The Antifungal Drug Amphotericin B Promotes Inflammatory Cytokine Release by a Toll-like Receptor- and CD14-dependent Mechanism

Sau, Keya; Mambula, Salamatu S.; Latz, Eicke; Henneke, Philipp; Golenbock, Douglas T.; Levitz, Stuart M.

doi:10.1074/jbc.m306137200

Cited by 195 publications

(115 citation statements)

References 57 publications

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“…Furthermore, the absence of immune or endothelial cells prevents the assessment of the nephrotoxic potential of immunologically active drugs. For example, the induction of pro-inflammatory cytokines via Tolllike receptors 36 is linked to the development of amphotericin B-induced nephrotoxicity in patients. 37 In our study the effects of amphotericin B on viability and expression of HO-1 in HPTECs was mild even at high doses, possibly because of a missing immune response in the cell culture system.…”

Section: Discussionmentioning

confidence: 99%

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

105

102

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Nephrotoxicity due to drugs and environmental chemicals accounts for significant patient mortality and morbidity, but there is no high throughput in vitro method for predictive nephrotoxicity assessment. We show that primary human proximal tubular epithelial cells (HPTECs) possess characteristics of differentiated epithelial cells rendering them desirable to use in such in vitro systems. To identify a reliable biomarker of nephrotoxicity, we conducted multiplexed gene expression profiling of HPTECs after exposure to six different concentrations of nine human nephrotoxicants. Only overexpression of the gene encoding heme oxygenase-1 (HO-1) significantly correlated with increasing dose for six of the compounds, and significant HO-1 protein deregulation was confirmed with each of the nine nephrotoxicants. Translatability of HO-1 increase across species and platforms was demonstrated by computationally mining two large rat toxicogenomic databases for kidney tubular toxicity and by observing a significant increase in HO-1 after toxicity using an ex vivo three-dimensional microphysiologic system (kidneyon-a-chip). The predictive potential of HO-1 was tested using an additional panel of 39 mechanistically distinct nephrotoxic compounds. Although HO-1 performed better (area under the curve receiver-operator characteristic curve [AUC-ROC]=0.89) than traditional endpoints of cell viability (AUC-ROC for ATP=0.78; AUC-ROC for cell count=0.88), the combination of HO-1 and cell count further improved the predictive ability (AUC-ROC=0.92). We also developed and optimized a homogenous time-resolved fluorescence assay to allow high throughput quantitative screening of nephrotoxic compounds using HO-1 as a sensitive biomarker. This cell-based approach may facilitate rapid assessment of potential nephrotoxic therapeutics and environmental chemicals. Drugs and environmental chemicals, such as aminoglycoside antibiotics, analgesics, chemotherapeutic agents, and heavy metals, as well as endemic toxins like aristolochic acid are a common cause of AKI or CKD. 1,2 Current approaches to conduct safety and risk assessment of compounds rely predominantly on animal studies, and these results are extrapolated to dose effects in humans despite knowledge that the typical responses of animal models and humans can differ greatly. 3 The lack of adequate models to accurately predict human toxicity contributes to an underestimation of the kidney toxic potential of new therapeutic candidates, which also explains why nephrotoxic effects in patients are often only detected during late phase

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Section: Discussionmentioning

confidence: 99%

A Quantitative Approach to Screen for Nephrotoxic Compounds In Vitro

Adler

Ramm

Hafner

et al. 2016

Journal of the American Society of Nephrology

105

102

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“…The pathophysiology and pharmacology of this activity are well-documented, and the proposed mechanism has been described as multifactorial (69) (70) . Early studies proposed renal tubular toxicity and afferent arteriolar vasoconstriction as possible physiological factors related to AmpB-induced nephrotoxicity, but the underlying mechanistic explanation for injury remains poorly understood (71) . Inflammation plays a central role in the pathogenesis of drug-induced kidney injury.…”

Section: Optimized Nanoparticle Delivery Systems For Ampb Based On Chmentioning

confidence: 99%

New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

Chávez-Fumagalli

Ribeiro

Castilho

et al. 2015

Rev. Soc. Bras. Med. Trop.

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Leishmaniasis is one of the six major tropical diseases targeted by the World Health Organization. It is a life-threatening disease of medical, social and economic importance in endemic areas. No vaccine is yet available for human use, and chemotherapy presents several problems. Pentavalent antimonials have been the drugs of choice to treat the disease for more than six decades; however, they exhibit high toxicity and are not indicated for children, for pregnant or breastfeeding women or for chronically ill patients. Amphotericin B (AmpB) is a second-line drug, and although it has been increasingly used to treat visceral leishmaniasis (VL), its clinical use has been hampered due to its high toxicity. This review focuses on the development and in vivo usage of new delivery systems for AmpB that aim to decrease its toxicity without altering its therapeutic efficacy. These new formulations, when adjusted with regard to their production costs, may be considered new drug delivery systems that promise to improve the treatment of leishmaniasis, by reducing the side effects and the number of doses while permitting a satisfactory cost-benefit rati

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“…Prototypical ligands for TLR2 include lipoteichoic acids and lipoproteins, but this TLR seems to have a broad spectrum of ligands. As examples, nonconventional ligands, such as proteins, e.g., porin from Neisseria species (33), toxins such as seeligeriolysin O of Listeria seeligeri (25) and even amphotericin B, a polyene antifungal agent (38), were reported to activate TLR2 signaling. Second, and this is a more probable explanation, interaction between EBV and TLR2 could imply binding of a viral epitope that was hidden by the presence of antibodies to gp350/220.…”

Section: Vol 81 2007 Ebv Is Recognized By Tlr2 8021mentioning

confidence: 99%