Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis

Puerta-Arias, Juan David; Pino-Tamayo, Paula Andrea; Arango, Jorge Luis Parra; Salazar-Peláez, Lina María; González, Ángel

doi:10.1093/mmy/myx087

Cited by 16 publications

(19 citation statements)

References 32 publications

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“…25 TIMP-1 and TIMP-2 are mainly expressed in epithelial cells, and TIMP-1 gene expression was up-regulated in pulmonary fibrosis in vivo. 45 TGF-β1 modulated the homeostasis between MMPs and TIMPs through p38 MAPK and ERK1/2 in breast cancer cells. 46 In current study, whether the gene or protein levels of TIMP-1 and TIMP-2 were all dose-dependent increases treated with Nano NiO.…”

Section: Discussionmentioning

confidence: 97%

“…It has been observed that the increased expression of MMP‐1 and MMP‐9 in idiopathic pulmonary fibrosis was related to the changes of TIMP‐1 and TIMP‐2 in A549 cells . TIMP‐1 and TIMP‐2 are mainly expressed in epithelial cells, and TIMP‐1 gene expression was up‐regulated in pulmonary fibrosis in vivo . TGF‐β1 modulated the homeostasis between MMPs and TIMPs through p38 MAPK and ERK1/2 in breast cancer cells .…”

Section: Discussionmentioning

confidence: 99%

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TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

Tian

Chang

Zhang

et al. 2019

Environmental Toxicology

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Nickel oxide nanoparticles (Nano NiO) could induce pulmonary fibrosis, however, the mechanisms are still unknown. The aim of the present study was to explore the roles of transforming growth factor‐β1 (TGF‐β1), mitogen‐activated protein kinase (MAPK) pathway and MMPs/TIMPs balance in Nano NiO‐induced pulmonary fibrosis. For that purpose, we first established Nano NiO‐induced human lung adenocarcinoma epithelial cells (A549 cells) model of collagen excessive formation through detecting the levels of hydroxyproline (Hyp) and type I collagen (Col‐I). Then the protein levels of TGF‐β1, MAPKs, and MMPs/TIMPs were assessed by Western blot. The results showed that Nano NiO resulted in the increased contents of Hyp, Col‐I, and TGF‐β1, the MAPK pathway activation and MMPs/TIMPs imbalance with a dose‐dependent manner. In addition, to investigate whether TGF‐β1 mediated MAPK signaling pathway, A549 cells were treated by 100 μg/mL Nano NiO combined with TGF‐β1, p38 MAPK, and ERK1/2 inhibitors (10 μM SB431542, 10 μM SB203580, and 10 μM U0126), respectively. We found that MAPK signal pathway was suppressed by TGF‐β1 inhibitor. Meanwhile, the increased contents of Hyp and Col‐I, and MMPs/TIMPs imbalance were alleviated by the p38 MAPK and ERK1/2 inhibitors, respectively. These findings indicated that the MAPK pathway and MMPs/TIMPs imbalance were involved in collagen excessive formation induced by Nano NiO.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

Tian

Chang

Zhang

et al. 2019

Environmental Toxicology

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“…Additionally, it also diminished the number of inflammatory cells—including neutrophils—in the lungs of mice infected with P . brasiliensis [ 27 ]. In the present study, it was observed that the ITC regulates the expression of the MMP-15 and TIMP-2 genes that have been recognized as inducers of pulmonary fibrosis [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Animal models of PCM have allowed characterization of the mechanisms involved in the development of pulmonary fibrosis, and evaluate diverse strategies to treat it. Thus, combined therapies including pentoxifylline plus ITC [ 26 ], or an anti- neutrophil monoclonal antibody alone or in combination with ITC [ 27 , 28 ], have showed that such treatment strategies reduced substantially the PF. However, the potential risk for using immunosuppressive drugs or biological agents, mainly in host with other unknown latent infections, should be considered [ 29 ].…”

Section: Introductionmentioning

confidence: 99%

Impaired anti-fibrotic effect of bone marrow-derived mesenchymal stem cell in a mouse model of pulmonary paracoccidioidomycosis

et al. 2017

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Bone marrow-derived mesenchymal stem cells (BMMSCs) have been consider as a promising therapy in fibrotic diseases. Experimental models suggest that BMMSCs may be used as an alternative therapy to treat chemical- or physical-induced pulmonary fibrosis. We investigated the anti-fibrotic potential of BMMSCs in an experimental model of lung fibrosis by infection with Paracoccidioides brasiliensis. BMMSCs were isolated and purified from BALB/c mice using standardized methods. BALB/c male mice were inoculated by intranasal infection of 1.5x106 P. brasiliensis yeasts. Then, 1x106 BMMSCs were administered intra venous at 8th week post-infection (p.i.). An additional group of mice was treated with itraconazole (ITC) two weeks before BMMSCs administration. Animals were sacrificed at 12th week p.i. Histopathological examination, fibrocytes counts, soluble collagen and fibrosis-related genes expression in lungs were evaluated. Additionally, human fibroblasts were treated with homogenized lung supernatants (HLS) to determine induction of collagen expression. Histological analysis showed an increase of granulomatous inflammatory areas in BMMSCs-treated mice. A significant increase of fibrocytes count, soluble collagen and collagen-3α1, TGF-β3, MMP-8 and MMP-15 genes expression were also observed in those mice. Interestingly, when combined therapy BMMSCs/ITC was used there is a decrease of TIMP-1 and MMP-13 gene expression in infected mice. Finally, human fibroblasts stimulated with HLS from infected and BMMSCs-transplanted mice showed a higher expression of collagen I. In conclusion, our findings indicate that late infusion of BMMSCs into mice infected with P. brasiliensis does not have any anti-fibrotic effect; possibly because their interaction with the fungus promotes collagen expression and tissue remodeling.

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“…The immunization with P10 in association with conventional drugs resulted in the absence of granulomas and areas with very few or undetectable yeast cells (37). Similarly, Naranjo and collaborators combined itraconazole-pentoxifylline treatment to reduce lung fibrosis in the murine model of PCM (36), and Puerta-Arias and collaborators were able to reduce the infection and pulmonary fibrosis with a combination of ITZ and monoclonal antibody against neutrophils (38).…”

Section: Discussionmentioning

confidence: 99%

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

Rodrigues-Vendramini

Marschalk

Toplak

et al. 2019

Antimicrob Agents Chemother

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Paracoccidioidomycosis (PCM), caused by Paracoccidioides, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics testing to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacological criteria (adsorption, distribution, metabolism, excretion, and toxicity) and was therefore used in in vitro experiments. Here we demonstrate that CP1 binds with a dissociation constant of 64 ± 1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity, with a 50% inhibitory concentration (IC50) of 47 ± 5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with a lower inflammatory response and is thus a promising candidate and lead structure for the development of drugs useful in PCM treatment.

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Itraconazole in combination with neutrophil depletion reduces the expression of genes related to pulmonary fibrosis in an experimental model of paracoccidioidomycosis

Cited by 16 publications

References 32 publications

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

TGF‐β1 mediated MAPK signaling pathway promotes collagen formation induced by Nano NiO in A549 cells

Impaired anti-fibrotic effect of bone marrow-derived mesenchymal stem cell in a mouse model of pulmonary paracoccidioidomycosis

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

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