Inflammatory and Cytotoxic Responses in Mouse Lungs Exposed to Purified Toxins f

[Guest guest]

The link does work and there is much more to this report (22 pages)

originally published online on June 15, 2005

Inflammatory and Cytotoxic Responses in Mouse Lungs Exposed to

Purified Toxins from Building Isolated

http://toxsci.oxfordjournals.org/cgi/content/full/87/1/213

In vitro and in vivo studies have shown that building-associated

Penicillium spores and spore extracts can induce significant

inflammatory responses in lung cells and animal models of lung

disease. However, because spores and spore extracts comprise

mixtures of bioactive constituents often including toxins, it is

impossible to resolve which constituent mediates inflammatory

responses. This study examined dose-response (0.5 nM, 2.5 nM, 5.0

nM, 12.5 nM/g body weight (BW) animal) and time-course (3, 6, 24 and

48 h post instillation (PI)) relationships associated with

inflammatory and cytotoxic responses in mouse lungs intratracheally

instilled with pure brevianamide A, mycophenolic acid, and

roquefortine C. High doses (5.0 nM and/or 12.5 nM/g BW animal) of

brevianamide A and mycophenolic acid, the dominant metabolites of P.

brevicompactum, and roquefortine C, the dominant metabolite of P.

chrysogenum, induced significant inflammatory responses within 6 h

PI, expressed as differentially elevated macrophage, neutrophil, MIP-

2, TNF, and IL-6 concentrations in the bronchioalveolar lavage fluid

(BALF) of intratracheally exposed mice. Macrophage and neutrophil

numbers were maximal at 24 h PI; responses of the other inflammatory

markers were maximal at 6 h PI. Except for macrophage numbers in

mycophenolic acid–treatment animals, cells exhibited significant

dose-dependent-like responses; for the chemo-/cytokine markers, dose

dependency was lacking except for MIP-2 concentration in

brevianamide A–treatment animals. It was also found that

brevianamide A induced cytotoxicity expressed as significantly

increased LDH concentration in mouse BALF, at concentrations of 12.5

nM/g BW animal and at 6 and 24 h PI. Albumin concentrations,

measured as a nonspecific marker of vascular leakage, were

significantly elevated in the BALF of mice treated with 12.5 nM/g nM

brevianamide A/animal from 6 to 24 h PI and in 5.0 nM/g

mycophenolic acid–treated animals at 6 to 24 h PI. These results

suggest that these three toxins from Penicillium species common on

damp materials in residential housing provoke compound-specific

toxic responses with different toxicokinetics. Moreover, that these

toxins can stimulate significant inflammatory responses in vivo

might help explain some of the indoor effects associated with

Penicillium spore exposures in indoor environments.