Essential role for IL-6 in postresuscitation inflammation in hemorrhagic shock

2001 ◽  
Vol 280 (2) ◽  
pp. C343-C351 ◽  
Author(s):  
Zhi Hong Meng ◽  
Kevin Dyer ◽  
Timothy R. Billiar ◽  
David J. Tweardy
Keyword(s):  
Hemorrhagic Shock ◽  
Nuclear Factor Κb ◽  
Organ Damage ◽  
Systemic Circulation ◽  
Lung Damage ◽  
Wild Type ◽  
Cross Sectional ◽  
Anti Inflammatory ◽  
Sectional Surface ◽  
Deficient Mice

Interleukin-6 (IL-6) is produced within multiple tissues and can be readily detected in the circulation in resuscitated hemorrhagic shock (HS). Instillation of IL-6 into lungs of normal rats induces polymorphonuclear neutrophilic granulocyte (PMN) infiltration and lung damage, while infusion of IL-6 into the systemic circulation of rats during resuscitation from HS reduces PMN recruitment and lung injury. The current study was designed to determine whether or not IL-6 makes an essential contribution to postresuscitation inflammation and which of the two effects of IL-6, its local proinflammatory effect or its systemic anti-inflammatory effect, is dominant in HS. Wild-type and IL-6-deficient mice were subjected to HS followed by resuscitation and death 4 h later. IL-6-deficient mice subjected to HS did not demonstrate any features of postresuscitation inflammation observed in wild-type mice, including increased PMN infiltration into the lungs, increased alveolar cross-sectional surface area, increased PMN infiltration into the liver, increased liver necrosis, increased signal transducer and activator of transcription 3 activation, and increased nuclear factor-κB activity. These findings indicate that IL-6 is an essential component of the postresuscitation inflammatory cascade in HS and that the local proinflammatory effects of IL-6 on PMN infiltration and organ damage in HS dominate over the anti-inflammatory effects of systemic IL-6.

Class B Scavenger Receptors BI and BII Protect Against LPS-induced Acute Lung Injury in Mice by Mediating LPS Clearance

2021 ◽  
Author(s):  
Irina N. Baranova ◽  
Alexander V. Bocharov ◽  
Tatyana G. Vishnyakova ◽  
Zhigang Chen ◽  
Anna A. Birukova ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Transgenic Mice ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Protective Role ◽  
Lung Damage ◽  
Wild Type ◽  
Class B ◽  
Anti Inflammatory

Recent studies suggest an anti-inflammatory protective role for class B scavenger receptor BI (SR-BI) in endotoxin-induced inflammation and sepsis. Other data, including ours, provide evidence for an alternative role of SR-BI, facilitating bacterial and endotoxin uptake, and contributing to inflammation and bacterial infection. Enhanced endotoxin susceptibility of SR-BI deficient mice due to their anti-inflammatory glucocorticoid deficiency complicates understanding SR-BI’s role in endotoxemia/sepsis, calling for use of alternative models. In this study, using hSR-BI and hSR-BII transgenic mice, we found that SR-BI and to a lesser extent its splicing variant SR-BII, protects against LPS-induced lung damage. At 20 hours after intratracheal LPS instillation the extent of pulmonary inflammation and vascular leakage was significantly lower in hSR-BI and hSR-BII transgenic mice compared to wild type mice. Higher bronchoalveolar lavage fluid (BALF) inflammatory cell count and protein content as well as lung tissue neutrophil infiltration found in wild type mice was associated with markedly (2-3 times) increased pro-inflammatory cytokine production as compared to transgenic mice following LPS administration. Markedly lower endotoxin levels detected in BALF of transgenic vs. wild type mice along with the significantly increased BODIPY-LPS uptake observed in lungs of hSR-BI and hSR-BII mice 20 hours after the IT LPS injection suggest that hSR-BI and hSR-BII-mediated enhanced LPS clearance in the airways could represent the mechanism of their protective role against LPS-induced acute lung injury.

Exercise Can Reverse the Phenotype of Biglycan Deficient Mice

2003 ◽  
Author(s):  
Joseph M. Wallace ◽  
Rupak M. Rajachar ◽  
Xiao-Dong Chen ◽  
Songtao Shi ◽  
Matthew R. Allen ◽  
...  
Keyword(s):  
Skeletal Development ◽  
Skeletal Growth ◽  
Treadmill Running ◽  
Wild Type ◽  
Connective Tissues ◽  
Cross Sectional ◽  
Age Dependent ◽  
Skeletal Phenotype ◽  
Deficient Mice ◽  
Wild Type Control

Biglycan (Bgn) is a small leucine-rich proteoglycan (SLRP) that is enriched in bone and other skeletal connective tissues and is responsible, in part, for the regulation of postnatal skeletal growth (Bianco, 1990). Mice lacking Bgn display reduced skeletal development and a lower peak bone mass that leads to age-dependent osteopenia (Xu, 1998). We hypothesized that mechanical loading could reverse the skeletal phenotype of Bgn knockout mice. To test this hypothesis, we determined the effects of treadmill running on the geometric, mechanical and mineral properties of Bgn deficient mice bones. After sacrifice, femora and tibiae were tested in 4 point bending and cross-sectional geometric properties and bone mineral parameters were measured. Exercise was able to partially reverse the skeletal phenotype of the Bgn knockouts by increasing both the geometric and mechanical properties of the tibiae to values equal to or greater than those of wild type control mice.

scholarly journals Complement factor 3 deficiency attenuates hemorrhagic shock-related hepatic injury and systemic inflammatory response syndrome

2010 ◽  
Vol 299 (5) ◽  
pp. R1175-R1182 ◽  
Author(s):  
Changchun Cai ◽  
Roop Gill ◽  
Hyun-Ae Eum ◽  
Zongxian Cao ◽  
Patricia A. Loughran ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Hemorrhagic Shock ◽  
Complement Activation ◽  
Tissue Injury ◽  
Soft Tissue Injury ◽  
High Mobility ◽  
Organ Damage ◽  
Heme Oxygenase 1 ◽  
Complement Factor ◽  
Wild Type

Although complement activation is known to occur in the setting of severe hemorrhagic shock and tissue trauma (HS/T), the extent to which complement drives the initial inflammatory response and end-organ damage is uncertain. In this study, complement factor 3-deficient (C3−/−) mice and wild-type control mice were subjected to 1.5-h hemorrhagic shock, bilateral femur fracture, and soft tissue injury, followed by 4.5-h resuscitation (HS/T). C57BL/6 mice were also given 15 U of cobra venom factor (CVF) or phosphate-buffered saline injected intraperitoneally, followed by HS/T 24 h later. The results showed that HS/T resulted in C3 consumption in wild-type mice and C3 deposition in injured livers. C3−/− mice had significantly lower serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and circulating DNA levels, together with much lower circulating interleukin (IL)-6, IL-10, and high-mobility group box 1 (HMGB1) levels. Temporary C3 depletion by CVF preconditioning also led to reduced transaminases and a blunted cytokine release. C3−/− mice displayed well-preserved hepatic structure. C3−/− mice subjected to HS/T had higher levels of heme oxygenase-1, which has been associated with tissue protection in HS models. Our data indicate that complement activation contributes to inflammatory pathways and liver damage in HS/T. This suggests that targeting complement activation in the setting of severe injury could be useful.

Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation

2006 ◽  
Vol 291 (3) ◽  
pp. G456-G463 ◽  
Author(s):  
Mark Lehnert ◽  
Tetsuya Uehara ◽  
Blair U. Bradford ◽  
Henrik Lind ◽  
Zhi Zhong ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Knockout Mice ◽  
Binding Protein ◽  
Neutrophil Infiltration ◽  
Wild Type ◽  
Hepatocellular Injury ◽  
Lipopolysaccharide Binding Protein ◽  
Hepatocellular Damage ◽  
Deficient Mice ◽  
Lipopolysaccharide Binding

Hemorrhagic shock and resuscitation cause endotoxemia and hepatocellular damage. Because lipopolysaccharide-binding protein (LBP) enhances cellular responses to endotoxin, our aim was to determine whether LBP contributes to hemorrhage/resuscitation-induced injury by comparing LBP knockout and wild-type mice. Under pentobarbital anaesthesia, wild-type and LBP-deficient mice were hemorrhaged to 30 mmHg for 3 h and then resuscitated with shed blood plus half the volume of lactated Ringer solution. Serum alanine aminotransferase (ALT) necrosis, neutrophil infiltration, and 4-hydroxynonenal by histology/cytochemistry and stress kinase activation by immunoblot analysis were then determined. ALT in wild-type mice was 2,461 ± 383 and 1,418 ± 194 IU/l (means ± SE), respectively, at 2 and 6 h after resuscitation versus sham ALT of 102 ± 6 IU/l. In LBP-deficient mice, ALT was blunted at both time points to 1,108 ± 340 and 619 ± 171 IU/l ( P < 0.05). Liver necrosis after 6 h was also attenuated from 3.5 ± 0.8% in wild-type mice to 1.3 ± 0.5% in LBP-deficient mice ( P < 0.05). After hemorrhage/resuscitation, neutrophil infiltration increased 71% more in wild-type than LBP knockout mice. Similarly, hepatic 4-hydroxynonenal staining, indicative of lipid peroxidation, decreased from 33.8 ± 4.5% in wild-type mice to 11.6 ± 1.9% in knockout mice ( P < 0.05). After hemorrhage/resuscitation, activation of MAPKs, JNK and ERK, occurred in wild-type mice, which was largely blocked in LBP-deficient mice. However, endotoxin in portal blood after resuscitation was not significantly different between wild-type and knockout mice. In conclusion, hemorrhagic shock and resuscitation to mice cause severe, LBP-mediated hepatocellular damage. An absence of LBP blunts hepatocellular injury with decreased neutrophil infiltration, oxidative stress, and c-Jun and ERK activation.

Abstract 260: Systemic Loss of p62 Reduces Pressure Overload Induced Cardiac Hypertrophy, Dysfunction and Apoptosis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Mannix Auger-Messier ◽  
Khosrow Rezvani ◽  
Scott Pattison
Keyword(s):  
Cardiac Hypertrophy ◽  
Pressure Overload ◽  
Heart Weight ◽  
Cardiomyocyte Hypertrophy ◽  
Wild Type ◽  
Protein Aggregate ◽  
Cross Sectional ◽  
Post Surgery ◽  
Deficient Mice

Introduction: p62 is a pleiotropic protein with defined roles in TNFα signaling, protein aggregate formation, and protein degradation processes. Current data suggest that p62 is a stress-response protein, with increased protein levels reported in TAC, MI, I/R, and protein aggregation models of cardiac disease. To date, there has been little study on the gain- or loss- of p62 function in cardiomyocyte/cardiac pathology. Our preliminary data found that adenoviral overexpression of p62 caused cardiomyocyte hypertrophy and cytotoxicity and that p62 was upregulated by pressure-overload stress. Hypothesis: Loss of p62 will be cardioprotective against pressure-overload pathology. Methods: Systemic p62 knockout mice underwent sham or transverse-aortic constriction surgery and were studied longitudinally to 8 weeks post-surgery by echocardiography. Results: Hearts from p62-null mice had significantly preserved cardiac function (%Fractional Shortening) over wild-type controls. p62-deficient mice had significantly less cardiac hypertrophy (heart weight/body weight ratios and myofiber cross-sectional areas) and showed no chamber dilation (LVED) in response to pressure-overload stress, unlike wild-types. Hearts from wild-type mice showed pronounced fibrotic remodeling and induction of apoptosis (TUNEL), while p62 knockouts had significantly less collagen staining and no evidence of apoptotic stimulation. Overexpression of p62 in rat neonatal cardiomyocytes significantly inhibited proteasomal catalytic activities (>50%) and showed increased indices of cardiomyocyte cell death. Conclusion: Our data show that induction of p62 is deleterious in vitro and that loss of p62 imparts cardioprotection against hemodynamic stress in vivo . The beneficial phenotype observed in hearts from p62-deficient mice may be due to p62-dependent mechanisms responsible for proteasomal dysfunction and apoptosis activation.

scholarly journals Essential Role of Induced Nitric Oxide in the Initiation of the Inflammatory Response after Hemorrhagic Shock

1998 ◽  
Vol 187 (6) ◽  
pp. 917-928 ◽  
Author(s):  
Christian Hierholzer ◽  
Brian Harbrecht ◽  
John M. Menezes ◽  
John Kane ◽  
John MacMicking ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Response ◽  
Hemorrhagic Shock ◽  
Messenger Rna ◽  
Nuclear Factor Κb ◽  
Organ Damage ◽  
Transcriptional Factors ◽  
Inos Inhibitor ◽  
Inos Knockout Mice ◽  
Inos Inhibition

Resuscitation from hemorrhagic shock induces profound changes in the physiologic processes of many tissues and activates inflammatory cascades that include the activation of stress transcriptional factors and upregulation of cytokine synthesis. This process is accompanied by acute organ damage (e.g., lungs and liver). We have previously demonstrated that the inducible nitric oxide synthase (iNOS) is expressed during hemorrhagic shock. We postulated that nitric oxide production from iNOS would participate in proinflammatory signaling. Using the iNOS inhibitor N6-(iminoethyl)-l-lysine or iNOS knockout mice we found that the activation of the transcriptional factors nuclear factor κB and signal transducer and activator of transcription 3 and increases in IL-6 and G-CSF messenger RNA levels in the lungs and livers measured 4 h after resuscitation from hemorrhagic shock were iNOS dependent. Furthermore, iNOS inhibition resulted in a marked reduction of lung and liver injury produced by hemorrhagic shock. Thus, induced nitric oxide is essential for the upregulation of the inflammatory response in resuscitated hemorrhagic shock and participates in end organ damage under these conditions.

scholarly journals Platelet-activating factor induces the processing of nuclear factor-κB p105 into p50, which mediates acute bowel injury in mice

2009 ◽  
Vol 297 (1) ◽  
pp. G76-G81 ◽  
Author(s):  
Shirley X. L. Liu ◽  
Runlan Tian ◽  
Heather Baskind ◽  
Wei Hsueh ◽  
Isabelle G. De Plaen
Keyword(s):  
Blood Pressure Monitoring ◽  
Platelet Activating Factor ◽  
Nuclear Factor Κb ◽  
Bowel Injury ◽  
Wild Type ◽  
Intestinal Hypoperfusion ◽  
Rats And Mice ◽  
Rapid Activation ◽  
Deficient Mice

Platelet-activating factor (PAF), an endogenous proinflammatory phospholipid, when injected intravascularly to rats and mice, causes shock, acute bowel injury, and a rapid activation of NF-κB p50-p50 with upregulation of the chemokine CXCL2 in the intestine. In this study, we investigate the mechanism of NF-κB activation and the role of the NF-κB p50 subunit in PAF-induced shock and acute bowel injury. NF-κB p50-deficient mice and wild-type mice were anesthetized and tracheotomized, and their carotid artery was cannulated for blood pressure monitoring, blood sampling, and PAF administration. For determination of bowel injury, shock, and survival, PAF (2.2 μg/kg, intra-arterially, i.a.) was injected. Two hours later, animals were euthanized, and their small intestines were removed for histological examination. For biochemical studies, PAF (1.5 μg/kg i.a.) was administered and the small intestine removed after 15–60 min. We found that PAF induced an increase in p105 processing within 30 min, but there were no changes in the levels of the NF-κB inhibitory proteins IκBα and β. NF-κB p50-deficient mice were protected against PAF-induced mortality, shock, intestinal hypoperfusion, and injury compared with wild-type animals. We also found that p50-deficient mice had decreased gene expression of CXCL2 and TNF and a decrease in CXCL2 protein production compared with wild-type mice. Our study suggests that PAF increases the processing of NF-κB p105 into p50, with upregulation of proinflammatory cytokines, which leads to PAF-induced systemic inflammatory response and acute bowel injury.

scholarly journals Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation

2008 ◽  
Vol 295 (4) ◽  
pp. R1109-R1114 ◽  
Author(s):  
C. P. Krzyszton ◽  
N. L. Sparkman ◽  
R. W. Grant ◽  
J. B. Buchanan ◽  
S. R. Broussard ◽  
...  
Keyword(s):  
Motor Performance ◽  
Motor Coordination ◽  
Interleukin 10 ◽  
Motor Deficits ◽  
Wild Type ◽  
Age Related ◽  
Anti Inflammatory ◽  
Deficient Mice ◽  
Anti Inflammatory Cytokine ◽  
Lps Treatment

The anti-inflammatory cytokine interleukin (IL)-10 is important for regulating inflammation in the periphery and brain, but whether it protects against infection- or age-related psychomotor disturbances and fatigue is unknown. Therefore, the present study evaluated motor coordination, time to fatigue, and several central and peripheral proinflammatory cytokines in male young adult (3-mo-old) and middle-aged (12-mo-old) wild-type (IL-10+/+) and IL-10-deficient (IL-10−/−) mice after intraperitoneal injection of lipopolysaccharide (LPS) or saline. No age-related differences were observed; therefore, data from the two ages were pooled and analyzed to determine effects of genotype and treatment. LPS treatment increased IL-1β, IL-6, and TNFα mRNA in all brain areas examined in IL-10+/+and IL-10−/−mice, but to a greater extent and for a longer time in IL-10−/−mice. Plasma IL-1β and IL-6 were increased similarly in IL-10+/+and IL-10−/−mice 4 h after LPS but remained elevated longer in IL-10−/−mice, whereas TNFα was higher in IL-10−/−mice throughout after LPS treatment. Motor performance and motor learning in IL-10+/+mice were not affected by LPS treatment; however, both were reduced in IL-10−/−mice treated with LPS compared with those treated with saline. Furthermore, although LPS reduced the time to fatigue in IL-10+/+and IL-10−/−mice, the effects were exacerbated in IL-10−/−mice. Thus the increased brain and peripheral inflammation induced by LPS in IL-10−/−mice was associated with increased coordination deficits and fatigue. These data suggest that IL-10 may inhibit motor deficits and fatigue associated with peripheral infections via its anti-inflammatory effects.

scholarly journals Wine constituents inhibit thrombosis but not atherogenesis in C57BL/6 apolipoprotein E-deficient mice

2006 ◽  
Vol 96 (2) ◽  
pp. 290-298 ◽  
Author(s):  
Thierry Soulat ◽  
Catherine Philippe ◽  
Claire Bal dit Sollier ◽  
Christophe Brézillon ◽  
Natacha Berge ◽  
...  
Keyword(s):  
Cardiovascular Events ◽  
Red Wine ◽  
Ex Vivo ◽  
Industrialized Countries ◽  
Wild Type ◽  
Cross Sectional ◽  
Atherosclerotic Lesions ◽  
Wine Polyphenols ◽  
In The Wild ◽  
Sectional Surface

Regular and moderate wine consumption is one of the explanations suggested for the lower incidence of cardiovascular events in France compared with other industrialized countries. We evaluated whether alcohol alone or combined with red wine polyphenols reduced plaque size and/or attenuated thrombotic reactivity at the site of advanced atherosclerotic lesions. Red wine extract, or purified (+)-catechin with alcohol, or alcohol alone, was added for 12 weeks to the drinking water of apoE-deficient (apoE−/−) C57B/ mice and wild-type counterparts. In the apoE−/−mice, all alcohol-containing mixtures were associated with a larger size of aortic atherosclerotic lesions. On the other hand, red wine extract and (+)-catechin significantly inhibited blood thrombotic reactivity (P<0·05) as assessed in a cylindrical perfusion chamber model of experimental thrombosis: area reductions in cross-sectional surface of theex vivothrombus were 64% and 63%, respectively. In the wild-type mice, red wine extract and (+)-catechin tended to reduce thrombogenicity, which was on the whole less marked than in the apoE−/−mice. These findings suggest that a moderate and regular consumption of red wine may protect against clinical cardiovascular events, mainly by attenuating the thrombogenic response rather than by reducing the development of atherosclerotic lesions. This antithrombogenic effect may include normalization of the abnormally high thrombogenic responsiveness in apoE−/−mice as well as a direct antithrombotic effect.

scholarly journals Functional Redundancy of the Nuclear Factor κB Inhibitors IκBα and IκBβ

1998 ◽  
Vol 188 (6) ◽  
pp. 1055-1062 ◽  
Author(s):  
Janet D. Cheng ◽  
Rolf-Peter Ryseck ◽  
Ricardo M. Attar ◽  
Donna Dambach ◽  
Rodrigo Bravo
Keyword(s):  
Expression Patterns ◽  
Nuclear Factor Κb ◽  
Functional Redundancy ◽  
Regulatory Sequence ◽  
Nuclear Factor ◽  
Wild Type ◽  
Biochemical Activity ◽  
Embryonic Fibroblasts ◽  
Developmental Defects ◽  
Deficient Mice

The transcription factor NF-κB is sequestered in the cytoplasm by the inhibitor proteins of the IκB family. Each member of the IκB exhibits structural and biochemical similarities as well as differences. In an effort to address the functional redundancy of two closely related IκB molecules, IκBα and IκBβ, we generated knock-in mice by replacing the IκBα gene with the IκBβ gene. The knock-in mice do not express IκBα, but express a T7-tagged IκBβ under the promoter and regulatory sequence of ikba. Unlike the IκBα-deficient mice, which display severe postnatal developmental defects and die by postnatal day 8, homozygous knock-in mice survive to adulthood, are fertile, and exhibit no apparent abnormalities. Furthermore, thymocytes and embryonic fibroblasts from the knock-in animals exhibit an inducible NF-κB response similar to that of wild-type animals. These results indicate that IκBα and IκBβ share significant similarities in their biochemical activity, and that they acquired their different functions from divergent expression patterns during evolution.

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