Gliotoxin non‐selectively induces apoptosis in fibrotic and normal livers

Hagens, Werner I.; Olinga, Peter; Meijer, Dirk K. F.; Groothuis, Geny M. M.; Beljaars, Leonie; Poelstra, Klaas

doi:10.1111/j.1478-3231.2005.01212.x

Cited by 53 publications

(50 citation statements)

References 22 publications

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“…However, the activation does not seem to be complete as preincubation of the cells with endotoxin further sensitized Kupffer cells to gliotoxin-induced death. These observations contrast a recent study reporting comparable gliotoxin-induced apoptosis of Kupffer cells and HSCs in normal and cirrhotic livers (54). The reason for this discrepancy may be that liver slices were incubated for 8h with gliotoxin in vitro (54), while we and others (1,24) investigated the effect of gliotoxin in vivo.…”

Section: Discussioncontrasting

confidence: 53%

Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition

Anselmi¹,

Stolz²,

Nalesnik³

et al. 2007

Journal of Hepatology

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Section: Discussioncontrasting

confidence: 53%

Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition

Anselmi¹,

Stolz²,

Nalesnik³

et al. 2007

Journal of Hepatology

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“…Although the mechanism by which gliotoxin exhibits its toxic effects is not clear, a number of studies using commercially produced gliotoxin or crude culture filtrates have shown that exposure can have profound immunosuppressive effects on different mammalian cell types: for example, gliotoxin induces death by apoptosis in neutrophils (42), macrophages (43), and human hepatocytes (16). Gliotoxin also appears to have immunomodulatory effects on human monocytes (18), mast cells (27), and T lymphocytes (37).…”

Section: Discussionmentioning

confidence: 99%

GliZ, a Transcriptional Regulator of Gliotoxin Biosynthesis, Contributes to Aspergillus fumigatus Virulence

et al. 2006

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Gliotoxin is a nonribosomal peptide produced by Aspergillus fumigatus. This compound has been proposed as an A. fumigatus virulence factor due to its cytotoxic, genotoxic, and apoptotic properties. Recent identification of the gliotoxin gene cluster identified several genes (gli genes) likely involved in gliotoxin production, including gliZ, encoding a putative Zn 2 Cys 6 binuclear transcription factor. Replacement of gliZ with a marker gene (⌬gliZ) resulted in no detectable gliotoxin production and loss of gene expression of other gli cluster genes. Placement of multiple copies of gliZ in the genome increased gliotoxin production. Using endpoint survival data, the ⌬gliZ and a multiple-copy gliZ strain were not statistically different from the wild type in a murine pulmonary model; however, both the wild-type and the multiple-copy gliZ strain were more virulent than ⌬laeA (a mutant reduced in production of gliotoxin and other toxins). A flow-cytometric analysis of polymorphonuclear leukocytes (PMNs) exposed to supernatants from wild-type, ⌬gliZ, complemented ⌬gliZ, and ⌬laeA strains supported a role for gliotoxin in apoptotic but not necrotic PMN cell death. This may indicate that several secondary metabolites are involved in A. fumigatus virulence.Aspergillus fumigatus, a saprophytic and opportunistic pathogenic filamentous fungus, causes mycotoxicosis, allergic reactions, and a life-threatening systemic disease called "invasive aspergillosis" (IA) in immunocompromised individuals. Insufficient defense mechanisms by the innate and acquired immune systems result in high IA mortality rates in neutropenic and immunosuppressed patients. The incidence of IA has increased in recent decades, largely due to an increased population of immunosuppressed patients at risk after organ transplantation or therapy for cancer. In spite of advances in early diagnosis and new antifungal therapy, IA continues to be a leading cause of death in these patients, with mortality rates reported to be as high as 80% to 95% (11).A. fumigatus virulence attributes contributing to IA are not likely to be due to a single factor but rather a combination of interactions of various molecules and biological properties of the fungus (22,32,40). Growth characteristics such as its high spore concentration in the air and its faster growth relative to any other airborne fungi at 40°C are thought to contribute to its virulence (22, 39). However, identification of unique, singlemolecule, virulence factors has been elusive in this system. One molecule hypothesized as a unique virulence factor is the secondary metabolite gliotoxin.Gliotoxin is a well-studied nonribosomal peptide toxin (14) and has long been fingered as a putative factor contributing to IA due to its cytotoxic (15), genotoxic (26), and apoptotic properties (21,29,38). A potential role for gliotoxin in IA was recently supported by genetic studies of an A. fumigatus secondary metabolite mutant, ⌬laeA, which was shown to be crippled in gliotoxin biosynthesis (5, 6). The loss of laeA in A. fumig...

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“…With continued refinements, however, liver slices again offer some unique advantages (664,668) and have more recently been used to test drug targeting methods (410,411), antifibrotic therapies (224), and cell fate during injury and repair following exposure to hepatotoxins (221). The slice technology can be complemented with either real-time PCR for stellate cell-specific genes (665) or laser-capture microdissection to enrich for stellate cells recovered from within the slice.…”

Section: Other Models: Liver Slices In Vivo Methodsmentioning

confidence: 99%

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Friedman

2008

Physiological Reviews

2,419

2,549

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The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Gliotoxin non‐selectively induces apoptosis in fibrotic and normal livers

Abstract: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.

Cited by 53 publications

References 22 publications

Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition

Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: Exacerbation by caspase and serine protease inhibition

GliZ, a Transcriptional Regulator of Gliotoxin Biosynthesis, Contributes to Aspergillus fumigatus Virulence

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

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