scholarly journals Leukocyte-derived extracellular superoxide dismutase does not contribute to airspace EC-SOD after interstitial pulmonary injury

2012 ◽  
Vol 302 (1) ◽  
pp. L160-L166 ◽  
Author(s):  
Michelle L. Manni ◽  
Michael W. Epperly ◽  
Wei Han ◽  
Timothy S. Blackwell ◽  
Steven R. Duncan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Superoxide Dismutase ◽  
Lung Injury ◽  
Knockout Mice ◽  
Inflammatory Diseases ◽  
Early Stage ◽  
Lavage Fluid ◽  
Extracellular Superoxide Dismutase ◽  
Wild Type ◽  
Lung Injury Model

The antioxidant enzyme extracellular superoxide dismutase (EC-SOD) is abundant in the lung and is known to limit inflammation and fibrosis following numerous pulmonary insults. Previous studies have reported a loss of full-length EC-SOD from the pulmonary parenchyma with accumulation of proteolyzed EC-SOD in the airspace after an interstitial lung injury. However, following airspace only inflammation, EC-SOD accumulates in the airspace without a loss from the interstitium, suggesting this antioxidant may be released from an extrapulmonary source. Because leukocytes are known to express EC-SOD and are prevalent in the bronchoalveolar lavage fluid (BALF) after injury, it was hypothesized that these cells may transport and release EC-SOD into airspaces. To test this hypothesis, C57BL/6 wild-type and EC-SOD knockout mice were irradiated and transplanted with bone marrow from either wild-type mice or EC-SOD knockout mice. Bone marrow chimeric mice were then intratracheally treated with asbestos and killed 3 and 7 days later. At both 3 and 7 days following asbestos injury, mice without pulmonary EC-SOD expression but with EC-SOD in infiltrating and resident leukocytes did not have detectable levels of EC-SOD in the airspaces. In addition, leukocyte-derived EC-SOD did not significantly lessen inflammation or early stage fibrosis that resulted from asbestos injury in the lungs. Although it is not influential in the asbestos-induced interstitial lung injury model, EC-SOD is still known to be present in leukocytes and may play an influential role in attenuating pneumonias and other inflammatory diseases.

Prevention of influenza-induced lung injury in mice overexpressing extracellular superoxide dismutase

2001 ◽  
Vol 280 (1) ◽  
pp. L69-L78 ◽  
Author(s):  
Hagir B. Suliman ◽  
Lisa K. Ryan ◽  
Lisa Bishop ◽  
Rodney J. Folz
Keyword(s):  
Superoxide Dismutase ◽  
Lung Injury ◽  
Influenza A ◽  
Lavage Fluid ◽  
Interferon Γ ◽  
Airway Epithelial Cells ◽  
Extracellular Superoxide Dismutase ◽  
Lung Pathology ◽  
Wild Type ◽  
Nitrite Nitrate

Reactive oxygen and nitrogen species such as superoxide and nitric oxide are released into the extracellular spaces by inflammatory and airway epithelial cells. These molecules may exacerbate lung injury after influenza virus pneumonia. We hypothesized that enhanced expression of extracellular superoxide dismutase (EC SOD) in mouse airways would attenuate the pathological effects of influenza pneumonia. We compared the pathogenic effects of a nonlethal primary infection with mouse-adapted Hong Kong influenza A/68 virus in transgenic (TG) EC SOD mice versus non-TG (wild-type) littermates. Compared with wild-type mice, EC SOD TG mice showed less lung injury and inflammation as measured by significant blunting of interferon-γ induction, reduced cell count and total protein in bronchoalveolar lavage fluid, reduced levels of lung nitrite/nitrate nitrotyrosine, and markedly reduced lung pathology. These results demonstrate that enhancing EC SOD in the conducting and distal airways of the lung minimizes influenza-induced lung injury by both ameliorating inflammation and attenuating oxidative stress.

Role of extracellular superoxide dismutase in bleomycin-induced pulmonary fibrosis

2002 ◽  
Vol 282 (4) ◽  
pp. L719-L726 ◽  
Author(s):  
Russell P. Bowler ◽  
Mike Nicks ◽  
Karrie Warnick ◽  
James D. Crapo
Keyword(s):  
Oxidative Stress ◽  
Superoxide Dismutase ◽  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Immunohistochemical Staining ◽  
Extracellular Superoxide Dismutase ◽  
Wild Type ◽  
Injured Lung ◽  
Intracellular Oxidative Stress

Bleomycin administration results in well-described intracellular oxidative stress that can lead to pulmonary fibrosis. The role of alveolar interstitial antioxidants in this model is unknown. Extracellular superoxide dismutase (EC-SOD) is the primary endogenous extracellular antioxidant enzyme and is abundant in the lung. We hypothesized that EC-SOD plays an important role in attenuating bleomycin-induced lung injury. Two weeks after intratracheal bleomycin administration, we found that wild-type mice induced a 106 ± 25% increase in lung EC-SOD. Immunohistochemical staining revealed that a large increase in EC-SOD occurred in injured lung. Using mice that overexpress EC-SOD specifically in the lung, we found a 53 ± 14% reduction in bleomycin-induced lung injury assessed histologically and a 17 ± 6% reduction in lung collagen content 2 wk after bleomycin administration. We conclude that EC-SOD plays an important role in reducing the magnitude of lung injury from extracellular free radicals after bleomycin administration.

Evidence for extracellular superoxide dismutase as a mediator of hemorrhage-induced lung injury

2003 ◽  
Vol 284 (4) ◽  
pp. L680-L687 ◽  
Author(s):  
Russell P. Bowler ◽  
John Arcaroli ◽  
Edward Abraham ◽  
Manisha Patel ◽  
Ling-Yi Chang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Superoxide Dismutase ◽  
Lung Injury ◽  
Fold Increase ◽  
Myeloperoxidase Activity ◽  
Extracellular Superoxide Dismutase ◽  
Wild Type ◽  
Neutrophil Accumulation ◽  
Deficient Mice ◽  
Severe Lung

Hemorrhage results in excessive production of superoxide that is associated with severe lung injury. We examined whether the superoxide dismutase (SOD) mimetic manganese(III) mesotetrakis (di- N-ethylimidazole) porphyrin (AEOL 10150) could attenuate this lung injury and whether extracellular (EC)-SOD-deficient mice would have increased hemorrhage-induced lung injury. Compared with wild-type mice, EC-SOD-deficient mice had increased lung neutrophil accumulation, a 3.9-fold increase in myeloperoxidase activity, a 1.5-fold increase in nuclear factor (NF)-κB activation, and a 1.5-fold increase in lipid peroxidation 1 h after hemorrhage. Pretreatment with AEOL 10150 did not attenuate neutrophil accumulation but significantly reduced NF-κB activation and lipid peroxidation in both wild-type and EC-SOD-deficient mice. The increase in hemorrhage-induced neutrophil accumulation in the lungs of EC-SOD-deficient mice suggests that EC-SOD might play a role in mediating neutrophil recruitment to the lung.

scholarly journals IL-17F depletion accelerates chitosan conduit guided peripheral nerve regeneration

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Feixiang Chen ◽  
Weihuang Liu ◽  
Qiang Zhang ◽  
Ping Wu ◽  
Ao Xiao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sciatic Nerve ◽  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
Knockout Mice ◽  
Inflammatory Markers ◽  
Nerve Repair ◽  
Peripheral Nerve Regeneration ◽  
Wild Type ◽  
Anti Inflammatory

AbstractPeripheral nerve injury is a serious health problem and repairing long nerve deficits remains a clinical challenge nowadays. Nerve guidance conduit (NGC) serves as the most promising alternative therapy strategy to autografts but its repairing efficiency needs improvement. In this study, we investigated whether modulating the immune microenvironment by Interleukin-17F (IL-17F) could promote NGC mediated peripheral nerve repair. Chitosan conduits were used to bridge sciatic nerve defect in IL-17F knockout mice and wild-type mice with autografts as controls. Our data revealed that IL-17F knockout mice had improved functional recovery and axonal regeneration of sciatic nerve bridged by chitosan conduits comparing to the wild-type mice. Notably, IL-17F knockout mice had enhanced anti-inflammatory macrophages in the NGC repairing microenvironment. In vitro data revealed that IL-17F knockout peritoneal and bone marrow derived macrophages had increased anti-inflammatory markers after treatment with the extracts from chitosan conduits, while higher pro-inflammatory markers were detected in the Raw264.7 macrophage cell line, wild-type peritoneal and bone marrow derived macrophages after the same treatment. The biased anti-inflammatory phenotype of macrophages by IL-17F knockout probably contributed to the improved chitosan conduit guided sciatic nerve regeneration. Additionally, IL-17F could enhance pro-inflammatory factors production in Raw264.7 cells and wild-type peritoneal macrophages. Altogether, IL-17F may partially mediate chitosan conduit induced pro-inflammatory polarization of macrophages during nerve repair. These results not only revealed a role of IL-17F in macrophage function, but also provided a unique and promising target, IL-17F, to modulate the microenvironment and enhance the peripheral nerve regeneration.

Ascorbic acid and CoQ10 ameliorate the reproductive ability of superoxide dismutase 1-deficient female mice†

2019 ◽  
Author(s):  
Naoki Ishii ◽  
Takujiro Homma ◽  
Jaeyong Lee ◽  
Hikaru Mitsuhashi ◽  
Ken-ichi Yamada ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Superoxide Dismutase ◽  
Coenzyme Q10 ◽  
Knockout Mice ◽  
Knockout Mouse ◽  
Superoxide Dismutase 1 ◽  
Wild Type ◽  
Positive Effects ◽  
Reproductive Ability ◽  
Ascorbic Acid Supplementation

Abstract Superoxide dismutase 1 suppresses oxidative stress within cells by decreasing the levels of superoxide anions. A dysfunction of the ovary and/or an aberrant production of sex hormones are suspected causes for infertility in superoxide dismutase 1-knockout mice. We report on attempts to rescue the infertility in female knockout mice by providing two antioxidants, ascorbic acid and/or coenzyme Q10, as supplements in the drinking water of the knockout mice after weaning and on an investigation of their reproductive ability. On the first parturition, 80% of the untreated knockout mice produced smaller litter sizes compared with wild-type mice (average 2.8 vs 7.3 pups/mouse), and supplementing with these antioxidants failed to improve these litter sizes. However, in the second parturition of the knockout mice, the parturition rate was increased from 18% to 44–75% as the result of the administration of antioxidants. While plasma levels of progesterone at 7.5 days of pregnancy were essentially the same between the wild-type and knockout mice and were not changed by the supplementation of these antioxidants, sizes of corpus luteum cells, which were smaller in the knockout mouse ovaries after the first parturition, were significantly ameliorated in the knockout mouse with the administration of the antioxidants. Moreover, the impaired vasculogenesis in uterus/placenta was also improved by ascorbic acid supplementation. We thus conclude that ascorbic acid and/or coenzyme Q10 are involved in maintaining ovarian and uterus/placenta homeostasis against insults that are augmented during pregnancy and that their use might have positive effects in terms of improving female fertility.

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.

Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity

Thorax ◽  
2020 ◽  
Vol 75 (3) ◽  
pp. 253-261 ◽  
Author(s):  
Inga Wessels ◽  
Johanna Theresa Pupke ◽  
Klaus-Thilo von Trotha ◽  
Alexander Gombert ◽  
Anika Himmelsbach ◽  
...  
Keyword(s):  
Lung Injury ◽  
Zinc Supplementation ◽  
Inflammatory Diseases ◽  
Risk Groups ◽  
Lavage Fluid ◽  
Neutrophil Recruitment ◽  
Polymorphonuclear Neutrophils ◽  
Lung Damage ◽  
Inflammatory Status

IntroductionZinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested.Methods64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well.ResultsInjecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail.ConclusionZinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.

Protective Role of Urinary Trypsin Inhibitor in Acute Lung Injury Induced by Lipopolysaccharide

2005 ◽  
Vol 230 (4) ◽  
pp. 281-287 ◽  
Author(s):  
Ken-ichiro Inoue ◽  
Hirohisa Takano ◽  
Rie Yanagisawa ◽  
Miho Sakurai ◽  
Akinori Shimada ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Trypsin Inhibitor ◽  
Inflammatory Diseases ◽  
Lavage Fluid ◽  
Intercellular Adhesion Molecule ◽  
Urinary Trypsin Inhibitor ◽  
Intercellular Adhesion Molecule 1 ◽  
Lung Water ◽  
Lps Challenge

Urinary trypsin inhibitor (UTI), a serine protease inhibitor, has been widely used as a drug for patients with acute inflammatory disorders such as disseminated intravascular coagulation, shock, and pancreatitis. However, direct contribution of UTI to inflammatory diseases has not been established. The present study analyzed acute inflammatory lung injury induced by lipopolysaccharide (LPS) in UTI-deficient (–/–) mice and corresponding wild-type (WT) mice. UTI (–/–) and WT mice were treated intratracheally with vehicle or LPS (125 μg/kg). The cellular profile of bronchoalveolar lavage fluid, lung water content, histology, and expression of proinflammatory molecules in the lung were evaluated. After LPS challenge, both genotypes of mice revealed neutrophilic lung inflammation and pulmonary edema. UTI (–/–) mice, however, showed more prominent infiltration of inflammatory cells and edema than WT mice. After LPS challenge in both genotypes of mice, the lung levels of mRNA and/or protein expression of interleukin-1β, macrophage inflammatory protein-1α, macrophage chemoattractant protein-1, keratinocyte chemoattractant, and intercellular adhesion molecule-1 (ICAM-1) were elevated in both groups, but to a greater extent in UTI (–/–) mice than in WT mice. These results suggest that UTI protects against acute lung injury induced by bacterial endotoxin, at least partly, through the inhibition of the enhanced local expression of proinflammatory cytokines, chemokines, and ICAM-1.

Transient Receptor Potential Melastatin 2 Protects Mice against Polymicrobial Sepsis by Enhancing Bacterial Clearance

2014 ◽  
Vol 121 (2) ◽  
pp. 336-351 ◽  
Author(s):  
XiaoWei Qian ◽  
Tomohiro Numata ◽  
Kai Zhang ◽  
CaiXia Li ◽  
JinChao Hou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Transient Receptor Potential ◽  
Cecal Ligation ◽  
Polymicrobial Sepsis ◽  
Bacterial Clearance ◽  
Cecal Ligation And Puncture ◽  
Bacterial Burden ◽  
Wild Type ◽  
Transient Receptor Potential Melastatin

Abstract Background: Recent studies suggest that the transient receptor potential melastatin 2 (TRPM2) channel plays an important role in inflammation and immune response. However, the role and mechanism of TRPM2 in polymicrobial sepsis remain unclear. Methods: The authors explored the effects of genetic disruption of TRPM2 on mortality (n = 15), bacterial clearance (n = 6), organ injury, and systemic inflammation during cecal ligation and puncture–induced sepsis. Electrophysiology, immunoblot, bacterial clearance experiment, and quantitative real-time polymerase chain reaction were used to explore the role and mechanism of TRPM2 in sepsis. Results: After cecal ligation and puncture, Trpm2-knockout mice had increased mortality compared with wild-type mice (73.3 vs. 40%, P = 0.0289). The increased mortality was associated with increased bacterial burden, organ injury, and systemic inflammation. TRPM2-mediated Ca2+ influx plays an important role in lipopolysaccharide or cecal ligation and puncture–induced heme oxygenase-1 (HO-1) expression in macrophage. HO-1 up-regulation decreased bacterial burden both in wild-type bone marrow–derived macrophages and in cecal ligation and puncture–induced septic wild-type mice. Disruption of TRPM2 decreased HO-1 expression and increased bacterial burden in bone marrow–derived macrophages. Pretreatment of Trpm2-knockout bone marrow–derived macrophages with HO-1 inducer markedly increased HO-1 expression and decreased bacterial burden. Pretreatment of Trpm2-knockout mice with HO-1 inducer reversed the susceptibility of Trpm2-knockout mice to sepsis by enhancing the bacterial clearance. In addition, septic patients with lower monocytic TRPM2 and HO-1 messenger RNA levels had a worse outcome compared with septic patients with normal monocytic TRPM2 and HO-1 messenger RNA levels. TRPM2 levels correlated with HO-1 levels in septic patients (r = 0.675, P = 0.001). Conclusion: The study data demonstrate a protective role of TRPM2 in controlling bacterial clearance during polymicrobial sepsis possibly by regulating HO-1 expression.

The Interferon-Inducible GTPase LRG-47 Regulates Hematopoietic Stem Cell Proliferation and Is Required for Maintenance of Normal Hematopoiesis during Microbial Infection.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2266-2266
Author(s):  
David Weksberg ◽  
Carl G. Feng ◽  
Alan Sher ◽  
Margaret A. Goodell
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Stem Cell ◽  
Knockout Mice ◽  
Progenitor Cell ◽  
Side Population ◽  
Constant Number ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Error Bars

Abstract Hematopoietic stem cells (HSCs) have a remarkable capacity to respond to proliferative stimuli, as they are able to reconstitute the blood following catastrophic injuries such as chemotherapy and lethal irradiation. Most work aimed at elucidating the genetic and molecular controls on this program of activation has focused on HSCs responding to these artificial stimuli, however there is a surprising paucity of information reflecting the response of HSCs to the types of stimuli encountered in a non-laboratory setting. Here we report that LRG-47, an interferon-inducible GTPase, is required for HSCs to respond to a variety of proliferative stimuli, including mycobaterial challenge. Previously studied solely in the context of the immune response to intracellular pathogens, LRG-47 is upregulated in HSCs during 5-fluorouracil-(5FU) induced proliferation, and we now show that LRG-47 −/− HSCs exhibit profound defects. LRG-47 −/− HSCs achieve only 4–8% of wild-type engraftment activity in competitive repopulation assays (Figure 1) and, strikingly, even transplantation in 25-fold excess over wild-type competitor fails to rescue this defect. We also demonstrate that LRG-47 −/− HSCs are impaired in colony-forming ability, and that LRG-47 −/− mice exhibit both a relative and absolute failure to expand the stem cell/progenitor compartments in response to 5FU (Figure 2). Intriguingly, we also show that infectious challenge with Mycobacterium avium stimulates an expansion of the progenitor cell (LSK) compartment in wild-type mice - and that LRG-47-deficient mice are unable to mount this response. These findings implicate LRG-47 as being required for effective proliferation of HSCs in response to various stimuli. Furthermore, these results imply that expansion at the progenitor cell level is a downstream effector mechanism of the cytokine-mediated immune response to infection. Ultimately, understanding the mechanisms by which HSCs sense and respond to proliferative stimuli has far-ranging applications, and our work establishes an important connection with the immune system as a regulator of this process. Infectious processes can now arguably join ex vivo HSC manipulation, mechanisms of hematologic malignancy, and transplantation medicine as areas of importance informed by an understanding of the controls on HSC activation, proliferation and quiescence. Figure 1. Competitive transplant of LRG-/- bone marrow. Whole bone marrow from wild type and LRG-47 -/- mice (CD45.2) admixed with a constant number of CD45.1 competitor cells (250,000) and transplanted into lethally irradiated recipients (CD45.1). Perecent chimerism was assessed every four weeks post-transplant (error bars = SEM). Figure 1. Competitive transplant of LRG-/- bone marrow. Whole bone marrow from wild type and LRG-47 -/- mice (CD45.2) admixed with a constant number of CD45.1 competitor cells (250,000) and transplanted into lethally irradiated recipients (CD45.1). Perecent chimerism was assessed every four weeks post-transplant (error bars = SEM). Figure 2. LRG-47 -/- fail to expand HSC compartment in response to SFU. Wild type and LRG-47 -/- mice were injected with SFU 6-days prior to side population (SP) analysis of HSC compartment. While wild-type mice showed the expected expansion of the HSC population (upper panels - gated), this response is impaired in the knockout mice (lower panels). Figure 2. LRG-47 -/- fail to expand HSC compartment in response to SFU. Wild type and LRG-47 -/- mice were injected with SFU 6-days prior to side population (SP) analysis of HSC compartment. While wild-type mice showed the expected expansion of the HSC population (upper panels - gated), this response is impaired in the knockout mice (lower panels).

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