scholarly journals Impaired Post-Irradiation Survival of Cyclooxygenase-2-Deficient Mice

2018 ◽  
pp. 809-812 ◽  
Author(s):  
M. HOFER ◽  
Z. HOFEROVÁ ◽  
A. GRUZDEV ◽  
L. DUŠEK ◽  
M. FALK
Keyword(s):  
Lethal Dose ◽  
Negative Influence ◽  
Cyclooxygenase 2 ◽  
Wild Type ◽  
Post Irradiation ◽  
Γ Rays ◽  
Males And Females ◽  
Cox 2 ◽  
Deficient Mice ◽  
Inflammatory Action

We investigated and evaluated post-irradiation survival in cyclooxygenase-2-deficient (COX-2 KO) mice. Thirty-day survival following exposure of COX-2 KO mice to a lethal dose of 8.5 Gy of γ-rays was observed to be statistically significantly lower in both males and females, as well as when the sexes were merged, in comparisons with their wild-type counterparts. These findings were related to the previous observations concerning the detrimental influence of the COX-2 genetic disruption on hematopoiesis in sublethally irradiated mice. Deteriorated post-irradiation survival of COX-2 KO mice confirmed the previously anticipated conclusion regarding negative influence of the anti-inflammatory action of COX-2 deficiency under the conditions of exposure of the animals to ionizing radiation.

scholarly journals Hematological Profile of Untreated or Ionizing Radiation-Exposed Cyclooxygenase-2-Deficient Mice

2017 ◽  
pp. 673-676 ◽  
Author(s):  
M. HOFER ◽  
Z. HOFEROVÁ ◽  
L. DUŠEK ◽  
K. SOUČEK ◽  
A. GRUZDEV
Keyword(s):  
Ionizing Radiation ◽  
Radiation Exposure ◽  
Cyclooxygenase 2 ◽  
Male Mice ◽  
Positive Role ◽  
Hematological Analysis ◽  
Γ Rays ◽  
Cox 2 ◽  
Deficient Mice ◽  
Inflammatory Action

We investigated hematopoiesis in untreated and ionizing radiation-exposed cyclooxygenase-2-deficient (COX-2 KO) mice. We performed a complex hematological analysis of 16 parameters in untreated COX-2 KO male mice or COX-2 KO male mice irradiated with the dose of 4 Gy of γ-rays and their wildtype littermates. At baseline, hematopoiesis was increased in COX-2-deficient mice, but attenuated by irradation in COX-2-deficient mice compared to wildtype. To conclude, the anti-inflammatory action of the COX-2 genetic disruption plays a positive role in hematopoiesis under basal conditions but is detrimental following radiation exposure.

COX-2-deficient mice are less prone to MPTP-neurotoxicity than wild-type mice

Neuroreport ◽  
2003 ◽  
Vol 14 (15) ◽  
pp. 1927-1929 ◽  
Author(s):  
Zhehui Feng ◽  
Dongdong Li ◽  
Peter C. W. Fung ◽  
Zhong Pei ◽  
David B. Ramsden ◽  
...  
Keyword(s):  
Wild Type ◽  
Cox 2 ◽  
Deficient Mice

Cytosolic phospholipase A2α regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation

2005 ◽  
Vol 288 (6) ◽  
pp. R1774-R1782 ◽  
Author(s):  
Adam Sapirstein ◽  
Hideyuki Saito ◽  
Sarah J. Texel ◽  
Tarek A. Samad ◽  
Eileen O’Leary ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Inflammatory Responses ◽  
Arachidonic Acid Metabolism ◽  
Cyclooxygenase 2 ◽  
Phospholipase A ◽  
Wild Type ◽  
Cytosolic Phospholipase ◽  
The Central Nervous System ◽  
Cox 2 ◽  
The Brain

The products of arachidonic acid metabolism are key mediators of inflammatory responses in the central nervous system, and yet we do not know the mechanisms of their regulation. The phospholipase A2 enzymes are sources of cellular arachidonic acid, and the enzymes cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1) are essential for the synthesis of inflammatory PGE2 in the brain. These studies seek to determine the function of cytosolic phospholipase A2α (cPLA2α) in inflammatory PGE2 production in the brain. We wondered whether cPLA2α functions in inflammation to produce arachidonic acid or to modulate levels of COX-2 or mPGES-1. We investigated these questions in the brains of wild-type mice and mice deficient in cPLA2α (cPLA2α−/−) after systemic administration of LPS. cPLA2α−/− mice had significantly less brain COX-2 mRNA and protein expression in response to LPS than wild-type mice. The reduction in COX-2 was most apparent in the cells of the cerebral blood vessels and the leptomeninges. The brain PGE2 concentration of untreated cPLA2α−/− mice was equal to their wild-type littermates. After LPS treatment, however, the brain concentration of PGE2 was significantly less in cPLA2α−/− than in cPLA2α+/+ mice (24.4 ± 3.8 vs. 49.3 ± 11.6 ng/g). In contrast to COX-2, mPGES-1 RNA levels increased equally in both mouse genotypes, and mPGES-1 protein was unaltered 6 h after LPS. We conclude that cPLA2α regulates COX-2 levels and modulates inflammatory PGE2 levels. These results indicate that cPLA2α inhibition is a novel anti-inflammatory strategy that modulates, but does not completely prevent, eicosanoid responses.

scholarly journals Interleukin (IL)-6, But Not IL-1, Induction in the Brain Downstream of Cyclooxygenase-2 Is Essential for the Induction of Febrile Response against Peripheral IL-1α

Endocrinology ◽  
2004 ◽  
Vol 145 (11) ◽  
pp. 5044-5048 ◽  
Author(s):  
Kyoko Kagiwada ◽  
Dai Chida ◽  
Tomoya Sakatani ◽  
Masahide Asano ◽  
Aya Nambu ◽  
...  
Keyword(s):  
Prostaglandin E2 ◽  
Cyclooxygenase 2 ◽  
Signaling Cascade ◽  
Endogenous Pyrogen ◽  
Febrile Response ◽  
Cox 2 ◽  
The Brain ◽  
Deficient Mice

Abstract IL-1 is an endogenous pyrogen produced upon inflammation or infection. Previously, we showed that, upon injection with turpentine, IL-1 is induced in the brain in association with the development of fever. The role of endogenous IL-1 in the brain and the signaling cascade to activate thermosensitive neurons, however, remain to be elucidated. In this report, febrile response was analyzed after peripheral injection of IL-1α. We found that a normal febrile response was induced even in IL-1α/β-deficient mice, indicating that production of IL-1 in the brain is not necessarily required for the response. In contrast, IL-6-deficient mice did not exhibit a febrile response. Cyclooxygenase (Cox)-2 expression in the brain was strongly induced 1.5 h after injection of IL-1α, whereas IL-6 expression was observed 3 h after the injection. Cox-2 expression in the brain was not influenced by IL-6 deficiency, whereas indomethacin, an inhibitor of cyclooxygenases, completely inhibited induction of IL-6. These observations suggest a mechanism of IL-1-induced febrile response in which IL-1 in the blood activates Cox-2, with the resulting prostaglandin E2 inducing IL-6 in the brain, leading to the development of fever.

scholarly journals Salmonella enterica Serovar Typhimurium Infection Induces Cyclooxygenase 2 Expression in Macrophages: Involvement of Salmonella Pathogenicity Island 2

2004 ◽  
Vol 72 (12) ◽  
pp. 6860-6869 ◽  
Author(s):  
Kei-ichi Uchiya ◽  
Toshiaki Nikai
Keyword(s):  
Signaling Pathway ◽  
Salmonella Enterica ◽  
Signal Transduction Pathway ◽  
Specific Inhibitor ◽  
Pathogenicity Island ◽  
Interleukin 10 ◽  
Cyclooxygenase 2 ◽  
Prostaglandin E ◽  
Wild Type ◽  
Cox 2

ABSTRACT Salmonella pathogenicity island 2 (SPI-2) is required for intramacrophage survival and systemic infection in mice. We have recently reported that Salmonella enterica causes activation of the protein kinase A (PKA) signaling pathway in a manner dependent on SPI-2, resulting in the upregulation of interleukin-10 expression in macrophages (K. Uchiya et al., Infect. Immun. 72:1964-1973, 2004). We show in the present study the involvement of SPI-2 in a signal transduction pathway that induces the expression of cyclooxygenase 2 (COX-2), an inducible enzyme involved in the synthesis of prostanoids. High levels of prostaglandin E2 (PGE2) and prostacyclin (PGI2), which are known to activate the PKA signaling pathway via their receptors, were induced in J774 macrophages infected with wild-type Salmonella compared to a strain carrying a mutation in the spiC gene, located within SPI-2. The increased production of both prostanoids was dependent on COX-2. COX-2 expression was dose dependently blocked by treatment with a specific inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, and the phosphorylation level of ERK1/2 was higher in macrophages infected with wild-type Salmonella compared to the spiC mutant. Taken together, these results indicate that Salmonella causes an SPI-2-dependent ERK1/2 activation that leads to increased COX-2 expression, resulting in the upregulation of PGE2 and PGI2 production in macrophages. A COX-2 inhibitor inhibited not only Salmonella-induced activation of the PKA signaling pathway but also growth of wild-type Salmonella within macrophages, suggesting that Salmonella utilizes the COX-2 pathway to survive within macrophages and that the mechanism involves activation of the PKA signaling pathway.

Low plasma renin and reduced renin secretory responses to acute stimuli in conscious COX-2-deficient mice

2007 ◽  
Vol 292 (1) ◽  
pp. F415-F422 ◽  
Author(s):  
Soo Mi Kim ◽  
Limeng Chen ◽  
Diane Mizel ◽  
Yuning G. Huang ◽  
Josie P. Briggs ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Genetic Background ◽  
Intraperitoneal Administration ◽  
Plasma Renin ◽  
Specific Requirement ◽  
Wild Type ◽  
Tail Vein ◽  
Cox 2 ◽  
Deficient Mice

In the current experiments, we determined the response of plasma renin concentration (PRC) to acute intraperitoneal administration of furosemide (40 mg/kg), hydralazine (2 mg/kg), isoproterenol (10 mg/kg), candesartan (50 μg), or quinaprilate (50 μg) in conscious wild-type (WT) and cyclooxygenase (COX)-2−/− mice on three different genetic backgrounds (mixed, C57BL/6, 129J). PRC was measured in plasma obtained by tail vein puncture. Basal PRC was significantly lower in COX-2−/− than WT mice independent of genetic background (51, 10, and 17% of WT in mixed, 129J, and C57BL/6). All five acute interventions caused significant increases of PRC in both COX-2+/+ and −/− mice, but the response was consistently less in COX-2-deficient mice (e.g., ΔPRC in ng ANG I·ml−1·h−1 caused by furosemide, isoproterenol, hydralazine, quinaprilate, or candesartan 4,699 ± 544, 3,534 ± 957, 2,522 ± 369, 9,453 ± 1,705, 66,455 ± 21,938 in 129J WT, and 201 ± 78, 869 ± 275, 140 ± 71, 902 ± 304, 2,660 ± 954 in 129J COX-2−/−). A low-NaCl diet and enalapril for 1 wk caused a 14-fold elevation of PRC in COX-2−/− mice and was associated with a greatly increased PRC response to acute furosemide (ΔPRC 201 ± 78 before and 15,984 ± 2,397 after low Na/enalapril). As measured by radiotelemetry, blood pressure and heart rate responses to furosemide, hydralazine, isoproterenol, candesartan, or quinaprilate were not different between COX-2 genotypes. In conclusion, chronic absence of COX-2 reduces renin expression, release, and PRC and is associated with a reduced ability to alter PRC during acute stimulation regardless of the nature of the stimulus. COX-2 activity does not appear to be a mandatory and specific requirement for furosemide-stimulated renin secretion.

scholarly journals COX-2 contributes to the maintenance of flow-induced dilation in arterioles of eNOS-knockout mice

2006 ◽  
Vol 291 (3) ◽  
pp. H1429-H1435 ◽  
Author(s):  
Dong Sun ◽  
Hong Liu ◽  
Changdong Yan ◽  
Azita Jacobson ◽  
Caroline Ojaimi ◽  
...  
Keyword(s):  
Endothelial Nitric Oxide Synthase ◽  
Immunohistochemical Staining ◽  
Gracilis Muscle ◽  
Wild Type ◽  
Basal Tone ◽  
Cox 2 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Deficient Mice ◽  
Cox 1

Our previous studies demonstrated that, in gracilis muscle arterioles of male mice deficient in the gene for endothelial nitric oxide synthase (eNOS), flow-induced dilation (FID) is mediated by endothelial PGs. Thus the present study aimed to identify the specific isoform of cyclooxygenase (COX) responsible for the compensatory mediation of FID in arterioles of eNOS-knockout (KO) mice. Experiments were conducted on gracilis muscle arterioles of male eNOS-KO and wild-type (WT) mice. Basal tone and magnitude of FID of arterioles were comparable in the two strains of mice. A role for COX isoforms in the mediation of the responses was assessed by use of valeryl salicylate (3 mM) and NS-398 (10 μM), inhibitors of COX-1 and COX-2, respectively. In eNOS-KO arterioles, valeryl salicylate or NS-398 alone inhibited FID (at maximal flow rate) by ∼51% and ∼58%, respectively. Administration of both inhibitors eliminated the dilation. In WT arterioles, inhibition of COX-2 did not significantly affect FID, whereas inhibition of COX-1 decreased the dilation by ∼57%. The residual portion of the response was abolished by additional administration of Nω-nitro-l-arginine methyl ester. Western blot analysis indicated a comparable content of COX-1 protein in arterioles of WT and eNOS-KO mice. COX-2 protein, which was not detectable in arterioles of WT mice, was strongly expressed in arterioles of eNOS-KO mice, together with an upregulation of COX-2 gene expression. Immunohistochemical staining confirmed the presence of COX-2 in the endothelium of eNOS-KO arterioles. In conclusion, COX-2-derived PGs are the mediators responsible for maintenance of FID in arterioles of eNOS-deficient mice.

scholarly journals Amelioration of Hippocampal Neuronal Damage after Transient Forebrain Ischemia in Cyclooxygenase-2—Deficient Mice*

2004 ◽  
Vol 24 (1) ◽  
pp. 107-113 ◽  
Author(s):  
Tsutomu Sasaki ◽  
Kazuo Kitagawa ◽  
Kanato Yamagata ◽  
Takako Takemiya ◽  
Shigeru Tanaka ◽  
...  
Keyword(s):  
Neuronal Death ◽  
Neuronal Damage ◽  
Early Stage ◽  
Cyclooxygenase 2 ◽  
Forebrain Ischemia ◽  
Transient Forebrain Ischemia ◽  
Selective Neuronal Death ◽  
Chemical Inhibition ◽  
Cox 2 ◽  
Deficient Mice

Several studies have suggested that cyclooxygenase-2 (COX-2) plays a role in ischemic neuronal death. Genetic disruption of COX-2 has been shown to reduce susceptibility to focal ischemic injury and N-methyl-D-aspartate-mediated neurotoxicity. The purpose of this study was to examine the effects of COX-2 deficiency on neuronal vulnerability after transient forebrain ischemia. Marked upregulation of COX-2 immunostaining in neurons was observed at the early stage and prominent COX-2 staining persisted in the CA1 medial sector and CA2 sector over 3 days after ischemia. The immunohistologic pattern of COX-2 staining in these sectors gradually condensed to a perinuclear location. The degree of hippocampal neuronal injury produced by global ischemia in COX-2–deficient mice was less than that in wild-type mice, coincident with attenuation of DNA fragmentation in the hippocampus. Also, treatment with a selective COX-2 inhibitor, nimesulide, after ischemia decreased hippocampal neuronal damages. These results of genetic disruption and chemical inhibition of cyclooxygenase-2 show that inhibition of COX-2 ameliorates selective neuronal death after transient forebrain ischemia in mice.

Defective expression of Tamm-Horsfall protein/uromodulin in COX-2-deficient mice increases their susceptibility to urinary tract infections

2005 ◽  
Vol 289 (1) ◽  
pp. F49-F60 ◽  
Author(s):  
Wenkai Dou ◽  
Sandra Thompson-Jaeger ◽  
Stanley J. F. Laulederkind ◽  
John W. Becker ◽  
Julia Montgomery ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Failure ◽  
Kidney Development ◽  
Specific Gene ◽  
Wild Type ◽  
Genes Encoding ◽  
Cox 2 ◽  
Tract Infections ◽  
End Stage ◽  
Deficient Mice

Mice lacking a functional cyclooxygenase-2 (COX-2) gene develop abnormal kidneys that contain hypoplastic glomeruli and reduced proximal tubular mass, and they often die of renal failure. A comparison of kidney-specific gene expression between wild-type and COX-2-deficient mice by cDNA microarrays revealed that although more than 500 mRNAs were differentially expressed between the two strains of mice depending on their ages, the genes encoding pre-pro-epidermal growth factor (pre-pro-EGF) and Tamm-Horsfall protein (THP)/uromodulin were aberrantly expressed in the kidneys of COX-2 −/− mice at all stages of their development. Downregulation of EGF could potentially affect renal development, and THP/uromodulin gene has been implicated in abnormal kidney development and end-stage renal failure in humans. We assessed in detail mechanism of defective THP/uromodulin gene expression and its potential consequences in COX-2-deficient mice. Consistent with the microarray data, the steady-state levels of THP/uromodulin mRNA were severely reduced in the COX-2 −/− kidney. Furthermore, reduced expression of renal THP/uromodulin, as assessed by Western blot and immunohistological methods, was closely corroborated by a corresponding decline in the urinary secretion of THP/uromodulin in COX-2 −/− mice. Finally, we demonstrate that the bladders of COX-2 −/− mice, in contrast to those of the wild-type mice, are highly susceptible to colonization by uropathogenic Escherichia coli.

Sign in / Sign up

Export Citation Format

Share Document