scholarly journals Serum amyloid A3 confers protection against acute lung injury in Pseudomonas aeruginosa-infected mice

2020 ◽  
Vol 318 (2) ◽  
pp. L314-L322 ◽  
Author(s):  
Yu Fan ◽  
Gufang Zhang ◽  
Chi Teng Vong ◽  
Richard D. Ye
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Knockout Mice ◽  
Superoxide Anion ◽  
Inflammatory Responses ◽  
Serum Amyloid ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Anion Production

Pseudomonas aeruginosa is a gram-negative bacterium associated with serious illnesses, including ventilator-associated pneumonia and various sepsis syndromes in humans. Understanding the host immune mechanisms against P. aeruginosa is, therefore, of clinical importance. The present study identified serum amyloid A3 (SAA3) as being highly inducible in mouse bronchial epithelium following P. aeruginosa infection. Genetic deletion of Saa3 rendered mice more susceptible to P. aeruginosa infection with decreased neutrophil superoxide anion production, and ex vivo treatment of mouse neutrophils with recombinant SAA3 restored the ability of neutrophils to produce superoxide anions. The SAA3-deficient mice showed exacerbated inflammatory responses, which was characterized by pronounced neutrophil infiltration, elevated expression of TNF-α, KC/CXCL1, and MIP-2/CXCL2 in bronchoalveolar lavage fluid (BALF), and increased lung microvascular permeability compared with their wild-type littermates. BALF neutrophils from Saa3 knockout mice exhibited reduced superoxide anion production compared with neutrophils from wild-type mice. Adoptive transfer of SAA3-treated neutrophils to Saa3 knockout mice ameliorated P. aeruginosa-induced acute lung injury. These findings demonstrate that SAA3 not only serves as a biomarker for infection and inflammation, but also plays a protective role against P. aeruginosa infection-induced lung injury in part through augmentation of neutrophil bactericidal functions.

OPC-6535, a Superoxide Anion Production Inhibitor, Attenuates Acute Lung Injury

1997 ◽  
Vol 72 (1) ◽  
pp. 70-77 ◽  
Author(s):  
Geoffrey L. Bloomfield ◽  
Philip C. Ridings ◽  
Charles R. Blocher ◽  
Bernard J. Fisher ◽  
Harvey J. Sugerman ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Superoxide Anion ◽  
Superoxide Anion Production ◽  
Anion Production

scholarly journals Nutritional Effects on Host Response to Lung Infections with Mucoid Pseudomonas aeruginosa in Mice

2004 ◽  
Vol 72 (3) ◽  
pp. 1479-1486 ◽  
Author(s):  
Anna M. van Heeckeren ◽  
Mark Schluchter ◽  
Lintong Xue ◽  
Juan Alvarez ◽  
Steven Freedman ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Docosahexaenoic Acid ◽  
Knockout Mice ◽  
Host Response ◽  
Inflammatory Responses ◽  
Liquid Diet ◽  
Wild Type ◽  
Agarose Beads ◽  
Lung Infections

ABSTRACT In cystic fibrosis, a recessive genetic disease caused by defects in the cystic fibrosis conductance regulator (CFTR), the main cause of death is lung infection and inflammation. Nutritional deficits have been proposed to contribute to the excessive host inflammatory response in both humans and Cftr-knockout mice. Cftr-knockout mice and gut-corrected Cftr-knockout mice expressing human CFTR primarily in the gut were challenged with Pseudomonas aeruginosa-laden agarose beads; they responded similarly with respect to bronchoalveolar lavage cell counts and levels of the acute-phase cytokines tumor necrosis factor alpha, interleukin-1β (IL-1β), and IL-6. Wild-type mice fed the liquid diet used to prevent intestinal obstruction in Cftr-knockout mice had inflammatory responses to P. aeruginosa-laden agarose beads similar to those of wild-type mice fed an enriched solid diet, so dietary effects are unlikely to account for differences between wild-type mice and mice with cystic fibrosis. Finally, since cystic fibrosis patients and Cftr-knockout mice have an imbalance in fatty acids (significantly lower-than-normal levels of docosahexaenoic acid), the effects of specific supplementation with docosahexaenoic acid of wild-type and Cftr-knockout mice on their inflammatory responses to P. aeruginosa-laden agarose beads were tested. There were no significant differences (P = 0.35) in cumulative survival rates between Cftr-knockout mice and wild-type mice provided with either the liquid diet Peptamen or Peptamen containing docosahexaenoic acid. In conclusion, diet and docosahexaenoic acid imbalances alone are unlikely to explain the differences in the host response to lung infections with mucoid P. aeruginosa between mice with cystic fibrosis and their wild-type counterparts.

scholarly journals The HMGB1-RAGE axis mediates traumatic brain injury–induced pulmonary dysfunction in lung transplantation

2014 ◽  
Vol 6 (252) ◽  
pp. 252ra124-252ra124 ◽  
Author(s):  
Daniel J. Weber ◽  
Adam S. A. Gracon ◽  
Matthew S. Ripsch ◽  
Amanda J. Fisher ◽  
Bo M. Cheon ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Acute Lung Injury ◽  
Brain Injury ◽  
Lung Injury ◽  
Lung Transplantation ◽  
Inflammatory Responses ◽  
Pulmonary Dysfunction ◽  
Wild Type ◽  
Hmgb1 Protein ◽  
Lung Dysfunction

Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE−/−) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs’ ability to expand), all of which were attenuated in RAGE−/−mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE−/−TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.

Extracellular superoxide anion production contributes to the virulence of Xanthomonas oryzae pv. oryzae

2009 ◽  
Vol 55 (2) ◽  
pp. 110-116 ◽  
Author(s):  
Xin Li ◽  
Xinyue Pang ◽  
Dejuan Zhi ◽  
Jinsheng Wang ◽  
Minquan Li ◽  
...  
Keyword(s):  
Electron Spin Resonance ◽  
Superoxide Anion ◽  
Positive Relationship ◽  
Xanthomonas Oryzae ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Spin Resonance ◽  
Anion Production ◽  
Type Strains ◽  
Extracellular Fraction

Endogenous superoxide anion production was determined by electron spin resonance in wild-type strains and avrXa7 mutants of Xanthomonas oryzae pv. oryzae . The localization of superoxide anion was carried out in the intra- and extra-cellular fractions. Results showed the presence of superoxide anion in multi-locations of X. oryzae pv. oryzae cells. The extracellular fraction was the major location of superoxide anion production. Furthermore, a positive relationship was shown between the levels of endogenous superoxide anion and the virulence of strains. These indubitable results suggested that the superoxide anion contributes to the virulence of X. oryzae pv. oryzae.

scholarly journals Human GM-CSF primes neutrophils for enhanced oxidative metabolism in response to the major physiological chemoattractants

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 18-21 ◽  
Author(s):  
RH Weisbart ◽  
L Kwan ◽  
DW Golde ◽  
JC Gasson
Keyword(s):  
Oxidative Metabolism ◽  
Superoxide Anion ◽  
Inflammatory Responses ◽  
Leukotriene B4 ◽  
Superoxide Anion Production ◽  
Gm Csf ◽  
Anion Production ◽  
Cytochrome C Reduction ◽  
Macrophage Colony

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a T cell- derived lymphokine which induces hematopoietic precursor cells to proliferate in vitro and differentiate to neutrophils and macrophages. GM-CSF also inhibits the motility of mature neutrophils (NIF-T activity), and primes neutrophils to enhance oxidative metabolism in response to the bacterial chemoattractant, N-formyl-methionyl-leucyl- phenylalanine (f-MLP). The present study was designed to determine whether this lymphokine also enhances neutrophil oxidative metabolism in response to the other major physiological chemoattractants which include complement-derived C5a, and the 5-lipoxygenation product of arachidonic acid, leukotriene B4 (LTB4). Superoxide anion production was measured as superoxide dismutase-inhibitable cytochrome C reduction. Purified biosynthetic GM-CSF enhanced superoxide anion production by neutrophils in response to f-MLP, C5a desArg, and LTB4. In contrast to several other factors which prime neutrophils, GM-CSF did not prime for an enhanced oxidative response to phorbol myristate acetate (PMA). These results suggest that GM-CSF may be an endogenous regulator of neutrophil inflammatory responses induced by the major physiological chemoattractants.

scholarly journals Role of Integrin αvβ6 in Acute Lung Injury Induced by Pseudomonas aeruginosa

2008 ◽  
Vol 76 (6) ◽  
pp. 2325-2332 ◽  
Author(s):  
Yuanlin Song ◽  
Jean Francois Pittet ◽  
Xiaozhu Huang ◽  
Hong He ◽  
Susan V. Lynch ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Endothelial Permeability ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Wild Type ◽  
Novel Therapy ◽  
Integrin Αvβ6 ◽  
In The Wild

ABSTRACT Deletion of integrin αvβ6 has been associated with significant protection in experiments where lung injury was induced by bleomycin, lipophilic polysaccharides, and high tidal volume ventilation. This has led to the suggestion that antibody blockade of this integrin is a novel therapy for acute lung injury. We questioned whether β6 gene deletion would also protect against Pseudomonas aeruginosa-induced acute lung injury. Wild-type and littermate β6-null mice, as well as recombinant soluble TGF-β receptor type II-Fc (rsTGF-βRII-Fc) and anti-αvβ6 treated wild-type mice, were instilled with live P. aeruginosa. Four or 8 h after bacterial instillation, the mice were euthanized, and either bronchoalveolar lavage fluid or lung homogenates were obtained. Deletion of the β6 gene resulted in an overall increase in inflammatory cells in the lungs. Bacterial numbers from the lung homogenates of infected β6-null mice were significantly decreased compared to the numbers in the wild-type mice (1.6 × 106 CFU versus 4.2 × 106 CFU [P < 0.01]). There were no significant differences in P. aeruginosa-mediated increases in lung endothelial permeability between wild-type and β6-null mice. Similarly, pretreatment with the αvβ6 antibody or with rsTGF-βRII-Fc did not significantly affect the P. aeruginosa-induced lung injury or rate of survival compared to pretreatment with control immunoglobulin G. We conclude that deletion or inhibition of the integrin αvβ6 did not protect animals from P. aeruginosa-induced lung injury. However, these therapies also did not increase the lung injury, suggesting that host defense was not compromised by this promising new therapy.

Abstract 1412: Critical Role Of Extracellular Sod For Protecting The Heart Against Myocardial Hypertrophy And Dysfunction After Myocardial Infarction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Elza D Deel ◽  
Zhongbing LU ◽  
Xin Xu ◽  
Guangshuo Zhu ◽  
Xinli Hu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ejection Fraction ◽  
Superoxide Anion ◽  
Left Ventricular ◽  
Wild Type ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Lv Remodeling ◽  
Anion Production ◽  
Lv Ejection Fraction

Extracellular SOD ( SOD3 ) contributes only a small fraction to total SOD activity in the normal heart, but is strategically located to scavenge free radicals in the extracellular compartment. SOD3 expression is decreased in the failing heart, but whether SOD3 can abrogate oxidative stress or modify left ventricular (LV) remodeling following myocardial infarction (MI) is unclear. To examine this question, we studied LV remodeling in SOD3 KO mice and wild type mice following MI. Under unstressed conditions, SOD3 KO had no effect on myocardial total SOD activity, SOD1 or SOD2 protein content, or myocardial nitrotyrosine or superoxide anion production, and caused no change in LV ejection fraction. However, 4 weeks or 8 weeks after MI, SOD3 KO mice developed more LV hypertrophy (8 weeks after MI, ventricular mass increased 1.64-fold in KO mice as compared to 1.35-fold in wild type mice, p<0.01) and had a greater reduction of LV ejection fraction (8 weeks after MI, LV ejection fraction was 35±2.4% in wild type mice as compared to 30±2.0% in KO mice, p<0.01). As compared with wild type mice, SOD3 KO mice had significantly greater increases of myocardial nitrotyrosine and superoxide anion production, a significantly greater decrease of ANP in the peri-infarct zone, and a significant more decrease of SERCA2a in both the peri-infarct and remote zones. In addition, MI caused greater activation of mitogen-activated protein kinase (MAPK) signaling pathways in SOD3 KO mice, as demonstrated by significantly greater increases of p-p38 Thr180/ Tyr182 , p-Erk Thr202/Tyr204 and p-JNK Thr183/Tyr185 in SOD3 KO mice 8 weeks after MI. The finding that SOD3 KO had no effect on myocardial total SOD activity, but significantly exacerbated MI induced LV remodeling implies that the specific extracellular location of SOD3 is more important than its contribution to overall SOD activity in protecting the heart against contractile dysfunction following myocardial infarct.

Abstract W P230: Tetrahydrobiopterin Attenuates Cerebrovascular Oxidative Stress in Tg2576 Mouse Model of Alzheimer’s Disease

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Anantha Vijay R Santhanam ◽  
Livius V d'Uscio ◽  
Zvonimir S Katusic
Keyword(s):  
Oxidative Stress ◽  
Enzymatic Activity ◽  
Superoxide Anion ◽  
Wild Type ◽  
Superoxide Anion Production ◽  
Cerebral Microvessels ◽  
Double Mutation ◽  
Enos Uncoupling ◽  
Anion Production ◽  
Tg2576 Mice

Background: The present study was designed to test the hypothesis that supplementation of tetrahydrobiopterin (BH4) to transgenic mice expressing the Swedish double mutation of human amyloid precursor protein (Tg2576 mice) results in restoration of BH4 levels required for activation of endothelial nitric oxide synthase (eNOS), and in turn, prevents oxidative stress in cerebral microvasculature. Methods: Cerebral microvessels were obtained from 4-5 months old female wild-type and Tg2576 mice. Biopterin levels, enzymatic activity of GTP cyclohydrolase I (GTPCH-I) and superoxide production were measured by HPLC. The effects of supplementation of BH4 on oxidative stress were studied by injecting wild-type and Tg2576 mice subcutaneously with 100 mol/kg (b.w.) of BH 4 ([ 6R ]-5,6,7,8-tetrahydro-L-biopterin dihydrochloride; [ 6R ]-BH4). Results: Enzymatic activity of GTPCH-I, rate limiting enzyme in BH4 biosynthesis, was not different between cerebral microvessels of wild-type and Tg2576 mice. However, bioavailability of BH4, was significantly reduced in cerebral microvessels of Tg2576 mice (P<0.05, n=8). Production of superoxide anions was significantly elevated in cerebral microvessels of Tg2576 mice (P<0.01, n=6), indicative of oxidative stress. This increased superoxide anion production was abolished by L-NAME, a NOS inhibitor, suggestive of eNOS uncoupling (P<0.05, n=6). Supplementation of [ 6R ]-BH4 to wild-type and Tg2576 mice resulted in significant increase in BH4 bioavailability (P<0.05, n=6). Notably, supplementation of [ 6R ]-BH4 abrogated the increase in superoxide anion production in cerebral microvessels of Tg2576 mice (P<0.05, n=5), while superoxide anion production remained unchanged in cerebral microvessels of WT mice. Furthermore, the inhibitory effects of L-NAME on superoxide anion production in cerebral microvessels of Tg2576 mice were abolished following [ 6R ]-BH4 supplementation (P<0.05, n=4). Conclusion: Supplementation of [ 6R ]-BH4 restored bioavailability of BH4, thereby abrogating superoxide anion production derived from eNOS. Our results suggest that uncoupling of eNOS contributes to oxidative stress in cerebral microvessels of Tg2576 mice.

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