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    Re: Rand & Miller~Inflammation From Fungi~Toxins

    Posted by Deborah on 12/28/09

    I heard Mighty Mouse is looking for you.....drop enough cheese
    and you might get some stalwart sidekicks until the chips are down.

    On 12/28/09, Mike B. wrote:
    > Do you have mouse lungs? If not, this is not applicable to
    > humans.
    > On 12/23/09, Sharon wrote:
    >> Arch Toxicol. 2009 Nov 11. [Epub ahead of print]
    >> Dectin-1 and inflammation-associated gene transcription and
    >> expression in mouse lungs by a toxic (1,3)-beta-D: glucan.
    >> Rand TG, Sun M, Gilyan A, Downey J, Miller JD.
    >> Department of Biology, Saint Mary's University, 923 Robie
    >> St., Halifax, NS, B3H 3C3, Canada,
    >> The form of (1-3)-beta-D: glucan found in the cell walls of
    >> the anamorphic Trichocomaceae that grow on damp building
    >> materials is considered to have potent toxic and
    >> inflammatory effects on cells of the respiratory system. It
    >> is also considered to have a potential role in the
    >> development of non-allergenic respiratory health effects.
    >> While human studies involving experimental exposures all
    >> point to the inflammatory potential of pure curdlan, a
    >> linear (1-3)-beta-D: glucan in a triple helix
    >> configuration, animal experiments result in conflicting
    >> conclusions concerning the inflammatory potency of this
    >> glucan. However, because mice appear to be a better model
    >> than guinea pigs for exploring the respiratory effects of
    >> curdlan and because molecular mechanisms associated with
    >> this glucan remain largely unknown, we conducted further
    >> work to clarify the role of curdlan on the inflammatory
    >> response using our mouse model of lung disease. This study
    >> used in situ hybridization (ISH) to probe dectin-1 mRNA
    >> transcription with a digoxigenin-labeled cDNA probe, with
    >> reverse transcription (RT)-PCR based arrays used to measure
    >> inflammation gene and receptor transcriptional responses.
    >> Also, immunohistochemistry (IHC) was used to probe dectin-1
    >> as well as anti-mouse Ccl3, Il1-alpha, and TNF-alpha
    >> expression to evaluate dose and time-course (4 and 12 h)
    >> postexposure (PE) response patterns in the lungs of
    >> intratracheally instilled mice exposed to a single 50 mul
    >> dose of curdlan at 10(-7), 10(-8), 10(-9), and 10(-10)
    >> M/animal (=4 mug to 4 ng curdlan/kg lung wt). Dectin-1 mRNA
    >> transcription and expression was observed in bronchiolar
    >> epithelium, alveolar macrophages (AMs), and alveolar type
    >> II cells (ATIIs) of lungs exposed to 4 mug to 40 ng
    >> curdlan/kg lung wt, at both time points. Compared to
    >> controls, array analysis revealed that 54 of 83 genes
    >> assayed were significantly modulated by curdlan. mRNA
    >> transcription patterns showed both dose and time
    >> dependency, with highest transcription levels in 10(-7) and
    >> 10(-8) M treatment animals, especially at 4-h PE. Nine gene
    >> mRNA transcripts (Ccl3, Ccl11, Ccl17, Ifng, Il1alpha, Il-
    >> 20, TNF-alpha, Tnfrsf1b, and CD40lg) were significantly
    >> expressed at all doses suggesting they may have a central
    >> role in immunomodulating curdlan exposures. IHC revealed
    >> Ccl3, Il1-alpha, and TNF-alpha expression in bronchiolar
    >> epithelium, AMs and ATIIs illustrate the important
    >> immunomodulatory role that these cells have in the
    >> recognition of, and response to glucan. Collectively, these
    >> results confirm the inflammatory nature of curdlan and
    >> demonstrate the complex of inflammation-associated gene
    >> responses induced by (1-3)-beta-D: glucan in triple helical
    >> forms. These observations also provide a biological basis
    >> for the irritant and inflammatory response to curdlan
    >> observed in humans and animals in experimental studies.
    >> Chem Biol Interact. 2010 Jan 5;183(1):113-24.
    >> Inflammation-associated gene transcription and expression
    >> in mouse lungs induced by low molecular weight compounds
    >> from fungi from the built environment.
    >> Miller JD, Sun M, Gilyan A, Roy J, Rand TG.
    >> Department of Chemistry, Carleton University, Ottawa,
    >> Ontario, Canada K1S 5B6.
    >> Few metabolites from fungi found indoors have been tested
    >> for inflammatory mediators endpoints in primary cultures of
    >> alveolar macrophages or in vivo. In this study, mice were
    >> intratracheally instilled with a single dose comprising 4x10
    >> (-5)moletoxin/kg lung wt dose of either atranone C,
    >> brevianamide, cladosporin, mycophenolic acid, neoechinulin
    >> A & B, sterigmatocystin or TMC-120A. These toxins are from
    >> fungi common on damp building materials. The dose used was
    >> comparable to the estimated doses of possible human
    >> exposure. Hematoxylin and eosin (H&E) histology and Alcian
    >> Blue/Periodic Acid Schiff (AB/PAS) histochemistry were used
    >> to evaluate lungs for time course (4h and 12h post-exposure
    >> (PE)) inflammatory and toxic changes. Reverse-transcription
    >> (RT)-PCR based arrays were also employed to evaluate time
    >> course inflammation-associated gene transcription in lung
    >> tissues of the different toxins. Immunohistochemistry (IHC)
    >> was used to probe MIP-2 and Tnf-alpha protein expression in
    >> treatment lungs to determine whether responses correspond
    >> with gene transcription data. Both histology and
    >> histochemistry revealed that toxin exposed lungs at 12h PE
    >> showed evidence of inflammation. H&E revealed that
    >> bronchioli were lined with irregularly thickened and
    >> sometimes sloughing epithelium and bronchiolar spaces
    >> supported infiltration of leukocytes, cellular and mucus-
    >> like debris while alveolar spaces supported swollen
    >> macrophages and modest amorphous debris accumulations. All
    >> toxin-instilled lungs exhibited copious mucus production
    >> and alveolar macrophages with red stained cytoplasm on
    >> bronchiolar surfaces, especially at 12h PE. Array analysis
    >> of 83 inflammation-associated genes extracted from lung
    >> tissue demonstrated a number of patterns, compared to
    >> controls. 82 genes assayed at 4h PE and 75 genes at 12h PE
    >> were significantly altered (p< or =0.05; >or =1.5-fold or <
    >> or =-1.5-fold change) in the different treatment animal
    >> groups. Expression of transcriptionally regulated genes was
    >> confirmed using immunohistochemistry that demonstrated MIP-
    >> 2 and Tnf-alpha staining in respiratory bronchiolar
    >> epithelia, alveolar macrophages and alveolar type II cells.
    >> The transcriptional regulation in these genes in the
    >> treatment groups suggests that they may serve central roles
    >> in the immunomodulation of toxin-induced pro-inflammatory
    >> lung responses. Hierarchical cluster analysis revealed
    >> significant patterns of gene transcription linking the
    >> response of the toxins at equimolar doses in three groups:
    >> (1) brevianamide, mycophenolic acid and neoechinulin B, (2)
    >> neoechinulin A and sterigmatocystin, and (3) cladosporin,
    >> atranone C and TMC-120. The results further confirm the
    >> inflammatory nature of metabolites/toxins from such fungi
    >> can contribute to the development of non-allergenic
    >> respiratory health effects

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