Optogenetic Manipulation of Olfactory Responses in Transgenic Zebrafish: A Neurobiological and Behavioral Study

Olfaction is an important neural system for survival and fundamental behaviors such as predator avoidance, food finding, memory formation, reproduction, and social communication. However, the neural circuits and pathways associated with the olfactory system in various behaviors are not fully understood. Recent advances in optogenetics, high-resolution in vivo imaging, and reconstructions of neuronal circuits have created new opportunities to understand such neural circuits. Here, we generated a transgenic zebrafish to manipulate olfactory signal optically, expressing the Channelrhodopsin (ChR2) under the control of the olfactory specific promoter, omp. We observed light-induced neuronal activity of olfactory system in the transgenic fish by examining c-fos expression, and a calcium indicator suggesting that blue light stimulation caused activation of olfactory neurons in a non-invasive manner. To examine whether the photo-activation of olfactory sensory neurons affect behavior of zebrafish larvae, we devised a behavioral choice paradigm and tested how zebrafish larvae choose between two conflicting sensory cues, an aversive odor or the naturally preferred phototaxis. We found that when the conflicting cues (the preferred light and aversive odor) were presented together simultaneously, zebrafish larvae swam away from the aversive odor. However, the transgenic fish with photo-activation were insensitive to the aversive odor and exhibited olfactory desensitization upon optical stimulation of ChR2. These results show that an aversive olfactory stimulus can override phototaxis, and that olfaction is important in decision making in zebrafish. This new transgenic model will be useful for the analysis of olfaction related behaviors and for the dissection of underlying neural circuits.

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P0053A METHOD FOR THE ISOLATION OF FLUORESCENT GLOMERULI FROM ZEBRAFISH LARVAE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0053 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Anna Iervolino ◽

Tim Lange ◽

Florian Siegerist ◽

Maximilian Schindler ◽

Giovambattista Capasso ◽

...

Keyword(s):

Glomerular Filtration ◽

Fluorescent Protein ◽

Transgenic Zebrafish ◽

Renal Tubules ◽

Glomerular Filtration Barrier ◽

Podocyte Injury ◽

Zebrafish Larvae ◽

Filtration Barrier ◽

Glomerular Damage

Abstract Background and Aims The zebrafish is a powerful animal model to study the glomerular morphology and the function of the permselectivity of the glomerular filtration barrier. Since zebrafish larvae develop quickly and can be bred to transparency, in vivo observation of these animals is possible. At 48 hours post fertilization (dpf), zebrafish develop a single filtering glomerulus which is attached to a pair of renal tubules. Like in mammals, the glomerular filtration barrier consists of a fenestrated endothelium, the glomerular basement membrane (GBM) and interdigitating podocyte foot processes bridged by a molecularly conserved slit diaphragm. By the use of genetically modified zebrafish strains with fluorescently labeled podocytes, it is possible to study alterations of the glomerulus during the development of renal disease directly in vivo and in vitro. As an injury model we used the nitroreductase/metronidazole (NTR/MTZ) zebrafish line to induce podocyte apoptosis and detachment from the GBM. Moreover, treatment of these larvae with MTZ induces glomerular injury that mimics focal segmental glomerulosclerosis (FSGS). The aim of our study was to establish a glomeruli isolation method which allows us to identify deregulation of miRNAs and mRNAs in the injured glomeruli by sequencing. Method The transgenic zebrafish strain Cherry (Tg(nphs2:Eco.nfsB-mCherry); mitfaw2/w2; mpv17a9/a9) which expresses the prokaryotic enzyme nitroreductase (NTR) fused to mCherry, a red fluorescent protein, under the control of the podocyte-specific podocin (nphs2) promoter in a transparent zebrafish strain, was used. The NTR/MTZ is a model of cell ablation to mimic podocyte injury. The prodrug MTZ (80 µM) is converted into a cytotoxin by NTR leading to a dose-dependent apoptosis exclusively in NTR-expressing podocytes. To induce podocyte injury, we treated Cherry larvae at 4 days post fertilization with MTZ (80 µM) freshly dissolved in 0.1% DMSO-E3 medium for 48 hours. Control larvae were treated with 0.1% DMSO-E3 medium. The treatment was stopped by a MTZ washout at 6 dpf. In order to perform the miRNA and mRNA sequencing on glomeruli isolated from MTZ-treated and control larvae we tried to establish a method to obtain total RNA samples of good quality. For this purpose, three different approaches were tested and validated: 1) Sieving method, 2) Fluorescence-Activated Cell Sorting method (FACS), and 3) manual isolation of glomeruli by using a micropipette. Results Zebrafish larvae developed a glomerular damage similar to FSGS after MTZ-treatment. MTZ-treated larvae showed severe pericardial edema, a reduction of the nephrin and podocin expression, proteinuria and an increased mortality rate at 8 dpf. After many tests we showed that glomeruli isolation using the sieving method and FACS were not efficient due to contaminations with other organs (sieving) and a loss of a large amount of cells per sample (FACS), respectively. Samples of the required quality for sequencing resulted only from the manual glomeruli isolation. Conclusion Here we describe methods to isolate fluorescent glomeruli from transgenic zebrafish larvae. For our studies, we used the NTZ/MTR kidney disease model in order to identify mRNAs and miRNAs regulated in response to glomerular damage. This technique will further allow to screen for healing drugs in high-throughput experiments.

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The CXCL12/CXCR4 signalling axis retains neutrophils at inflammatory sites in zebrafish

10.1101/626978 ◽

2019 ◽

Cited By ~ 3

Author(s):

Hannah M. Isles ◽

Kimberly Herman ◽

Anne L. Robertson ◽

Catherine A. Loynes ◽

Lynne R. Prince ◽

...

Keyword(s):

Inflammatory Disease ◽

Tissue Damage ◽

Tissue Injury ◽

Transgenic Zebrafish ◽

Sequencing Data ◽

Cxcr4 Antagonist ◽

Reverse Migration ◽

Zebrafish Larvae ◽

Inflammation Resolution

AbstractThe inappropriate retention of neutrophils in the lung is a major driver of the excessive tissue damage characteristic of respiratory inflammatory diseases including COPD, ARDS and cystic fibrosis. The molecular programmes which orchestrate neutrophil recruitment to inflammatory sites through chemotactic guidance have been well studied. However, how neutrophil sensitivity to these cues is modulated during inflammation resolution is not understood. The identification of neutrophil reverse migration as a mechanism of inflammation resolution and the ability to modulate this therapeutically has identified a new target to treat inflammatory disease. Here we investigate the role of the CXCL12/CXCR4 signalling axis in modulating neutrophil retention at inflammatory sites. We used an in vivo tissue injury model to study inflammation using transgenic zebrafish larvae. Expression of cxcl12a and cxcr4b during the tissue damage response was assessed using in situ hybridisation and analysis of RNA sequencing data. CRISPR/Cas9 was used to knockdown cxcl12a and cxcr4b in zebrafish larvae. The CXCR4 antagonist AMD3100 was used to block the Cxcl12/Cxcr4 signalling axis pharmacologically. We identified that cxcr4b and cxcl12a are expressed at the wound site in zebrafish larvae during the inflammatory response. Following tail-fin transection, removal of neutrophils from inflammatory sites is significantly increased in cxcr4b and cxcl12a CRISPR knockdown larvae. Pharmacological inhibition of the Cxcl12/Cxcr4 signalling axis accelerates inflammation resolution, an effect caused by an increase in neutrophil reverse migration. The findings of this study suggest that CXCR4/CXCL12 signalling may play an important role in neutrophil retention at inflammatory sites, identifying a potential new target for the therapeutic removal of neutrophils from the lung in chronic inflammatory disease.

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MO030IDENTIFICATION OF REGULATED MRNAS AND MIRNAS IN GLOMERULI ISOLATED FROM AN FSGS-LIKE ZEBRAFISH MODEL

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab080.002 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Anna Iervolino ◽

Tim Lange ◽

Sabrina Siccardi ◽

Florian Siegerist ◽

Francesca Pia Caruso ◽

...

Keyword(s):

Glomerular Filtration ◽

Slit Diaphragm ◽

Whole Body ◽

Transgenic Zebrafish ◽

Glomerular Filtration Barrier ◽

Zebrafish Larvae ◽

Filtration Barrier ◽

Podocyte Detachment ◽

Go Terms

Abstract Background and Aims The zebrafish (Danio rerio) is a powerful animal model to study glomerular morphology and the function of the permselectivity of the glomerular filtration barrier. Since zebrafish larvae develop quickly and can be bred to become transparent, in vivo observation of these animals is possible. At 48 hours post fertilization, zebrafish larvae develop a single glomerulus which is attached to a pair of tubules. Like in mammals, the glomerular filtration barrier consists of a fenestrated endothelium, the glomerular basement membrane and interdigitating podocyte foot processes bridged by a slit diaphragm. By using genetically modified zebrafish strains with fluorescently labeled podocytes, it is possible to study alterations of the glomerulus during the development of renal disease like focal segmental glomerulosclerosis (FSGS) directly in vivo. FSGS is characterized by podocyte loss, the effacement of their foot processes as well as scarring of the glomerulus. To study FSGS in zebrafish larvae, we induced podocyte detachment by the use of a zebrafish strain expressing the enzyme nitroreductase converting metronidazole into a toxic substance specifically in podocytes. The aim of our study was to collect glomeruli for the identification of mRNAs as well as miRNAs by RNA_Seq that are up- and down-regulated in the glomeruli of this FSGS-like disease model. Method The transgenic zebrafish strain Cherry (Tg(nphs2:GAL4); Tg(UAS:Eco.nfsB-mCherry); mitfaw2/w2; mpv17a9/a9) which expresses the prokaryotic enzyme nitroreductase (NTR) fused to mCherry, a red fluorescent protein, under the control of the podocyte-specific podocin (nphs2) promoter in a transparent zebrafish strain, was utilized. After addition of metronidazole (MTZ) into the tank water, MTZ is converted into a cytotoxin by NTR leading to dose-dependent apoptosis exclusively in podocytes. Cherry larvae were treated at 4 days post fertilization (dpf) for 48 h with 80 µM MTZ. MTZ-treated and control larvae were homogenized at 6 dpf. The cell suspension was diluted, and red-fluorescent glomeruli were collected using a micropipette and a microscope. Total RNA was isolated, and integrity was checked by a Bioanalyzer. Libraries were generated with a MACE kit and True Quant small RNA seq kit by GenXPro. Constructs were amplified by PCR and sequenced on an Illumina Hiseq 2000. Normalization and statistical analysis for differential gene expression were done using DESeq2. Results Zebrafish larvae showed severe whole-body edema, proteinuria, loss of podocytes and an increased mortality rate after MTZ-treatment. The glomerular histology resembled mammalian FSGS. We found that only the RNA of manually collected glomeruli had an excellent quality. Using RNA_Seq, we identified a total of 16941 genes. DESeq2 analysis showed 494 up-regulated and 473 down-regulated genes. Gene ontology (GO) enrichment analysis of up-regulated genes revealed a total of 167 that are significantly enriched in GO terms (e.g. metabolic processes, immune response and ion transport). Down-regulated genes were enriched in 14 GO terms and most of them are linked to normal glomerular function and the slit diaphragm. DESeq2 analysis identified 200 miRNAs of 777 small RNAs. Some of these miRNA are already described to be regulated in different glomerular diseases like FSGS, lupus nephritis, IgA nephropathy and diabetic nephropathy. Conclusion We analyzed isolated glomeruli from transgenic zebrafish larvae that developed a FSGS-like disease. By sequencing, we have found mRNAs and miRNAs that were significantly regulated after the onset of disease. Detailed knowledge of these mRNAs and miRNA-based gene regulation will help to uncover the pathomechanism as well as to develop therapeutics for the treatment of FSGS.

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SELECTIVE INHIBITION OF KRAS SIGNALING BY COMBINATION OF LOW DOSE RAPAMYCIN AND PACLITAXEL IN VIVO

Advances in molecular oncology ◽

10.17650/2313-805x-2018-5-2-42-49 ◽

2018 ◽

Vol 5 (2) ◽

pp. 42-49

Author(s):

M. N. Yurova ◽

D. R. Safina ◽

I. V. Mizgirev

Keyword(s):

Signaling Pathway ◽

Fluorescent Protein ◽

Combined Treatment ◽

Transgenic Fish ◽

Selective Inhibition ◽

Epidermal Cells ◽

Transgenic Zebrafish ◽

Dependent Manner ◽

Green Fluorescent

Background.Therapy with compounds potentially capable to block KRAS oncogene signaling pathway is perspective direction in modern oncopharmacology. The aim of current study was to investigate effects of the combined treatment with rapamycin (RAP) and paclitaxel (PAC) in transgenic zebrafish (Danio rerio) with constant expression of mutant KRASV12 oncogene conjugated to green fluorescent protein (GFP) in epidermal cells. This strain has a modified phenotype due to epidermal hyperplasia and expression of GFP reporter at skin of embryos and adult fish.Materials and methods.Fish embryos 6 hpf were exposed to 0.1 % DMSO solution (control) and various doses of the drugs or combinations thereof. GFP expression in epidermal cells was morphometrically measured at 72 hpf.Results.Dose-related decrease in phenotypic changes up to complete epidermal normalization under RAP 50–400 nM treatment was observed. Treatment with nontoxic for embryos doses of PAC 50–250 nM increased fluorescence level in a dose-dependent manner, indicating an activation of KRAS signaling. Using of lower doses of RAP (10 and 25 nM) or PAC (10 nM) had no statistically significant effect on expression of transformed phenotype. Whereas combined treatment (RAP 10–25 nM and PAC 10–50 nM) dramatically decreased level of epidermal fluorescence and completely normalized phenotype of transgenic fish.Conclusions.Thus, mutual potentiating effect of RAP and PAC in low doses which leads to selective inhibition of the KRAS signaling pathway was revealed, indicating the prospect of further studies of these drugs combination for targeted cancer therapy.

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In vivo assay of cortical microcircuitry in frontotemporal dementia: a platform for experimental medicine studies

10.1101/416388 ◽

2018 ◽

Cited By ~ 1

Author(s):

Alexander D Shaw ◽

Laura E Hughes ◽

Rosalyn Moran ◽

Ian Coyle-Gilchrist ◽

Tim Rittman ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Neural Circuits ◽

Case Control ◽

Experimental Medicine ◽

Non Invasive ◽

Cortical Responses ◽

Sensory Predictions ◽

Local Coupling ◽

Laminar Specificity

AbstractThe analysis of neural circuits can provide critical insights into the mechanisms of neurodegeneration and dementias, and offer potential quantitative biological tools to assess novel therapeutics. Here we use behavioural variant frontotemporal dementia (bvFTD) as a model disease. We demonstrate that inversion of canonical microcircuit models to non-invasive human magnetoecphalography can identify the regional- and laminar-specificity of bvFTD pathophysiology, and their parameters can accurately differentiate patients from matched healthy controls. Using such models, we show that changes in local coupling in frontotemporal dementia underlie the failure to adequately establish sensory predictions, leading to altered prediction error responses in a cortical information-processing hierarchy. Using machine learning, this model-based approach provided greater case-control classification accuracy than conventional evoked cortical responses. We suggest that this approach provides an in vivo platform for testing mechanistic hypotheses about disease progression and pharmacotherapeutics.

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Live cell imaging of Salmonella Typhimurium interaction with zebrafish larvae after injection and immersion delivery methods

10.7287/peerj.preprints.2319 ◽

2016 ◽

Author(s):

Macarena A Varas ◽

Alonso Fariña ◽

Francisco Díaz-Pascual ◽

Javiera Ortíz-Severín ◽

Andrés E Marcoleta ◽

...

Keyword(s):

Immune Response ◽

Bacterial Infections ◽

Inoculum Size ◽

Live Cell ◽

Transgenic Zebrafish ◽

Human Pathogens ◽

Zebrafish Model ◽

Zebrafish Larvae ◽

Serovar Typhimurium

Surrogate host models have been employed to study bacterial virulence mechanisms of important human pathogens. Particularly, zebrafish (Danio rerio) has been used to determine the role of vertebrate innate immunity during bacterial infections. The easy-to-obtain large number of embryos and optical transparency of larvae allow live cell imaging of the infection progress and the major cellular types of the innate immune system that develop during the first days of embryogenesis. In zebrafish model, microinjecting bacteria into embryos and/or larvae can cause infection. Alternatively, an infection can be generated by static immersion of larvae on a microbial suspension. Both methods differ in the mode and time of infection, inoculum size and host response. In this work, we compare the in vivo immune response induced by Salmonella enterica serovar Typhimurium (S. Typhimurium) inoculated by immersion and microinjection in zebrafish larvae. To this end, an immersion protocol using transgenic zebrafish larvae was developed for in vivo monitoring of GFP-tagged S. Typhimurium infection progress and immune response during 72 h. The infection progress was compared to that of zebrafish larvae inoculated by microinjection. Our results in zebrafish corroborate previous Salmonella virulence studies in murine models and reveal that host-pathogen interaction not only depends on the virulence of the strain, but also on the inoculation method and host conditions.

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Zebrafish model of amyloid light chain cardiotoxicity: regeneration versus degeneration

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00788.2018 ◽

2019 ◽

Vol 316 (5) ◽

pp. H1158-H1166 ◽

Cited By ~ 6

Author(s):

Shikha Mishra ◽

Shaurya Joshi ◽

Jennifer E. Ward ◽

Eva P. Buys ◽

Deepak Mishra ◽

...

Keyword(s):

Light Chain ◽

Cardiac Dysfunction ◽

Transgenic Fish ◽

Control Fish ◽

Transgenic Zebrafish ◽

Al Amyloidosis ◽

Zebrafish Model ◽

Disease Mechanisms ◽

Amyloid Light Chain

Cardiac dysfunction is the most frequent cause of morbidity and mortality in amyloid light chain (AL) amyloidosis caused by a clonal immunoglobulin light chain (LC). Previously published transgenic animal models of AL amyloidosis have not recapitulated the key phenotype of cardiac dysfunction seen in AL amyloidosis, which has limited our understanding of the disease mechanisms in vivo, as well as the development of targeted AL therapeutics. We have developed a transgenic zebrafish model in which a λ LC derived from a patient with AL amyloidosis is conditionally expressed in the liver under the control of the Gal4 upstream activation sequence enhancer system. Circulating LC levels of 125 µg/ml in these transgenic zebrafish are comparable to median pathological serum LC levels. Functional analysis links abnormal contractile function with evidence of cellular and molecular proteotoxicity in the heart, including increased cell death and autophagy. However, despite pathological and functional phenotypes analogous to human AL, the lifespan of the transgenic fish is comparable to control fish without the expressed AL-LC transgene. Nuclear labeling experiments suggest increased cardiac proliferation in the transgenic fish, which can be counteracted by treatment with a small molecule proliferation inhibitor leading to increased zebrafish mortality because of cardiac apoptosis and functional deterioration. This transgenic zebrafish model provides a platform to study underlying AL disease mechanisms in vivo further.NEW & NOTEWORTHY Heart failure is a major cause of mortality in amyloid light (AL) amyloidosis, yet it has been difficult to model in animals. We report the generation of a transgenic zebrafish model for AL amyloidosis with pathological concentration of circulating human light chain protein that results in cardiac dysfunction. The light chain toxicity triggers regeneration in the zebrafish heart resulting in functional compensation early in life, but with age develops into cardiac dysfunction.

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A study of somatolactin actions by ectopic expression in transgenic zebrafish larvae

Journal of Molecular Endocrinology ◽

10.1677/jme-09-0173 ◽

2010 ◽

Vol 45 (5) ◽

pp. 301-315 ◽

Cited By ~ 11

Author(s):

Guohui Wan ◽

King Ming Chan

Keyword(s):

Fatty Acid Synthase ◽

Fluorescent Protein ◽

Regulatory Element ◽

Ectopic Expression ◽

Gene Promoter ◽

Transgenic Fish ◽

Fish Growth ◽

Marker Genes ◽

Transgenic Zebrafish

Somatolactin (SL) is a fish-specific hormone that belongs to the prolactin (PRL) and GH family. Recently, two forms of SL, SLα and SLβ, have been found in some species, and may have different actions and functions. To investigate the role of SL in fish growth and metabolism, we generated transgenic fish founders with ectopic expression of SLα and SLβ to study the physiological functions and actions of these SLs among several marker genes. We fused the cDNAs encoding the precursor SLs in frame to a zebrafish β-actin gene promoter to generate transgenic zebrafish lines that were coinjected with a green fluorescent protein (GFP) driven by the same promoter. The transgenic zebrafish were selected based on GFP expression and confirmed by genomic PCR, Southern blot analysis, and transgene expression. Investigations into the expression of marker genes in larvae on different pathways using real-time PCR have provided a general understanding of the actions of SLs. This study found that the overexpression of SLα and SLβ in vivo significantly enhanced the transcription of IGFs, insulin, leptin, sterol regulatory element binding protein 1, and fatty acid synthase, as well as the expression level of vitellogenin and proopiomelanocortin, while causing reduced levels of catalase and glutathione S-transferase in the larvae of transgenic zebrafish.

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Suppression of apoptosis by bcl-2 overexpression in lymphoid cells of transgenic zebrafish

Blood ◽

10.1182/blood-2004-08-3073 ◽

2005 ◽

Vol 105 (8) ◽

pp. 3278-3285 ◽

Cited By ~ 74

Author(s):

David M. Langenau ◽

Cicely Jette ◽

Stephane Berghmans ◽

Teresa Palomero ◽

John P. Kanki ◽

...

Keyword(s):

Apoptotic Cell ◽

Microscopic Analysis ◽

Green Fluorescence Protein ◽

Transgenic Fish ◽

Fold Increase ◽

Lymphoid Cells ◽

Transgenic Zebrafish ◽

Zebrafish Model ◽

Induced Apoptosis

AbstractThe zebrafish is an attractive vertebrate model for genetic studies of development, apoptosis, and cancer. Here we describe a transgenic zebrafish line in which T- and B-lymphoid cells express a fusion transgene that encodes the zebrafish bcl-2 protein fused to the enhanced green fluorescence protein (EGFP). Targeting EGFP-bcl-2 to the developing thymocytes of transgenic fish resulted in a 2.5-fold increase in thymocyte numbers and a 1.8-fold increase in GFP-labeled B cells in the kidney marrow. Fluorescent microscopic analysis of living rag2-EGFP-bcl-2 transgenic fish showed that their thymocytes were resistant to irradiation- and dexamethasone-induced apoptosis, when compared with control rag2-GFP transgenic zebrafish. To test the ability of bcl-2 to block irradiation-induced apoptosis in malignant cells, we compared the responsiveness of Myc-induced leukemias with and without EGFP-bcl-2 expression in living transgenic zebrafish. T-cell leukemias induced by the rag2-EGFP-Myc transgene were ablated by irradiation, whereas leukemias in double transgenic fish expressing both Myc and EGFP-bcl-2 were resistant to irradiation-induced apoptotic cell death. The forward genetic capacity of the zebrafish model system and the ability to monitor GFP-positive thymocytes in vivo make this an ideal transgenic line for modifier screens designed to identify genetic mutations or small molecules that modify bcl-2-mediated antiapoptotic pathways. (Blood. 2005;105:3278-3285)

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A transgenic zebrafish model of neutrophilic inflammation

Blood ◽

10.1182/blood-2006-05-024075 ◽

2006 ◽

Vol 108 (13) ◽

pp. 3976-3978 ◽

Cited By ~ 548

Author(s):

Stephen A. Renshaw ◽

Catherine A. Loynes ◽

Daniel M.I. Trushell ◽

Stone Elworthy ◽

Philip W. Ingham ◽

...

Keyword(s):

Time Course ◽

Digital Image Analysis ◽

Experimental Manipulation ◽

In Vivo Model ◽

Transgenic Zebrafish ◽

Zebrafish Model ◽

Similar Time ◽

Zebrafish Larvae ◽

Fluorescent Cells

Abstract We have established an in vivo model for genetic analysis of the inflammatory response by generating a transgenic zebrafish line that expresses GFP under the neutrophil-specific myeloperoxidase promoter. We show that inflammation is induced after transection of the tail of zebrafish larvae and that this inflammation subsequently resolves over a similar time course to mammalian systems. Quantitative data can be generated from this model by counting of fluorescent cells or by digital image analysis. In addition, we show that the resolution of experimentally induced inflammation can be inhibited by the addition of a pancaspase inhibitor, zVD.fmk, demonstrating that experimental manipulation of the resolution of inflammation is possible in this model.

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