A Novel ELR-CXC Chemokine Antagonist Reduces Intestinal Ischemia Reperfusion-Induced Mortality, and Local and Remote Organ Injury

Zhao, Xixing; Town, Jennifer; Yang, A. W.; Zhang, Xiaobei; Paur, Nicole; Sawicki, Grzegorz; Gordon, John

doi:10.1016/j.jss.2009.04.047

Cited by 25 publications

(18 citation statements)

References 44 publications

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“…While statistically significant, the modest increases of IFNγ, IL-1α and IL-2 in maternal serum following G31P treatment were unanticipated and may not be biologically significant. Previous research in rats shows that G31P does not increase IL-1β, IL-6, or CXCL2 in rat lung or jejunum (Zhao et al, 2010), which is consistent with our findings from maternal serum. Therefore, systemic G31P treatment does not cause the release of proinflammatory mediators in rats.…”

Section: Inflammatory Response Of Pregnant Rodents To Polyi:c Treatmentsupporting

confidence: 93%

“…injections of G31P (500 μg/kg; 1 h before, 48 h after, and 96 h after polyI:C or saline treatment). Previous studies using this dose and treatment protocol for G31P confirm the drug's effectiveness at blocking CXCR1 and CXCR2 following systemic inflammatory challenges for at least 48 h (Gordon et al, 2005Li et al, 2002;Zhao et al, , 2010. Other than injections, weight, and temperature recordings (8, 24 and 48 h after treatment) dams were undisturbed until postnatal day (PND) 1, when litters were weighed and culled to a maximum of ten pups (6 males where possible).…”

Section: Maternal Treatment For Behavioral Experimentsmentioning

confidence: 71%

“…CXCL1 signals through two receptors (CXCR1 and CXCR2) which can be blocked by the CXCR1/R2 antagonist CXCL8 K11R/G31P (G31P), a synthetic, mutated form of human IL-8 that binds CXCR1/R2 with high affinity (Gordon et al, 2005;Zhao et al, 2009). The potent activity of G31P has been demonstrated in rodent models of airway inflammation (Wei et al, 2013;Zhao et al, 2009) and ischemia-reperfusion injury (Zhao et al, 2010). Thus, our hypothesis was that treating pregnant dams with G31P before and after polyI:C would prevent the effects of elevated CXCL1 on behavioral changes in the offspring.…”

Section: Introductionmentioning

confidence: 99%

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Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Ballendine

Greba

Dawicki

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Research suggests that maternal immune activation (MIA) during pregnancy increases the risk of neurodevelopmental disorders including schizophrenia and autism in the offspring. Current theories suggest that inflammatory mediators including cytokines and chemokines may underlie the increased risk of these disorders in humans. For example, elevated maternal interleukin-8 (IL-8) during pregnancy is associated with increased risk of schizophrenia in the offspring. Given this association, the present experiments examined ELR-CXC chemokines CXCL1 and CXCL2, rodent homologues of human IL-8, and activation of their receptors (CXCR1 and CXCR2) in an established rodent model of MIA. Pregnant Long Evans rats were treated with the viral mimetic polyinosinic-polycytidylic acid (polyI:C; 4 mg/kg, i.v.) on gestational day 15. Protein analysis using multiplex assays and ELISA showed that polyI:C significantly increased maternal serum concentrations of interleukin-1β, tumor necrosis factor, and CXCL1 3 h after administration. Subsequent experiments tested the role of elevated maternal CXCL1 on behavior of the offspring by administering a CXCR1/CXCR2 antagonist (G31P; 500 μg/kg, i.p.; 1 h before, 48 and 96 h after polyI:C treatment). The male offspring of dams treated with polyI:C demonstrated subtle impairments in prepulse inhibition (PPI), impaired associative and crossmodal recognition memory, and altered behavioral flexibility in an operant test battery. While G31P did not completely reverse the behavioral impairments caused by polyI:C, it enhanced PPI during adolescence and strategy set-shifting and reversal learning during young adulthood. These results suggest that while polyI:C treatment significantly increases maternal CXCL1, elevations of this chemokine are not solely responsible for the effects of polyI:C on the behavior of the offspring.

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Section: Inflammatory Response Of Pregnant Rodents To Polyi:c Treatmentsupporting

confidence: 93%

Section: Maternal Treatment For Behavioral Experimentsmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

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Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Ballendine

Greba

Dawicki

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

Self Cite

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“…ALI is characterized by the development of hypoxemia, damage to the alveolar-capillary membrane barrier, pulmonary edema and resultant respiratory failure [7]; therefore, it is important to reduce the immune response in order to avoid multi-organ injury. Several protective approaches for I/R injury have been investigated by targeting such individual mediators or mechanisms as antioxidants, anti-leukocyte factors and anticomplements [8][9][10][11][12].…”

mentioning

confidence: 99%

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Barut¹,

Özaçmak²,

TURAN³

et al. 2016

CIM

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Purpose: Multiple organ failure, including acute lung injury, is a common complication of intestinal ischemia and reperfusion (I/R) injury and contributes to its high mortality rate. Activated polymorphonuclear neutrophils and reactive oxygen species contribute to the lung injury caused by intestinal I/R. Mineralokortikoid receptor antagonist spironolactone has a protective effect against I/R injury in animal models of retina, kidney, heart, and brain. The aim of the present study is to investigate the effect of aldosteron receptor blocker spironolactone on lung injury induced by intestinal I/R.Methods: Wistar albino rats were divided into four groups: (1) sham control; (2) intestinal I/R (30 min of ischemia by superior mesenteric artery occlusion followed by 3 h of reperfusion); (3) spironolactone pretreatment (20 mg/kg) + I/R; and, (4) spironolactone pretreatment without I/R. Spironolactone was given orally 3 days prior to intestinal I/R. A marker for lipid peroxidation (malondialdehyde; MDA), an indicator or oxidation state (reduced glutathione; GSH), an index of polymorphonuclear neutrophil sequestration (myeloperoxidase; MPO), inducible nitric oxide synthase (iNOS) immunoreactivity, and the histopathology of the lung tissue were analyzed.Results: Spironolactone pretreatment markedly reduced intestinal I/R-induced lung injury as indicated by histology and MDA and MPO levels. Moreover, the pretreatment decreased the iNOS immunoreactivity. Conclusion:The present study strongly suggests that spironolactone pretreatment decreased neutrophil infiltration, iNOS induction, oxidative stress, and histopathological injury in an experimental model of intestinal I/R induced-lung injury of rats.

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“…It is also elevated in concanavalin A-induced hepatotoxicity mediated by CD4+ T cells (Ajuebor et al, 2004). On the other hand, MIP-2 plays a critical role in the recruitment of neutrophils (Tanimoto et al, 2007), and ELR (Glu-Leu-Arg)-containing CXC chemokines, including MIP-2, are known to have protective effects in liver injury (Zhao et al, 2010). MIP-2 overexpression in liver protected the APAP-induced liver injury due to rapid liver regeneration depending on C-C chemokine receptor 2 expression (Hogaboam et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Hepatotoxicants induce cytokine imbalance in response to innate immune system

et al. 2015

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-In recent years, attention has been paid to innate immune systems as mechanisms to initiate or promote drug-induced liver injury (DILI). Kupffer cells are hepatic resident macrophages and might be involved in the pathogenesis of DILI by release of pro-and anti-inflammatory mediators such as cytokines, chemokines, reactive oxygen species, and/or nitric oxides. The purpose of this study was to investigate alterations in mediator levels induced by hepatotoxic compounds in isolated Kupffer cells and discuss the relation between balance of each cytokine or chemokine and potential of innate immune-mediated DILI. Primary cultured rat Kupffer cells were treated with hepatotoxic (acetaminophen, troglitazone, trovafloxacin) or non-hepatotoxic (pioglitazone, levofloxacin) compounds with or without lipopolysaccharide (LPS). After 24 hr treatment, cell supernatants were collected and various levels of mediators released by Kupffer cells were examined. Although hepatotoxicants had no effect on the LPS-induced tumor necrosis factor-alpha (TNF-α) secretion, they enhanced the release of pro-inflammatory cytokine interleukin-1 beta (IL-1β) and suppressed the anti-inflammatory cytokines interleukin-6 (IL-6) and interleukin-10 (IL-10) induced by LPS. These cytokine shifts were not associated with switching the phenotypes of M1 and M2 macrophages in Kupffer cells. In conclusion, the present study suggested that the levels of some specific cytokines are affected by DILI-related drugs with LPS stimulation, and imbalance between pro-and anti-inflammatory cytokines, induced by the up-regulation of IL-1β and the down-regulation of IL-6 or IL-10, plays a key role in innate immune-mediated DILI.

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A Novel ELR-CXC Chemokine Antagonist Reduces Intestinal Ischemia Reperfusion-Induced Mortality, and Local and Remote Organ Injury

Cited by 25 publications

References 44 publications

Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: Implications for neurodevelopmental psychiatric disorders

Reduction of Acute Lung Injury by Administration of Spironolactone After Intestinal Ischemia and Reperfusion in Rats

Hepatotoxicants induce cytokine imbalance in response to innate immune system

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