Effect of irradiation, cyclophosphamide, and etoposide (VP-16) on number of peripheral blood and peritoneal leukocytes in mice under normal conditions and during acute inflammatory reaction

Wout, J. W. Van’t; Linde, I.; Leijh, P. C. J.; Furth, R. van

doi:10.1007/bf00918959

Cited by 48 publications

(38 citation statements)

References 13 publications

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“…To determine whether macrophages are a driving force in arthritis development, we injected 4-week-old Pggt1b fl/fl LC mice with etoposide, which reduces levels of circulating monocytes by greater than 90% and has little effect on granulocytes and lymphocytes (23,24). After 8 weeks of treatment, the mean synovitis score was reduced by 72%, and the mean bone erosion score was reduced by 35% ( Figure 1E).…”

Section: Resultsmentioning

confidence: 99%

Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

Khan¹,

Ibrahim²,

Jonsson³

et al. 2011

J. Clin. Invest.

101

106

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RHO family proteins are important for the function of inflammatory cells. They are modified with a 20-carbon geranylgeranyl lipid in a process catalyzed by protein geranylgeranyltransferase type I (GGTase-I). Geranylgeranylation is viewed as essential for the membrane targeting and activity of RHO proteins. Consequently, inhibiting GGTase-I to interfere with RHO protein activity has been proposed as a strategy to treat inflammatory disorders. However, here we show that mice lacking GGTase-I in macrophages develop severe joint inflammation resembling erosive rheumatoid arthritis. The disease was initiated by the GGTase-I-deficient macrophages and was transplantable and reversible in bone marrow transplantation experiments. The cells accumulated high levels of active GTP-bound RAC1, CDC42, and RHOA, and RAC1 remained associated with the plasma membrane. Moreover, GGTase-I deficiency activated p38 and NF-κB and increased the production of proinflammatory cytokines. The results challenge the view that geranylgeranylation is essential for the activity and localization of RHO family proteins and suggest that reduced geranylgeranylation in macrophages can initiate erosive arthritis.

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Section: Resultsmentioning

confidence: 99%

Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

Khan¹,

Ibrahim²,

Jonsson³

et al. 2011

J. Clin. Invest.

101

106

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“…T. glabrata is often more resistant than C. albicans and is therefore more difficult to treat. Experimental data indicate that neither amphotericin B nor the triazoles (fluconazole and itraconazole) are able to decrease the number of CFU in the kidneys of persistently neutropenic mice with systemic C. albicans infection (19). D0870 showed no in vivo effect with D0870-resistant isolates which had variable in vitro susceptibility to fluconazole.…”

Section: Methodsmentioning

confidence: 97%

Treatment of disseminated Torulopsis glabrata infection with DO870 and amphotericin B

Atkinson

Bocanegra

Colombo

et al. 1994

Antimicrob Agents Chemother

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One day prior to challenge, the organisms were subcultured to 50 ml of brain heart infusion (BHI) broth (BBL, Cockeysville, Md.). The fungi were incubated on a shaker at 37°C overnight, washed twice with 0.9% NaCl, quantified with a hemacytometer, and adjusted to the desired concentration in normal saline. The counts were verified by determining CFU counts with 10-fold serial dilutions in 0.9% NaCl. Each mouse was infected with 1.1 x 108 to 7 x 108 CFU/ml in the lateral tail vein given in a 0.2-ml volume. The T. glabrata cells were agitated between each injection to achieve a uniform suspension.Activity in vitro. The in vitro susceptibility studies were performed by the broth macrodilution technique proposed by the National Committee for Clinical Laboratory Standards (7). The medium was RPMI 1640 with glutamine, buffered by MOPS (morpholinepropanesulfonic acid) at pH 7.0 (American Bioganics, Niagara Falls, N.Y.). The inoculum was prepared from 24-h Sabouraud dextrose agar (Difco Laboratories, Detroit, Mich.) subcultures of T. glabrata incubated at 35°C. Colonies of T. glabrata were suspended in 5 ml of sterile distilled water, and the cell density was adjusted with a spectrophotometer to a 0.5 McFarland standard at a 530-nm wavelength. The working suspension was a 1:100 dilution of the organisms followed by a 1:20 dilution of the suspension with RPMI broth medium. A volume of 0.9 ml of the adjusted solution was dispensed into tubes containing 0.1 ml of 10 times the concentrations of the drugs to be tested. The test tubes were incubated at 35°C for 48 h.

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“…24,25 The induction of neutropenia by Cy has been well documented. [26][27][28] Two intraperitoneal injections for a total dose of 250 mg/kg (150 mg/kg at day 1 and 100 mg/kg at day 4) were sufficient to induce severe neutropenia. On day 5, Cy-treated mice had approximately 90% fewer circulating neutrophils than di the untreated group.…”

Section: Disruption Of Pten Enhances Pulmonary Neutrophil Accumulatiomentioning

confidence: 99%

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

Jia

Pichavant

et al. 2009

Blood

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Neutropenia and related infections are the most important dose-limiting toxicities in anticancer chemotherapy and radiotherapy. In this study, we explored a new strategy for augmenting host defense in neutropenia-related pneumonia. Phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P 3 ) signaling in neutrophils was elevated by depleting PTEN, a phosphatidylinositol 3-phosphatase that hydrolyzes PtdIns(3,4,5)P 3 . In myeloidspecific PTEN knockout mice, significantly more neutrophils were recruited to the inflamed lungs during neutropeniaassociated pneumonia. Using an adoptive transfer technique, we demonstrated that this enhancement could be caused directly by PTEN depletion in neutrophils. In addition, disruption of PTEN increased the recruitment of macrophages and elevated proinflammatory cytokines/chemokine levels in the inflamed lungs, which could also be responsible for the enhanced neutrophil recruitment. Depleting PTEN also significantly delayed apoptosis and enhanced the bacteria-killing capability of the recruited neutrophils. Finally, we provide direct evidence that enhancement of neutrophil function by elevating PtdIns(3,4,5)P 3 signaling can alleviate pneumonia-associated lung damage and decrease pneumonia-elicited mortality. Collectively, these results not only provide insight into the mechanism of action of PTEN and PtdIns(3,4,5)P 3 signaling pathway in modulating neutrophil function during lung infection and inflammation, but they also establish PTEN and related pathways as potential therapeutic targets for treating neutropenia-associated pneumonia. (Blood. 2009; 113:4930-4941)

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Effect of irradiation, cyclophosphamide, and etoposide (VP-16) on number of peripheral blood and peritoneal leukocytes in mice under normal conditions and during acute inflammatory reaction

Cited by 48 publications

References 13 publications

Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

Geranylgeranyltransferase type I (GGTase-I) deficiency hyperactivates macrophages and induces erosive arthritis in mice

Treatment of disseminated Torulopsis glabrata infection with DO870 and amphotericin B

Targeted deletion of tumor suppressor PTEN augments neutrophil function and enhances host defense in neutropenia-associated pneumonia

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