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    Re: Rand & Miller~Inflammation From Fungi~Toxins

    Posted by Mike B. on 12/28/09

    Do you have mouse lungs? If not, this is not applicable to

    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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