Endotoxins are lipopolysaccharide (LPS) complexes of the outer cell wall of gram-negative bacteria, usually pathogens such as E. coli, Salmonella, Shigella and Pseudomonas, etc.
The LPS are maintained within the outer cell wall until autolysis of the bacteria which releases them into the surrounding environment. They are pyrogenic (fever producing), antigenic and cause inflammation through the activation of the complement system via CD14 protein, the TLR4-signaling pathway and release of inflammatory cytokines, e.g., TNF-a. CD14 protein binds LPS and transfers them to the TLR4 receptor.
Clinical or experimental outcome include fever, leukopenia, hypoglycemia, hypotension, impaired perfusion of essential organs (brain, heart, kidney), activation of C3 and the complement cascade, bleeding, intravascular coagulation, septic shock and death.
In addition, LPS also causes an increased production of the long pentraxin PTX3 (Cunningham et al, 2005; Imamura et al, 2007) and in the maturation of dendritic cells evoking Th1 and Th17 responses (Iwamoto et al, 2007).
LPS are present in the indoor environment of normal and water-damaged homes and buildings (Douwes et al, 2006; Gorny, 2004; Gorny et al, 2002; Park et al, 2000, 2006; Rao et al, 2007b).
In transgenic mouse models, endotoxins interact with the TLR4-signaling pathway, CD14 phenotype, TNF-a and other factors leading to increased airway inflammation (Jung et al, 2006; Martinez, 2007a,b; Togbe et al, 2007).
In addition, in vitro and in vivo animal models of neurological diseases have shown that intra-peritoneal (i.p.), i.v. and intracerebral administration cause expression of pro-inflammatory markers of microglia (Qin et al, 2004), as well as the induction of oligodendrocyte injury via TLR4 (Lehnardt et al, 2002).
Intracerebral or systemic administration of endotoxin exacerbates microglial inflammatory response and increases neuronal cell death in ME7 prion mouse model (Cunningham et al, 2005).
Moreover, systemic inflammation (e.g., infectious states) appears to be involved in chronic neurodegenerative disease (e.g., Alzheimer, Parkinson). The increased synthesis of inflammatory cytokines and other mediators during infections and/or systemic LPS challenge promote an inflammatory
response that may contribute to the progression of chronic neurological disease (Cunningham et al, 2005; Godbout et al, 2005; Perry, 2004; Polentarutti et al, 2000).
Co-exposure of mice to vomitoxin and LPS caused a synergistic increase in TNF-a messenger RNA (mRNA) as well as plasma TNF-a and IL-6. Marked cell death (apoptosis) and loss occurred
in the lymphatic organs, thymus, Peyer’s patches, spleen and bone marrow (Islam et al, 2002; Zhou et al, 1999, 2000). The priming of mice with LPS lowered the dosage of deoxynivalenol causing upregulation of inflammatory cytokines (IL-a and -b, IL6 and TNF-a) and massively increased the thymus apoptosis (Islam et al, 2002).
Similarly, in vitro priming of TLR of murine macrophages and human whole blood cultures renders macrophages sensitive to exposure to mycotoxins and other xenobiotics. The LPS-sensitized macrophages have an increased production of mRNA of IL-1b, IL-6 and TNF-a after exposure to deoxynivalenol (DON), satratoxin G and zeralenone (Pestka and Zhou, 2006).
Also, administration of aflatoxin B1 and endotoxin to rats augments liver sinusoidal damage and clotting by converting soluble fibrinogen to insoluble fibrin clots (Luyendyk et al, 2003).
Finally, nasal inflammation, inflammatory cytokine production and atrophy of the olfactory nerve and olfactory bulbs in mice are enhanced by the co-administration of LPS and roridin A (Islam et al, 2007).
In conclusion, mold agents and LPS exposure are synergistic with adverse effects on organ systems, including the brain, leading to a systemic inflammatory response.