Uptake and efflux kinetics, and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis

2017 ◽  
Vol 31 (3) ◽  
pp. 311-318 ◽  
Author(s):  
Taotao Wang ◽  
Qianting Yang ◽  
Lu Chen ◽  
Ying Li ◽  
Ti Meng ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Aspergillus Fumigatus ◽  
Early Treatment ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis ◽  
Intracellular Activity ◽  
Pulmonary Epithelial Cells ◽  
Efflux Kinetics

Successfully treated invasive pulmonary aspergillosis in a patient with diabetic ketoacidosis

Open Medicine ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. 685-688
Author(s):  
Ryo Kumagai ◽  
Gen Ohara ◽  
Shinya Sato ◽  
Kunihiko Miyazaki ◽  
Katsunori Kagohashi ◽  
...  
Keyword(s):  
Early Intervention ◽  
Invasive Aspergillosis ◽  
Diabetic Ketoacidosis ◽  
Amphotericin B ◽  
Early Treatment ◽  
Liposomal Amphotericin ◽  
Invasive Pulmonary Aspergillosis ◽  
Full Recovery ◽  
Liposomal Amphotericin B ◽  
Pulmonary Aspergillosis

AbstractWe report herein a case of diabetic ketoacidosis associated with invasive aspergillosis that was successfully treated with liposomal amphotericin-B (L-AMB). Early intervention after confirming the diagnosis of invasive pulmonary aspergillosis is very important, and initiating early treatment with L-AMB can lead to a full recovery.

scholarly journals Evaluation of a commercial quantitative Aspergillus fumigatus-specific IgM assay for the diagnosis of invasive pulmonary aspergillosis

Medicine ◽  
2017 ◽  
Vol 96 (51) ◽  
pp. e9436 ◽  
Author(s):  
Yake Yao ◽  
Hua Zhou ◽  
Yihong Shen ◽  
Qing Yang ◽  
Jian Ye ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Invasive Pulmonary Aspergillosis ◽  
Pulmonary Aspergillosis

scholarly journals Antifungal effect of all-trans retinoic acid against Aspergillus fumigatus in vitro and in a pulmonary aspergillosis in vivo model

2020 ◽  
Author(s):  
Elena Campione ◽  
Roberta Gaziano ◽  
Elena Doldo ◽  
Daniele Marino ◽  
Mattia Falconi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Aspergillus Fumigatus ◽  
Rat Model ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Antifungal Drugs ◽  
Pulmonary Aspergillosis ◽  
Fungistatic Activity

AIM: Aspergillus fumigatus is the most common opportunistic fungal pathogen and causes invasive pulmonary aspergillosis (IPA), with high mortality among immunosuppressed patients. Fungistatic activity of all-trans retinoic acid (ATRA) has been recently described in vitro. We evaluated the efficacy of ATRA in vivo and its potential synergistic interaction with other antifungal drugs. MATERIALS AND METHODS: A rat model of IPA and in vitro experiments were performed to assess the efficacy of ATRA against Aspergillus in association with classical antifungal drugs and in silico studies used to clarify its mechanism of action. RESULTS: ATRA (0.5 and 1 mM) displayed a strong fungistatic activity in Aspergillus cultures, while at lower concentrations, synergistically potentiated fungistatic efficacy of sub-inhibitory concentration of Amphotericin B (AmB) and Posaconazole (POS). ATRA also enhanced macrophagic phagocytosis of conidia. In a rat model of IPA, ATRA reduced mortality similarly to Posaconazole. CONCLUSION: Fungistatic efficacy of ATRA alone and synergistically with other antifungal drugs was documented in vitro, likely by inhibiting fungal Hsp90 expression and Hsp90-related genes. ATRA reduced mortality in a model of IPA in vivo. Those findings suggest ATRA as suitable fungistatic agent, also to reduce dosage and adverse reaction of classical antifungal drugs, and new therapeutic strategies against IPA and systemic fungal infections.

ADAMTS13 Regulates Neutrophil Recruitment in a Mouse Model of Invasive Pulmonary Aspergillosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4109-4109
Author(s):  
Markus Radsak ◽  
Steve Prüfer ◽  
Katharina Ebner ◽  
Michael Weber ◽  
Sebastian Reuter ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Mouse Model ◽  
Aspergillus Fumigatus ◽  
Fungal Infections ◽  
Invasive Pulmonary Aspergillosis ◽  
Polymorphonuclear Neutrophils ◽  
Formyl Peptide Receptor ◽  
Wild Type ◽  
Pulmonary Aspergillosis

Abstract Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. The main mechanism regulating the size and prothrombotic activity of VWF is the specific proteolytic activity of ADAMTS-13. To determine the relevance of this regulatory pathway for the innate inflammatory response by polymorphonuclear neutrophils (PMN), we employed a mouse model of invasive pulmonary aspergillosis (IPA) where PMN functionality is crucial for fungal clearance and survival. IPA was induced by intratracheal application of Aspergillus fumigatus conidia in wild-type (129/Sv/Pas) or Adamts13 deficient (Adamts13-/-) mice. After PMN depletion using a anti-Gr-1 specific antibody, all mice infected with Aspergillus fumigatus conidia developed neutropenia and succumbed due to lethal IPA. In contrast, all undepleted wild-type mice survived the infection. Interestingly, Aspergillus fumigatus infection in Adamts13-/- mice was lethal in 20% of the animals displaying a more severe course of IPA, as indicated by an increased fungal burden in lung homogenates along with increased levels of albumin and the inflammatory mediators IL-1β, IL-6, TNF-α, KC and MCP-1 in the bronchio-alveolar lavage fluid (BALF) compared to wild-type controls. Beyond this, we observed a decreased number of PMN in BALF of infected Adamts13-/- mice compared to wild-type mice. Lung histology sections demonstrated a more pronounced perivascular leukocyte infiltration in further support of a dysregulated inflammatory response in Adamts13-/- mice. Importantly, we observed no general defect in the activation of neutrophil effector functions as demonstrated by the normal induction of the oxidative burst, phagocytosis, degranulation, L-selectin shedding and apoptosis in response to formyl-peptide receptor agonists or exposure to Aspergillus fumigatus conidia or hyphae in vitro. Therefore, we conclude that the proteolytic regulation of VWF by ADAMTS-13 in an important mechanism to control PMN recruitment in the regulation of the innate inflammatory response in invasive fungal infections. Disclosures Radsak: Celgene: Research Funding.

scholarly journals Effects of Cinnamaldehyde on the Cell Wall ofA. fumigatusand Its Application in Treating Mice with Invasive Pulmonary Aspergillosis

2018 ◽  
Vol 2018 ◽  
pp. 1-8
Author(s):  
Jiehua Deng ◽  
Gangsheng Wang ◽  
Jihong Li ◽  
Yile Zhao ◽  
Xiaolu Wang
Keyword(s):  
Cell Wall ◽  
Treatment Group ◽  
Aspergillus Fumigatus ◽  
Invasive Pulmonary Aspergillosis ◽  
Colony Form Unit ◽  
Positive Control ◽  
Positive Control Group ◽  
Control Group ◽  
Pulmonary Aspergillosis ◽  
Icr Mice

Background.The invasive pulmonary aspergillosis is a kind of high incidence of disease with difficulties in treatment, poor prognosis, and high mortality.Objectives.The study aimed to reveal the effect of cinnamaldehyde on the fungal cell wall and verify its efficacy on invasive pulmonary aspergillosis on immunosuppressed Institute of Cancer Research mice (ICR mice).Methods.ICR mice were given cyclophosphamide 200 mg.kg−1. d−1by intraperitoneal injection for 2 days. On the 4th day, the mice were given 50μLofAspergillosis fumigatusspore (107colony form unit CFU/mL) by intranasal injection to establish immunosuppressive animal models with invasiveAspergillosis fumigatusinfection. Then the mice in treatment group orally administered cinnamaldehyde for 14 consecutive days, while voriconazole was given to the mice in the positive control group.Results.The clearance rate of pulmonary fungi, cure rate, and reduction of 1,3-β-D-glucans in treatment group were 80.00%, 80.00%, and 81.00%, respectively while in positive control group they were 67.00%, 60.00%, and 62.00%, respectively. There were significant differences in the results between two groups as mentioned above (P<0.05). Electron microscopy showed that, in treatment group, the cell wall ofAspergillus fumigatuswas dissolved and detached and the cell surface was incomplete. There were edema, degeneration, and necrosis in nucleus and organelle, which lead to cellular necrocytosis. The cytomembrane ofAspergillus fumigatuswas intact, clear, and complete, whereas the cytomembrane in the positive control group disappeared. The hyphal morphology ofAspergillus fumigatuswas deformed, but the cell wall was intact.Conclusion.Cinnamaldehyde has a good curative effect in the treatment of invasive pulmonary aspergillus infection in immunodeficient mice. It mainly affects the synthesis of 1,3-β-D-glucans from the cytoderm ofAspergillus fumigatusbut does not affect cell wall. It would potentially be an effective and novel drug for targeted treatment ofAspergillus fumigatusdeep infection.

scholarly journals Therapeutic effects of pentoxifylline on invasive pulmonary aspergillosis in immunosuppressed mice

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chunlai Feng ◽  
Ming Zhang ◽  
Sujuan Zhang ◽  
Jun Zhang ◽  
Chong Li ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Invasive Pulmonary Aspergillosis ◽  
Treatment Strategies ◽  
Severe Infection ◽  
Neutrophil Infiltration ◽  
Survival Duration ◽  
Therapeutic Effects ◽  
Pulmonary Aspergillosis ◽  
Fungal Burden ◽  
Immunosuppressed Mice

Abstract Background The most common and severe infection of Aspergillus fumigatus is invasive pulmonary aspergillosis (IPA), which is usually seen in immunocompromised patients. Neutropenia is the primary risk factor implicated in IPA; however, IPA also occurs in patients without neutropenia, namely, those who are immunosuppressed owing to long-term corticosteroid use. With IPA-associated mortality as high as 51–79%, novel and effective treatment strategies are urgently needed. Pentoxifylline (PTX) has been shown to competitively inhibit the family 18 chitinases in fungi, which may be an new antifungal therapy. Hence, the aim of our study was to compare neutropenic and non-neutropenic IPA mouse models, and to evaluate the effect of PTX on IPA in immunosuppressed mice. Methods C57BL/6J mice were pre-treated with cyclophosphamide and hydrocortisone. Neutropenic model IPA mice (CTX-IPA) and non-neutropenic IPA mice (HC-IPA) were established by intranasal administration of Aspergillus fumigatus spore suspension. A subset of each group was injected with PTX post-infection. Among these groups, we compared overall survival, pulmonary fungal burden, lung hispathology, and myeloperoxidase (MPO), interleukin 8 (IL-8), and mammalian chitinase concentration in the bronchoalveolar lavage fluid (BALF). Results The survival rate of the HC-IPA group was higher than that of the CTX-IPA group, and pulmonary fungal burden was also lower (p < 0.05). The CTX-IPA group showed infiltration of alveolae and blood vessels by numerous hyphae of A. fumigatus. The HC-IPA group exhibited destruction of bronchi, expansion of alveolar septa, increased macrophages aggregation, significant neutrophil infiltration and a few hyphae in peribronchial areas. After PTX treatment, improvement was observed in survival duration and pulmonary fungal burden in HC-IPA mice. MPO and IL-8 levels were lower in the HC-IPA + PTX group compared to the corresponding levels in the HC-IP group. Chitotriosidase (CHIT1) and Chitinase 3-like 1 (CHI3L1) expression in the HC-IPA group was decreased after PTX treatment (p < 0.05). Conclusion PTX was found to exert a therapeutic effect in a non-neutropenic mouse model of IPA, which may lead to the development of novel strategies for IPA treatment.

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