RESUMO
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.
Assuntos
Antineoplásicos , Mucosite , Animais , Antineoplásicos/uso terapêutico , Camptotecina/efeitos adversos , Eosinófilos/patologia , Humanos , Mucosa Intestinal/patologia , Irinotecano/efeitos adversos , Camundongos , Mucosite/induzido quimicamente , Mucosite/tratamento farmacológico , Mucosite/patologiaRESUMO
AIMS: Exercise training increases circulating and tissue levels of angiotensin-(1-7) [Ang-(1-7)], which was shown to attenuate inflammation and fibrosis in different diseases. Here, we evaluated whether Ang-(1-7)/Mas receptor is involved in the beneficial effects of aerobic training in a chronic model of asthma. MATERIAL AND METHODS: BALB/c mice were subjected to a protocol of asthma induced by ovalbumin sensitization (OVA; 4 i.p. injections) and OVA challenge (3 times/week for 4 weeks). Simultaneously to the challenge period, part of the animals was continuously treated with Mas receptor antagonist (A779, 1 µg/h; for 28 days) and trained in a treadmill (TRE; 60% of the maximal capacity, 1 h/day, 5 days/week during 4 weeks). PGC1-α mRNA expression (qRT-PCR), plasma IgE and lung cytokines (ELISA), inflammatory cells infiltration (enzymatic activity assay) and airway remodeling (by histology) were evaluated. KEY FINDINGS: Blocking the Mas receptor with A779 increased IgE and IL-13 levels and prevented the reduction in extracellular matrix deposition in airways in OVA-TRE mice. Mas receptor blockade prevented the reduction of myeloperoxidase activity, as well as, prevented exercise-induced IL-10 increase. These data show that activation of Ang-(1-7)/Mas receptor pathway is involved in the anti-inflammatory and anti-fibrotic effects of aerobic training in an experimental model of chronic asthma. SIGNIFICANCE: Our results support exercise training as a non-pharmacological tool to defeat lung remodeling induced by chronic pulmonary inflammation. Further, our result also supports development of new therapy based on Ang-(1-7) or Mas agonists as important tool for asthma treatment in those patients that cannot perform aerobic training.
Assuntos
Angiotensina I/metabolismo , Asma/terapia , Fragmentos de Peptídeos/metabolismo , Pneumonia/terapia , Angiotensina I/sangue , Animais , Asma/sangue , Asma/metabolismo , Modelos Animais de Doenças , Terapia por Exercício , Masculino , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/sangue , Pneumonia/sangue , Pneumonia/metabolismoRESUMO
Skin wounds are an important clinical problem which affects millions of people worldwide. The search for new therapeutic approaches to improve wound healing is needed. The present study aimed to evaluate the effects of the oral treatment with the skin-related probiotics Lactobacillus johnsonii LA1 (LJ), L. paracasei ST11 (LP), and L. rhamnosus LPR (LR) in a model of excisional skin wounds in Swiss mice. The animals received daily oral gavage of PBS or 1 × 107 colony-forming units of LJ, LP, or LR, singly, beginning just after the creation of wounds until euthanasia. Blood flow was evaluated by laser Doppler perfusion imaging. Myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities were used to assess the accumulation of neutrophils and macrophages, respectively. The wound tissue was also collected for histological analyses (H&E, Toluidine blue, and Picrosirius red staining). The macroscopic wound closure rate was faster only in mice treated with LR, but not with LJ and LP, when compared to mice treated with PBS. Histological evaluations showed that treatment with LR stimulated wound epithelization when compared to PBS. Further analyses showed that wounds from LR-treated mice presented a significant decrease in macrophage (p < 0.001) and mast cell (p < 0.001) infiltration, along with improved angiogenesis (p < 0.001) and blood flow (p < 0.01). Of note, collagen deposition and scarring were reduced in LR-treated mice when compared to PBS-treated mice. In conclusion, our results show that the oral treatment with Lactobacillus rhamnosus accelerates skin wound closure and reduces scar, besides to reducing inflammation and fibrogenesis and improving angiogenesis in the wounded skin.
Assuntos
Cicatriz , Lacticaseibacillus rhamnosus , Probióticos/uso terapêutico , Pele/lesões , Cicatrização , Animais , Cicatriz/prevenção & controle , CamundongosRESUMO
Skin wound healing is a complex process involving different events such as blood coagulation, inflammation, new blood vessels formation, and extracellular matrix deposition. These events can be observed by using histology techniques. However, the lack of the standardization of such parameters impacts on the reproducibility of results. Here, we describe a protocol to perform macroscopic and microscopic analyses of the events that occur during skin wound healing using the experimental model of excisional wounds in rats.
RESUMO
Subcutaneous implantation of synthetic materials and biomedical devices often induces abnormal tissue healing - the foreign body reaction-which impairs their function. In particular, Interferon-γ (IFN-γ) is a critical endogenous mediator of inflammation and plays a key role in a wide variety of biological responses including tissue healing. However, the contribution of endogenous IFN-γ on different features of the foreign body response induced by synthetic implants regarding neovascularization, inflammation, and fibrogenesis is not well known. Here, we evaluated inflammatory angiogenesis and fibrogenesis induced by implantation of polyether-polyurethane sponges in mice targeted disrupted of the interferon-γ gene (IFN-γ-/- ) and wild-type (WT). The hemoglobin content, the number of vessels, and blood flow (evaluated by LDPI-laser Doppler perfusion imaging) were decreased in the implants from IFN-γ-/- as compared to WT mice. Likewise, neutrophils and macrophages accumulation (MPO and NAG activities, respectively) was decreased in IFN-γ-/- implants. Interestingly, while the local content of VEGF, TNF-α, CXCL-1/KC, as measured by ELISA, and iNOS expression, as measured by qPCR, were significantly reduced, the content of IL-10 was greatly increased in the implants from IFN-γ-/- mice as compared to WT mice. No alterations were observed in CCL-2/MCP-1 levels. Lastly, the collagen deposition, assessed by Picro-Sirius red-stained histological sections, was also reduced in IFN-γ-/- implants. Altogether, these data suggest that IFN-γ activity contributes to inflammatory angiogenesis and fibrogenesis in synthetic implants and that lack of IFN-γ expression attenuates foreign body reaction to implants in mice. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2243-2250, 2018.
Assuntos
Reação a Corpo Estranho/patologia , Interferon gama/deficiência , Próteses e Implantes , Tela Subcutânea/patologia , Animais , Colágeno/metabolismo , Fibrose , Regulação da Expressão Gênica , Leucócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Neovascularização Fisiológica , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
PURPOSE: To investigated the inflammatory, angiogenic and fibrogenic activities of the Schinus terebinthifolius Raddi leaves oil (STRO) on wound healing. METHODS: The excisional wound healing model was used to evaluate the effects of STRO. The mice were divided into two groups: Control, subjected to vehicle solution (ointment lanolin/vaseline base), or STRO- treated group, administered topically once a day for 3, 7 and 14 days post-excision. We evaluated the macroscopic wound closure rate; the inflammation was evaluated by leukocytes accumulation and cytokine levels in the wounds. The accumulation of neutrophil and macrophages in the wounds were determined by assaying myeloperoxidase and N-acetyl-ß-D-glucosaminidase activities. The levels of TNF-α, CXCL-1 and CCL-2 in wound were evaluated by ELISA assay. Angiogenesis and collagen fibers deposition were evaluated histologically. RESULTS: We observed that macroscopic wound closure rate was improved in wounds from STRO-group than Control-group. The wounds treated with STRO promoted a reduction in leucocyte accumulation and in pro-inflammatory cytokine. Moreover, STRO treatment increased significantly the number of blood vessels and collagen fibers deposition, as compared to control group. CONCLUSION: Topical application of STRO display anti-inflammatory and angiogenic effects, as well as improvement in collagen replacement, suggesting a putative use of this herb for the development of phytomedicines to treat inflammatory diseases, including wound healing.
Assuntos
Anacardiaceae/química , Indutores da Angiogênese/uso terapêutico , Inflamação/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Óleos de Plantas/uso terapêutico , Cicatrização/efeitos dos fármacos , Animais , Colágeno/análise , Imuno-Histoquímica , Masculino , Camundongos , Folhas de Planta/química , Tela Subcutânea/efeitos dos fármacos , Tela Subcutânea/patologia , Fatores de TempoRESUMO
Purpose: To investigated the inflammatory, angiogenic and fibrogenic activities of the Schinus terebinthifolius Raddi leaves oil (STRO) on wound healing. Methods: The excisional wound healing model was used to evaluate the effects of STRO. The mice were divided into two groups: Control, subjected to vehicle solution (ointment lanolin/vaseline base), or STRO- treated group, administered topically once a day for 3, 7 and 14 days post-excision. We evaluated the macroscopic wound closure rate; the inflammation was evaluated by leukocytes accumulation and cytokine levels in the wounds. The accumulation of neutrophil and macrophages in the wounds were determined by assaying myeloperoxidase and N-acetyl--D-glucosaminidase activities. The levels of TNF-, CXCL-1 and CCL-2 in wound were evaluated by ELISA assay. Angiogenesis and collagen fibers deposition were evaluated histologically. Results: We observed that macroscopic wound closure rate was improved in wounds from STRO-group than Control-group. The wounds treated with STRO promoted a reduction in leucocyte accumulation and in pro-inflammatory cytokine. Moreover, STRO treatment increased significantly the number of blood vessels and collagen fibers deposition, as compared to control group. Conclusion: Topical application of STRO display anti-inflammatory and angiogenic effects, as well as improvement in collagen replacement, suggesting a putative use of this herb for the development of phytomedicines to treat inflammatory diseases, including wound healing.
Assuntos
Animais , Ratos , Anacardiaceae/química , Anti-Inflamatórios/uso terapêutico , CicatrizaçãoRESUMO
Purpose: To investigated the inflammatory, angiogenic and fibrogenic activities of the Schinus terebinthifolius Raddi leaves oil (STRO) on wound healing. Methods: The excisional wound healing model was used to evaluate the effects of STRO. The mice were divided into two groups: Control, subjected to vehicle solution (ointment lanolin/vaseline base), or STRO- treated group, administered topically once a day for 3, 7 and 14 days post-excision. We evaluated the macroscopic wound closure rate; the inflammation was evaluated by leukocytes accumulation and cytokine levels in the wounds. The accumulation of neutrophil and macrophages in the wounds were determined by assaying myeloperoxidase and N-acetyl--D-glucosaminidase activities. The levels of TNF-, CXCL-1 and CCL-2 in wound were evaluated by ELISA assay. Angiogenesis and collagen fibers deposition were evaluated histologically. Results: We observed that macroscopic wound closure rate was improved in wounds from STRO-group than Control-group. The wounds treated with STRO promoted a reduction in leucocyte accumulation and in pro-inflammatory cytokine. Moreover, STRO treatment increased significantly the number of blood vessels and collagen fibers deposition, as compared to control group. Conclusion: Topical application of STRO display anti-inflammatory and angiogenic effects, as well as improvement in collagen replacement, suggesting a putative use of this herb for the development of phytomedicines to treat inflammatory diseases, including wound healing.(AU)
Assuntos
Animais , Ratos , Anacardiaceae/química , Anti-Inflamatórios/uso terapêutico , CicatrizaçãoRESUMO
Abstract Purpose: To investigated the inflammatory, angiogenic and fibrogenic activities of the Schinus terebinthifolius Raddi leaves oil (STRO) on wound healing. Methods: The excisional wound healing model was used to evaluate the effects of STRO. The mice were divided into two groups: Control, subjected to vehicle solution (ointment lanolin/vaseline base), or STRO- treated group, administered topically once a day for 3, 7 and 14 days post-excision. We evaluated the macroscopic wound closure rate; the inflammation was evaluated by leukocytes accumulation and cytokine levels in the wounds. The accumulation of neutrophil and macrophages in the wounds were determined by assaying myeloperoxidase and N-acetyl-β-D-glucosaminidase activities. The levels of TNF-α, CXCL-1 and CCL-2 in wound were evaluated by ELISA assay. Angiogenesis and collagen fibers deposition were evaluated histologically. Results: We observed that macroscopic wound closure rate was improved in wounds from STRO-group than Control-group. The wounds treated with STRO promoted a reduction in leucocyte accumulation and in pro-inflammatory cytokine. Moreover, STRO treatment increased significantly the number of blood vessels and collagen fibers deposition, as compared to control group. Conclusion: Topical application of STRO display anti-inflammatory and angiogenic effects, as well as improvement in collagen replacement, suggesting a putative use of this herb for the development of phytomedicines to treat inflammatory diseases, including wound healing.