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1.
Immunology ; 165(3): 355-368, 2022 03.
Article in English | MEDLINE | ID: mdl-34964126

ABSTRACT

Mucositis is a major clinical complication associated with cancer treatment and may limit the benefit of chemotherapy. Leukocytes and inflammatory mediators have been extensively associated with mucositis severity. However, the role of eosinophils in the pathophysiology of chemotherapy-induced mucositis remains to be elucidated. Here, using GATA-1-deficient mice, we investigated the role of eosinophils in intestinal mucositis. There was marked accumulation of eosinophils in mice given irinotecan and eosinophil ablation inhibited intestinal mucositis. Treatment with Evasin-4, a chemokine receptor antagonist, reduced the recruitment of eosinophils and decreased irinotecan-induced mucositis. Importantly, Evasin-4 did not interfere negatively with the antitumour effects of irinotecan. Evasin-4 was of benefit for mice given high doses of irinotecan once Evasin-4-treated mice presented delayed mortality. Altogether, our findings suggest that Evasin-4 may have significant mucosal-protective effects in the context of antineoplastic chemotherapy and may, therefore, be useful in combination with anticancer treatment in cancer patients.


Subject(s)
Antineoplastic Agents , Mucositis , Animals , Antineoplastic Agents/therapeutic use , Camptothecin/adverse effects , Eosinophils/pathology , Humans , Intestinal Mucosa/pathology , Irinotecan/adverse effects , Mice , Mucositis/chemically induced , Mucositis/drug therapy , Mucositis/pathology
2.
PLoS One ; 10(4): e0123004, 2015.
Article in English | MEDLINE | ID: mdl-25875016

ABSTRACT

Graft versus host disease (GVHD) is an immunological disorder triggered by bone marrow transplantation that affects several organs, including the gastrointestinal tract and liver. Fullerenes and their soluble forms, fullerols, are nanocomposites with a closed symmetrical structure with anti-inflammatory and anti-oxidant properties. The present study evaluated the effects of treatment with the fullerol (C60(OH)18-20) in the development and pathogenesis of GVHD in a murine model. Mice with experimental GVHD that were treated with the fullerol showed reduced clinical signs of disease and mortality compared with untreated mice. Treatment with the fullerol decreased the hepatic damage associated with reduced hepatic levels of reactive oxygen species, pro-inflammatory cytokines and chemokines (IFN-γ TNF-α, CCL2, CCL3 and CCL5) and reduced leukocyte accumulation. The amelioration of GVHD after treatment with the fullerol was also associated with reduced intestinal lesions and consequent bacterial translocation to the blood, liver and peritoneal cavity. Moreover, the fullerol treatment alleviated the GVHD while preserving effects of the graft against a leukemia cell line (GFP+P815). In summary, the fullerol was effective in reducing the GVHD inflammatory response in mice and may suggest novel ways to treat this disease.


Subject(s)
Antineoplastic Agents/chemistry , Fullerenes/chemistry , Graft vs Host Disease/therapy , Nanocomposites/chemistry , Animals , Bone Marrow Transplantation/adverse effects , Cell Line, Tumor , Disease Models, Animal , Inflammation , Liver/pathology , Macrophages/cytology , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Neutrophils/cytology , Reactive Oxygen Species/metabolism
3.
Am J Pathol ; 184(7): 2023-34, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24952429

ABSTRACT

Irinotecan is a useful chemotherapeutic for the treatment of various cancers. Irinotecan treatment is associated with mucositis, which clearly limits the use of the drug. Mechanisms that account for mucositis are only partially known. This study assessed mechanisms and the role of inflammasome activation in irinotecan-induced mucositis. Mucositis in mice was induced by irinotecan injection in C57BL/6 wild-type, gp91phox(-/-), il-18(-/-), casp-1(-/-), and asc(-/-) mice once a day for 4 consecutive days. In some experiments, mice received apocynin to inhibit NADPH oxidase (NOX), IL-1 receptor antagonist, or IL-18 binding protein to prevent activation of IL-1 and IL-18 receptors, respectively. Mice were euthanized 7 days after the beginning of irinotecan treatment, and small intestines were collected for analysis. Irinotecan treatment resulted in increased IL-1ß and IL-18 production in ileum and NOX-2-dependent oxidative stress. gp91phox(-/-) and apocynin-treated mice had diminished oxidative stress and less severe mucositis. Furthermore, treatment with apocynin decreased caspase-1 activation and IL-1ß and IL-18 production in the ileum. asc(-/-) and casp-1(-/-) mice also had less intestinal injury and decreased IL-1ß and IL-18 production. Finally, both the absence of IL-18 and IL-1ß resulted in reduced inflammatory response and attenuated intestinal injury. NOX-2-derived oxidative stress mediates inflammasome activation and inflammasome-dependent production of IL-1ß and IL-18, which mediate tissue injury during irinotecan-induced mucositis in mice.


Subject(s)
Inflammasomes/metabolism , Interleukin-18/metabolism , Interleukin-1beta/metabolism , Mucositis/metabolism , Reactive Oxygen Species/metabolism , Animals , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Caspase 1/metabolism , Ileum/metabolism , Ileum/pathology , Irinotecan , Male , Membrane Glycoproteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mucositis/chemically induced , NADPH Oxidase 2 , NADPH Oxidases/metabolism , Oxidative Stress
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