Nitric oxide participation in granulomatous response induced by Paracoccidioides brasiliensis infection in mice

Nishikaku, Angela Satie; Molina, Raphael Fagnani Sanchez; Ribeiro, Luciana Cristina; Scavone, Renata; Albe, Bernardo Paulo; Cunha, Cláudia S.; Burger, Eva

doi:10.1007/s00430-009-0113-x

Cited by 22 publications

(20 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…and pro-cytokines involved in fibroblast activation and granuloma organization (e.g., pro-TNF-α and pro- TGF-β) [66], [67], [68]. In the intraperitoneal model of PCM using WT and iNOS −/− mice [69], NO production was associated with increased MMP9 activity and the loose organization of granulomas developed by WT mice. In the pulmonary model employed in the present study we suppose that the NO produced by the WT mice inhibited the production of TNF-α, which is required for granuloma organization, and of TGF-β, which is needed for tissue repair and Treg cell expansion.…”

Section: Discussionmentioning

confidence: 99%

“…The TGF-β-induced Treg cell differentiation apparently contributed to the controlled tissue pathology even in the presence of the augmented immune response of the iNOS −/− mice. The study by Nishikako et al [69] revealed additional important information on the influence of NO in granuloma formation and disease outcome. At late stages of infection (120 days post-infection, not evaluated in our model), i.p.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TNF-α and CD8+ T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis

et al. 2013

View full text Add to dashboard Cite

BackgroundNitric oxide (NO), a key antimicrobial molecule, was previously shown to exert a dual role in paracoccidioidomycosis, an endemic fungal infection in Latin America. In the intravenous and peritoneal models of infection, NO production was associated with efficient fungal clearance but also with non-organized granulomatous lesions. Because paracoccidioidomycosis is a pulmonary infection, we aimed to characterize the role of NO in a pulmonary model of infection.Methodology/Principal FindingsC57Bl/6 wild type (WT) and iNOS−/− mice were i.t. infected with 1×106 Paracoccidioides brasiliensis yeasts and studied at several post-infection periods. Unexpectedly, at week 2 of infection, iNOS−/− mice showed decreased pulmonary fungal burdens associated with an M2-like macrophage profile, which expressed high levels of TGF-β impaired ability of ingesting fungal cells. This early decreased fungal loads were concomitant with increased DTH reactions, enhanced TNF-α synthesis and intense migration of activated macrophages, CD4+ and CD8+ T cells into the lungs. By week 10, iNOS−/− mice showed increased fungal burdens circumscribed, however, by compact granulomas containing elevated numbers of activated CD4+ T cells. Importantly, the enhanced immunological reactivity of iNOS−/− mice resulted in decreased mortality rates. In both mouse strains, depletion of TNF-α led to non-organized lesions and excessive influx of inflammatory cells into the lungs, but only the iNOS−/− mice showed increased mortality rates. In addition, depletion of CD8+ cells abolished the increased migration of inflammatory cells and decreased the number of TNF-α and IFN-γ CD4+ and CD8+ T cells into the lungs of iNOS−/− mice.Conclusions/SignificanceOur study demonstrated that NO plays a deleterious role in pulmonary paracoccidioidomycosis due to its suppressive action on TNF-α production, T cell immunity and organization of lesions resulting in precocious mortality of mice. It was also revealed that uncontrolled fungal growth can be overcome by an efficient immune response.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TNF-α and CD8+ T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Previous studies suggest osteopontin is a critical player in the formation of granulomas (18,26). Therefore, we investigated osteopontin in MWCNT-induced granulomas.…”

Section: Expression Of Osteopontin Mrna Is Up-regulated In Granulomatmentioning

confidence: 92%

Novel Murine Model of Chronic Granulomatous Lung Inflammation Elicited by Carbon Nanotubes

Huizar

Malur

Midgette

et al. 2011

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Lung granulomas are associated with numerous conditions, including inflammatory disorders, exposure to environmental pollutants, and infection. Osteopontin is a chemotactic cytokine produced by macrophages, and is implicated in extracellular matrix remodeling. Furthermore, osteopontin is up-regulated in granulomatous disease, and osteopontin null mice exhibit reduced granuloma formation. Animal models currently used to investigate chronic lung granulomatous inflammation bear a pathological resemblance, but lack the chronic nature of human granulomatous disease. Carbon nanoparticles are generated as byproducts of combustion. Interestingly, experimental exposures to carbon nanoparticles induce pulmonary granuloma-like lesions. However, the recruited cellular populations and extracellular matrix gene expression profiles within these lesions have not been explored. Because of the rapid resolution of granulomas in current animal models, the mechanisms responsible for persistence have been elusive. To overcome the limitations of previous models, we investigated whether a model using multiwall carbon nanoparticles would resemble chronic human lung granulomatous inflammation. We hypothesized that pulmonary exposure to multiwall carbon nanoparticles would induce granulomas, elicit a macrophage and T-cell response, and mimic other granulomatous disorders with an up-regulation of osteopontin. This model demonstrates: (1) granulomatous inflammation, with macrophage and T-cell infiltration; (2) resemblance to the chronicity of human granulomas, with persistence up to 90 days; and (3) a marked elevation of osteopontin, metalloproteinases, and cell adhesion molecules in granulomatous foci isolated by laser-capture microdissection and in alveolar macrophages from bronchoalveolar lavage. The establishment of such a model provides an important platform for mechanistic studies on the persistence of granuloma.

show abstract

“…36 Similarly, the production of nitric oxide (NO) by monocytes stimulated by P. brasiliensis seems to exert a negative modulatory effect on the formation of granulomas and a positive effect on fungal spread, leading to the dissemination of PCM. 37 Experimental studies in patients with PCM indicate that resistance to the fungus is dependent on activities of T Helper cells and macrophages/monocytes, mediated by IFN-γ and TNF-α. 27 The synergistic effect between these two cytokines is essential for host resistance and effective fungicidal activity against P. brasiliensis.…”

Section: Immunopathogenesis Of Pcmmentioning

confidence: 99%

Imunologia da paracoccidioidomicose

Fortes¹,

Miot

Kurokawa³

et al. 2011

An. Bras. Dermatol.

View full text Add to dashboard Cite

Paracoccidioidomycosis is the most prevalent systemic mycosis in Latin America, among immunecompetent patients. It's caused by the dimorphic fungus Paracoccidioiddes brasiliensis. Investigations regarding its immunopathogenesis are very important in the understanding of aspects related to natural history, as the protective immunity, and the relationship between host and parasite; also favoring the knowledge about clinical patterns and the elaboration of therapeutic strategies. The disease clinical polymorphism depends, at least, of the immune response profile according to the tissue and blood released citokynes, resulting in tissue damage. Keywords: Allergy and immunology; Cytokines; Paracoccidioides; Paracoccidioidomycosis Resumo: Paracoccidioidomicose é a mais prevalente micose sistêmica na América Latina, em pacientes imunocompetentes, sendo causada pelo fungo dimórfico Paracoccidioiddes brasiliensis. O estudo da sua imunopatogênese é importante na compreensão de aspectos relacionados à história natural, como a imunidade protetora, e à relação entre hospedeiro e parasita, favorecendo o entendimento clínico e a elaboração de estratégias terapêuticas. O polimorfismo clínico da doença depende, em última análise, do perfil de resposta imune que prevalece expresso pelo padrão de citocinas teciduais e circulantes, além da qualidade da resposta imune desencadeada, que levam ao dano tecidual.

show abstract

Nitric oxide participation in granulomatous response induced by Paracoccidioides brasiliensis infection in mice

Cited by 22 publications

References 44 publications

TNF-α and CD8+ T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis

TNF-α and CD8+ T Cells Mediate the Beneficial Effects of Nitric Oxide Synthase-2 Deficiency in Pulmonary Paracoccidioidomycosis

Novel Murine Model of Chronic Granulomatous Lung Inflammation Elicited by Carbon Nanotubes

Imunologia da paracoccidioidomicose

Contact Info

Product

Resources

About