Antarctic Strain of Rhodotorula mucilaginosa UFMGCB 18,377 Attenuates Mucositis Induced by 5-Fluorouracil in Mice.

Mucositis is one of the most strenuous side effects caused by chemotherapy drugs, such as 5-fluorouracil (5-FU), during the treatment of several types of cancers. The disease is so prevalent and aggressive that many patients cannot resist such symptoms. However, despite its frequency and clinical significance, there is no effective treatment to prevent or treat mucositis. Thus, the use of probiotics as an adjuvant for the treatment has gained prominence. In the present study, we evaluated the effectiveness of oral administration of the Antarctic strain of Rhodotorula mucilaginosa UFMGCB 18,377 as an alternative to minimize side effects of 5-FU-induced mucositis in mice. Body weight, food consumption, stool consistency, and presence of blood in the feces were assessed daily in mice orally treated or not with the yeast and submitted or not to experimental mucositis. Blood, bones, and intestinal tissues and fluid were used to determine intestinal permeability and immunological, microbiological, and histopathological parameters. Treatment with R. mucilaginosa UFMGCB 18,377 was able to decrease clinical signs of the disease, such as reduction of food intake and body weight loss, and also decreased the number of intestinal enterobacteria and intestinal length shortening. Additionally, treatment was able to decrease the levels of MPO and EPO activities and inflammatory infiltrates, as well as the histopathological lesions characteristic of mucositis in the jejunum and ileum. Results of the present study showed that the oral administration of R. mucilaginosa UFMGCB 18,377 protected mice against mucositis induced by 5-FU.

Leukotrienes target F-actin/cofilin-1 to enhance alveolar macrophage anti-fungal activity.

Candida albicans is the most common opportunistic fungal pathogen and causes local and systemic disease in immunocompromised patients. Alveolar macrophages (AMs) are pivotal for the clearance of C. albicans from the lung. Activated AMs secrete 5-lipoxygenase-derived leukotrienes (LTs), which in turn enhance phagocytosis and microbicidal activity against a diverse array of pathogens. Our aim was to investigate the role of LTB(4) and LTD(4) in AM antimicrobial functions against C. albicans and the signaling pathways involved. Pharmacologic and genetic inhibition of LT biosynthesis as well as receptor antagonism reduced phagocytosis of C. albicans when compared with untreated or WT controls. Conversely, exogenous LTs of both classes augmented base-line C. albicans phagocytosis by AMs. Although LTB(4) enhanced mainly mannose receptor-dependent fungal ingestion, LTD(4) enhanced mainly dectin-1 receptor-mediated phagocytosis. LT enhancement of yeast ingestion was dependent on protein kinase C-δ (PKCδ) and PI3K but not PKCα and MAPK activation. Both LTs reduced activation of cofilin-1, whereas they enhanced total cellular F-actin; however, LTB(4) accomplished this through the activation of LIM kinases (LIMKs) 1 and 2, whereas LTD(4) did so exclusively via LIMK-2. Finally, both exogenous LTB(4) and LTD(4) enhanced AM fungicidal activity in an NADPH oxidase-dependent manner. Our data identify LTB(4) and LTD(4) as key mediators of innate immunity against C. albicans, which act by both distinct and conserved signaling mechanisms to enhance multiple antimicrobial functions of AMs.

Impaired phagocytosis by alveolar macrophages from diabetic rats is related to the deficient coupling of LTs to the Fc gamma R signaling cascade.

Diabetic individuals are more susceptible to infections and this seems to be related to impaired phagocyte function. Alveolar macrophages (AMs) are the first barrier to prevent respiratory infections. Leukotrienes (LTs) increase AM phagocytic activity via Fc gamma R. In this study, we compared AMs from diabetic and non-diabetic rats for phagocytosis via Fc gamma R and the roles of LTs and insulin. Diabetes was induced in male Wistar rats by alloxan (42 mg/kg, i.v.); macrophages were obtained by bronchoalveolar lavage and IgG-opsonised sheep red blood cells (IgG-SRBC) were used as targets. LTs were added to the AMs 5 min before the addition of IgG-SRBC. AMs were treated with a LT synthesis inhibitor (zileuton, 10 microM), or antagonists of the LTB(4) receptor (CP105.696, 10 microM) or cys-LT receptor (MK571, 10 microM), 30 or 20 min before the addition of IgG-SRBC, respectively. We found that the phagocytosis of IgG-SRBC by AMs from diabetic rats is impaired compared with non-diabetic rats. Treatment with the LT inhibitor/antagonists significantly reduced AM phagocytosis in non-diabetic but not diabetic rats. During the phagocytosis of IgG-SRBC LTB(4) and LTC(4) were produced by AMs from both groups. The addition of exogenous LTB(4) or LTD(4) potentiated phagocytosis similarly in both groups. Phagocytosis was followed by the phosphorylation of PKC-delta, ERK and Akt. This was reduced by zileuton treatment in AMs from non-diabetic but not diabetic rats. The addition of insulin to AMs further increased the phagocytosis by increasing PKC-delta phosphorylation. These results suggest that the impaired phagocytosis found in AMs from diabetic rats is related to a deficient coupling of LTs to the Fc gamma R signaling cascade and that insulin has a key role in this coupling. An essential role for insulin in innate immunity is suggested.