Inhaled LPS causes adverse airway responses in healthy individuals as well as individuals with asthma and other respiratory conditions. Healthy volunteers challenged with LPS had variable airway responsiveness (Kline et al, 1999). Eight sensitive subjects had at least a 20% decline in the FEV1, at a dose of 6.5 mg or less, while 11 hyporesponsive subjects maintained an FEV1 at least 90% after inhaling 41 mg of LPS. Peripheral monocytes from the hyporesponsive individuals released fewer IL-6 and IL-8 than the sensitive subjects.
The interaction between the environment and lung responsiveness is a complicated gene-environment interaction (Martinez, 2007a). The interactions involve TLR2 and -4 and IL-1 receptors as well as polymorphism of CD14 protein (Liebers et al, 2008; Martinez, 2007b; Simpson et al, 2006). In addition, down-stream adaptor molecules, e.g., My88 and TRAM, are also involved (Tanimura et al, 2008). Furthermore, other genes (e.g, IL-13, DEFB1, TLR2, TRL4) seem to have a role in the phenotypic complex condition referred to as asthma.
Apparently, IgEmediated conditions are not the norm, while the role of IL-4, IL-5, eosinophils and neutrophils are difficult to control (Martinez, 2007a,b). Thus, children with CC genotype at –159 of CD14 have a decreased risk of allergic sensitization to endotoxins while having an increased risk of non-atopic wheezing (Simpson et al, 2006).
Also, it has been shown that the CC allele of CD14 is a risk factor for allergic phenotypes at a low concentration of endotoxins, whereas the TT allele is a risk factor for higher concentrations of LPS (Martinez, 2007b). In conclusion, gene and air pollution interactions in asthma and endotoxins are complex and require more genome-associated studies with better assessment of exposure and phenotype (London, 2007).
In conclusion, synergism between endotoxins and mycotoxins has been demonstrated in vitro and in animal models. As discussed above, LPS enhance the damage to the olfactory epithelium, tract and bulb of roridin A in mice.
In addition, exposure to LPS and aflatoxin B1 enhances liver toxicity in rats. Treated animals had damage to sinusoidal cells and hepatocytes with increased alanine aminotranserase and fibrin deposition (Barton et al, 2001; Luyendyk et al, 2002, 2003).
Oral administration of vomitoxin with simultaneously injected LPS in mice produced a significant enhancement of TNF-a, IL-6 and IL-1b in spleen cells (Zhou et al, 1999). A similarly designed study resulted in an increase of apoptosis of lymphocytes in the spleen, thymus and Peyer’s patches (Zhou et al, 2000).
Finally, in vitro priming of murine and human whole blood macrophages enhances the proinflammatory cytokine production (Pestka and Zhou, 2006).
Two questions arise from these observations:
(1) What role does the genetic polymorphism CD14 protein have in synergism of LPS and mycotoxins?
(2) Are the children with CD14 CC genotypes more or less sensitive to the inflammatory conditions caused by mycotoxins?