Production of Tumor Necrosis Factor‐α in Granulocytopenic Mice with Pulmonary Candidiasis and Its Modification with Granulocyte Colony‐Stimulating Factor

Futenma, Mitsuhiko; Kawakami, Kazuyoshi; Saitô, Atsushi

doi:10.1111/j.1348-0421.1995.tb02221.x

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…It thus appears likely that inhibition of TNF-␣ (27) anecdotally demonstrated increased IL-8 levels in serum of a febrile neutropenic patient during C. albicans infection and a gradual decline of IL-8 during recovery. The most relevant study, however, was reported by Futenma et al (7). Pulmonary candidiasis was established in Cy-injected, neutropenic mice, resulting in increased levels of TNF-␣ in serum and bronchoalveolar lavage fluid, as well as significant mortality.…”

Section: Discussionmentioning

confidence: 96%

Immunomodulatory and Protective Effects of Moxifloxacin againstCandida albicans-Induced Bronchopneumonia in Mice Injected with Cyclophosphamide

Shalit

Horev-Azaria

Fabian

et al. 2002

Antimicrob Agents Chemother

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In a previous study, moxifloxacin was shown to ameliorate immunosuppression and enhance cytokine production in several tissues, including the lungs of cyclophosphamide-injected mice. We examined here the effects of moxifloxacin on Candida albicans lung infection in cyclophosphamide-injected mice. Mice were injected on day 0 with 250 mg of cyclophosphamide/kg, and on days 1 to 4 they were given moxifloxacin at 22.5 mg/kg/day compared to controls given ceftazidime at 75 mg/kg/day or saline. On day 6, C. albicans (10 7 CFU/ mouse) was inoculated intratracheally, and animals were observed for the development of bronchopneumonia, weight loss, mortality, the presence of C. albicans, and lung cytokine production. Histopathology on day 10 postinoculation revealed bronchopneumonia in 50, 67, and 0% of saline-, ceftazidime-, and moxifloxacintreated mice, respectively (P < 0.05). The mortality rates were 28, 17, and 5%, respectively (P < 0.05), and weight loss occurred at 20, 32, and 0%, respectively (P < 0.05). By day 15, C. albicans was eliminated from all moxifloxacin-treated mice but was still isolated from lung homogenates of 50 to 60% of the saline-and ceftazidime-treated groups. Among the cytokines tested on days 0 to 15, we found an increased production of tumor necrosis factor alpha, KC (functional interleukin-8), and gamma interferon in the lungs of ceftazidimeand saline-treated controls compared to the moxifloxacin pretreatment that abolished their secretion. In conclusion, moxifloxacin protected cyclophosphamide-injected mice from C. albicans-induced lung infection and significantly reduced pneumonia, weight loss, and mortality despite the lack of direct antifungal activity. This is most likely due to an immunomodulating activity conferred by moxifloxacin, as shown in this model and in our previous studies. Its potential protective role should be studied in patients undergoing chemotherapy and immune suppression.

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Section: Discussionmentioning

confidence: 96%

Immunomodulatory and Protective Effects of Moxifloxacin againstCandida albicans-Induced Bronchopneumonia in Mice Injected with Cyclophosphamide

Shalit

Horev-Azaria

Fabian

et al. 2002

Antimicrob Agents Chemother

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“…The TNF-contents in macrophage culture supernatants were measured by a bioassay with L-929 cells, as previously described [32].…”

Section: Measurement Of Tnf-mentioning

confidence: 99%

Contribution of tumour necrosis factor-alpha (TNF-α) in host defence mechanism against Cryptococcus neoformans

Kawakami

Xie

Tohyama

et al. 1996

Clinical and Experimental Immunology

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SUMMARYWe investigated the role of TNF-in the host defence mechanism against infection with a virulent strain of Cryptococcus neoformans. Administration of exogenous recombinant human TNF-significantly prolonged the survival time of mice infected by intratracheal instillation of the organism. Surprisingly, neutralizing MoAb to murine TNF-did not shorten their survival time, a finding inconsistent with previous results. To investigate the cause of this inconsistency, we examined the production of TNFin the lungs of infected mice. During the course of cryptococcosis, there was little or no generation of TNF-mRNA in the lung. This might be partly due to a direct inhibitory action of the fungal microorganism on TNF-production by macrophages. In vitro production of TNF-by murine interferon-gamma (IFN-)-and lipopolysaccharide (LPS)-stimulated macrophages was strongly inhibited by co-culturing with the whole yeast cells. In contrast, administration of recombinant murine IL-12 markedly induced TNF-production and the neutralizing anti-TNF-MoAb strongly blocked IL-12-induced protection of mice against cryptococcal infection. These results indicate that endogenously synthesized TNF-has the potential to contribute to the elimination of C. neoformans and partly mediates the protective effect of IL-12.

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“…High levels of TNF-␣ in BALF have been noted in lung diseases (5,48). A study using a lethal model of pulmonary candidiasis in a neutropenic mouse demonstrated a high level of TNF-␣ in BALF that was inhibited significantly by successful treatment with G-CSF (12). The TNF-␣ in BALF was also observed in other animal models with pneumonia caused by Histoplasma capsulatum (43) and Pseudomonas aeruginosa (7).…”

Section: Discussionmentioning

confidence: 99%

“…Resistance to T. asahii infection was markedly lowered by CY. CY, a common agent used to obtain immunocompromised animal models (2,12,13,19,37,45), causes transient decreases in PMN, monocyte, and lymphocyte counts. The neutropenia in our CY model persisted for 6 days; however, most of the animals died after that period.…”

Section: Discussionmentioning

confidence: 99%

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Effects of granulocyte and granulocyte-macrophage colony-stimulating factors in a neutropenic murine model of trichosporonosis

et al. 1997

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We produced disseminated trichosporonosis in a neutropenic murine model with Trichosporon asahii, which was identified by DNA relatedness analysis. We then assessed the efficacy of granulocyte colony-stimulating factor (G-CSF) (30 to 100 g/kg of body weight per day) and granulocyte-macrophage colony-stimulating factor (GM-CSF) (0.8 to 2 g/kg ⅐ day). The administration of G-CSF either before or after infection improved the survival rate from less than 25% up to 100% (P < 0.05). The effects of G-CSF on organ clearance and histological examinations were most remarkable in the lungs. The levels of tumor necrosis factor alpha (TNF-␣) in bronchoalveolar lavage fluid (BALF) of neutropenic and G-CSF-pretreated mice were 60 ؎ 6 ng/ml and 18 ؎ 6 pg/ml, respectively, at 24 h after infection. Immunohistologically, alveolar macrophages proved to be the main source of TNF-␣ in BALF. GM-CSF increased neutrophil counts less significantly than did G-CSF and increased the lethality (P < 0.05) with a high level of TNF-␣ in BALF. Expecting to inhibit TNF-␣, we administered anti-TNF-␣ intraperitoneally at the dose completely inhibiting TNF-␣ in plasma (2 ؋ 10 4 U), but the TNF-␣ level in BALF and the lethality increased. Though the number of neutrophils at the early stage of infection appeared to be the most critical, the results suggest that other host defense mechanisms, such as TNF-␣ overproduction in the lungs, have an important role in the prognosis of trichosporonosis.

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Production of Tumor Necrosis Factor‐α in Granulocytopenic Mice with Pulmonary Candidiasis and Its Modification with Granulocyte Colony‐Stimulating Factor

Abstract: Abstract:In the present study, a lethal model of pulmonary candidiasis was established using granulocytopenic mice with cyclophosphamide.

Cited by 14 publications

References 36 publications

Immunomodulatory and Protective Effects of Moxifloxacin againstCandida albicans-Induced Bronchopneumonia in Mice Injected with Cyclophosphamide

Immunomodulatory and Protective Effects of Moxifloxacin againstCandida albicans-Induced Bronchopneumonia in Mice Injected with Cyclophosphamide

Contribution of tumour necrosis factor-alpha (TNF-α) in host defence mechanism against Cryptococcus neoformans

Effects of granulocyte and granulocyte-macrophage colony-stimulating factors in a neutropenic murine model of trichosporonosis

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