct intestinal cooling in the prevention of IRI and SIRS. A rat lethal hemorrhage model was produced by bleeding 50% of the total blood volume. A balloon catheter was inserted into the aorta for the implementation of REBOA. A novel TransRectal Intra-Colon (TRIC) device was placed in the descending colon and activated from 10 min after the bleeding to maintain the intra-colon temperature at 37 °C (TRIC37°C group) or 12 °C (TRIC12°C group) for 270 min. The upper body temperature was maintained at as close to 37 °C as possible in both groups. Blood samples were collected before hemorrhage and after REBOA. The organ injury biomarkers and inflammatory cytokines were evaluated by ELISA method. Blood based organ injury biomarkers (endotoxin, creatinine, AST, FABP1/L-FABP, cardiac troponin I, and FABP2/I-FABP) were all drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated these increased organ injury biomarkers. Plasma levels of pro-inflammatory cytokines TNF-α, IL-1b, and IL-17F were also drastically increased in TRIC37°C group after REBOA. TRIC12°C significantly downregulated the pro-inflammatory cytokines. In contrast, TRIC12°C significantly upregulated the levels of anti-inflammatory cytokines IL-4 and IL-10 after REBOA. Amazingly, the mortality rate was 100% in TRIC37°C group whereas 0% in TRIC12°C group after REBOA. Directly cooling the intestine offered exceptional protection of the abdominal organs from IRI and SIRS, switched from a harmful pro-inflammatory to a reparative anti-inflammatory response, and mitigated mortality in the rat model of REBOA management of lethal hemorrhage.

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The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01098-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6317-6327 ◽

Cited By ~ 21

Author(s):

Hussein Traboulsi ◽

Alexandre Cloutier ◽

Kumaraswamy Boyapelly ◽

Marc-André Bonin ◽

Éric Marsault ◽

...

Keyword(s):

Influenza Virus ◽

Virus Infection ◽

Inflammatory Response ◽

Lung Inflammation ◽

Inflammatory Cell ◽

Influenza Virus Infection ◽

Cytokine Gene Expression ◽

Cell Recruitment ◽

Inflammatory Cell Recruitment ◽

Anti Inflammatory

ABSTRACTThe host response to influenza virus infection is characterized by an acute lung inflammatory response in which intense inflammatory cell recruitment, hypercytokinemia, and a high level of oxidative stress are present. The sum of these events contributes to the virus-induced lung damage that leads to high a level of morbidity and mortality in susceptible infected patients. In this context, we identified compounds that can simultaneously reduce the excessive inflammatory response and the viral replication as a strategy to treat influenza virus infection. We investigated the anti-inflammatory and antiviral potential activities of isoliquiritigenin (ILG). Interestingly, we demonstrated that ILG is a potent inhibitor of influenza virus replication in human bronchial epithelial cells (50% effective concentration [EC50] = 24.7 μM). In addition, our results showed that this molecule inhibits the expression of inflammatory cytokines induced after the infection of cells with influenza virus. We demonstrated that the anti-inflammatory activity of ILG in the context of influenza virus infection is dependent on the activation of the peroxisome proliferator-activated receptor gamma pathway. Interestingly, ILG phosphate (ILG-p)-treated mice displayed decreased lung inflammation as depicted by reduced cytokine gene expression and inflammatory cell recruitment. We also demonstrated that influenza virus-specific CD8+effector T cell recruitment was reduced up to 60% in the lungs of mice treated with ILG-p (10 mg/kg) compared to that in saline-treated mice. Finally, we showed that administration of ILG-p reduced lung viral titers and morbidity of mice infected with the PR8/H1N1 virus.

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Inflammatory Response in Patients under Coronary Artery Bypass Grafting Surgery and Clinical Implications: A Review of the Relevance of Dexmedetomidine Use

ISRN Anesthesiology ◽

10.1155/2014/905238 ◽

2014 ◽

Vol 2014 ◽

pp. 1-28 ◽

Cited By ~ 5

Author(s):

Neusa Maria Heinzmann Bulow ◽

Elisângela Colpo ◽

Marta Frescura Duarte ◽

Eduardo Francisco Mafassioly Correa ◽

Rochelle Silveira Schlosser ◽

...

Keyword(s):

Cardiopulmonary Bypass ◽

Coronary Artery ◽

Coronary Artery Bypass Grafting ◽

Inflammatory Response ◽

Coronary Artery Bypass ◽

Ischemia Reperfusion ◽

Artery Bypass ◽

Bypass Grafting ◽

Artery Bypass Grafting ◽

Anti Inflammatory

Despite the fact that coronary artery bypass grafting surgery (CABG) with cardiopulmonary bypass (CPB) prolongs life and reduces symptoms in patients with severe coronary artery diseases, these benefits are accompanied by increased risks. Morbidity associated with cardiopulmonary bypass can be attributed to the generalized inflammatory response induced by blood-xenosurfaces interactions during extracorporeal circulation and the ischemia/reperfusion implications, including exacerbated inflammatory response resembling the systemic inflammatory response syndrome (SIRS). The use of specific anesthetic agents with anti-inflammatory activity can modulate the deleterious inflammatory response. Consequently, anti-inflammatory anesthetics may accelerate postoperative recovery and better outcomes than classical anesthetics. It is known that the stress response to surgery can be attenuated by sympatholytic effects caused by activation of central (α-)2-adrenergic receptor, leading to reductions in blood pressure and heart rate, and more recently, that they can have anti-inflammatory properties. This paper discusses the clinical significance of the dexmedetomidine use, a selective (α-)2-adrenergic agonist, as a coadjuvant in general anesthesia. Actually, dexmedetomidine use is not in anesthetic routine, but this drug can be considered a particularly promising agent in perioperative multiple organ protection.

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UPEI-400, a Conjugate of Lipoic Acid and Scopoletin, Mediates Neuroprotection in a Rat Model of Ischemia/Reperfusion

10.20944/preprints201610.0083.v1 ◽

2016 ◽

Author(s):

Barry J. Connell ◽

Monique C. Saleh ◽

Desikan Rajagopal ◽

Tarek M. Saleh

Keyword(s):

Cell Death ◽

Lipoic Acid ◽

Ischemia Reperfusion ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Covalent Bond ◽

Male Rats ◽

In Vivo Model ◽

Naturally Occurring ◽

Anti Inflammatory

Background: Previously, our laboratory has provided evidence that pre-administration of the antioxidant, lipoic acid covalently bonded to various naturally occurring antioxidants, enhanced neuroprotective capacity compared to the administration of lipoic acid on its own. The naturally occurring compound scopoletin, a coumarin derivative, has been shown in various in vitro studies to have both antioxidant and anti-inflammatory mechanism of actions. To date, the effect of scopoletin on neuronal cell death in an in vivo model of ischemia or ischemia-reperfusion has not been investigated. Therefore, the present investigation was designed to determine if scopoletin on its own, or a co-drug consisting of lipoic acid and scopoletin covalent bond, named UPEI-400, would be capable of demonstrating a similar neuroprotective efficacy. Methods: Using a rodent model of stroke in male rats (anesthetized with Inactin®; 100 mg/kg, iv), the middle cerebral artery was permanently occluded for 6 hours (pMCAO), or in separate animals, occluded for 30 min followed by 5.5 hrs of reperfusion (ischemia/reperfusion; I/R). Results: Pre-administration of either scopoletin or UPEI-400 significantly decreased infarct volume in the I/R model (p<0.05), but not in the pMCAO model of stroke. However, UPEI-400 was ~1000 times more potent as compared to scopoletin on its own. The optimal dose of UPEI-400 was then injected during the occlusion and at several time points during reperfusion and significant neuroprotection was observed for up to 150 mins following the start of reperfusion (p<0.05). Conclusion: The data suggest that synthetic combination of scopoletin with lipoic acid (UPEI-400) is a more effective neuroprotectant that either compound on their own. Also, since UPEI-400 was only effective in a model of I/R, it is possible that it may act to enhance neuronal antioxidant capacity and/or upregulate anti-inflammatory pathways to prevent the neuronal cell death.

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CYP2J2 and EETs Protect Against Pulmonary Hypertension with Lung Ischemia-Reperfusion Injury In Vivo and In Vitro

10.21203/rs.3.rs-855996/v1 ◽

2021 ◽

Author(s):

Yun Ding ◽

Pengjie Tu ◽

Yiyong Chen ◽

Yangyun Huang ◽

Xiaojie Pan ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Response ◽

Reperfusion Injury ◽

Lung Tissue ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Tnf Α ◽

Anti Inflammatory

Abstract Background Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), which exert anti-inflammatory, anti-apoptotic, pro-proliferative, and antioxidant effects on the cardiovascular system. However, the role of CYP2J2 and EETs in pulmonary arterial hypertension (PAH) with lung ischemia-reperfusion injury (LIRI) remains unclear. In the present study, we investigated the effects of CYP2J2 overexpression and exogenous EETs on PAH with LIRI in vitro and in vivo.Methods CYP2J2 gene was transfected into rat lung tissue by recombinant adeno-associated virus (rAAV) to increase the levels of EETs in serum and lung tissue. A rat model of PAH with LIRI was constructed by tail vein injection of monocrotaline (50 mg/kg) for 4 weeks, followed by clamping of the left pulmonary hilum for 1 h and reperfusion for 2 h. In addition, we established a cellular model of human pulmonary artery endothelial cells (HPAECs) with TNF-α combined with hypoxic reoxygenation (anoxia for 8 h and reoxygenation for 16 h) to determine the effect and mechanism of exogenous EETs.Results CYP2J2 overexpression significantly reduced the inflammatory response, oxidative stress and apoptosis associated with lung injury in PAH with LIRI. In addition, exogenous EETs suppressed inflammatory response and reduced intracellular reactive oxygen species (ROS) production and inhibited apoptosis in a tumor necrosis factor alpha (TNF-α) combined hypoxia-reoxygenation model of HPAECs. Our further studies revealed that the anti-inflammatory effects of CYP2J2 overexpression and EETs might be mediated by PPARγ pathway; the anti-apoptotic effects might be mediated by the PI3K/Ak pathway.Conclusions CYP2J2 overexpression and EETs protect against PAH with LIRI via anti-inflammation, anti-oxidative stress and anti-apoptosis, suggesting that increased levels of EETs may be a promising strategy for the prevention and treatment of PAH with LIRI.

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Intestinal preconditioning prevents systemic inflammatory response in hemorrhagic shock. Role of HO-1

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00348.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. G408-G414 ◽

Cited By ~ 57

Author(s):

Fabienne Tamion ◽

Vincent Richard ◽

Yann Lacoume ◽

Christian Thuillez

Keyword(s):

Inflammatory Response ◽

Hemorrhagic Shock ◽

Intestinal Ischemia ◽

Ischemia Reperfusion ◽

Systemic Inflammatory Response ◽

Organ Injury ◽

Lung Edema ◽

Heme Oxygenase 1 ◽

Intestinal Ischemia Reperfusion

Intestinal ischemia-reperfusion has been implicated in the systemic inflammatory response and organ injury in hemorrhagic shock, but the exact role of the intestine has never been directly demonstrated. Preconditioning (PC) with brief periods of intermittent ischemia is a known potent anti-ischemic intervention and thus can be used as a tool to assess the role of local intestinal ischemia-reperfusion injury in systemic inflammatory response. Thus rats were first subjected to sham surgery or intestinal preconditioning with four cycles of 1-min ischemia and 10 min of reperfusion 24 h before hemorrhagic shock followed by resuscitation. PC reduced fluid requirements, lung edema, and lactate and tumor necrosis factor-α production. These effects were abolished by the heme-oxygenase-1 (HO-1) inhibitor tin protoporphyrin (Sn-PP). PC induced more than fivefold in intestinal HO-1 expression. These results suggest that intestinal ischemia-reperfusion is a major trigger for inflammatory response and organ injury in nonseptic shock. HO-1 appears to play an important role in the protective effect of intestinal preconditioning.

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