In order to understand the relative strain differences and LA effects in parallel, we compared the mean expression values of WKY saline control rats with those of WKY LA, SI I saline, SH LA, SHHF saline, and SHHF LA rats and determined relative (old differences.
SH rats exposed to LA demonstrated an effect on pathways assigned to cancer, whereas SHHF rats had this pathway affected significantly at baseline as well as after IA exposure (Figure 3).
As indicated in Figure 4, many genes related to inflammation were induced at baseline in SH rats and to some degree in SHHF rats compared with WKY controls.
Genes expressed at high levels in the lungs of control SH and SHHF rats, including the gene for matrix metal-Ioproteinase-9 and some oncogenes, are grouped in cluster 1.
Fe accumulation in fiber-laden macrophages was primarily noted in SHHF rats with Fe overload.
We have shown that SH and SHHF rats have increased baseline pulmonary inflammation and Fe overload that relates to the severity of disease (SHHF > SH) (Shannahan et al.
Gene expression analysis revealed that the LA effect on inflammatory genes that regulate innate immunity is still evident at 3 months postexposure in WKY rats but less so in SHHF and SH rats.
at 3 months after LA exposure, SH and SHHF rats are unable to sustain increased inflammatory gene expression despite their elevated baseline lung neutrophils.
Even though the LA-induced neutrophilic influx had subsided in all three strains at 3 months, the inflammatory gene expression still remained induced in WKY rats compared with SH and SHHF rats, which express high baseline levels of these genes.
The exacerbated progressive accumulation of Fe within fiber-laden alveolar macrophages in the SHHF rats supports the hypothesis that the increased availability of cellular Fe leads to accumulation of Fe at the site of fiber deposition within the lung.
Surprisingly, only the SHHF rats developed atypical hyperplastic lesions at 3 months after exposure to LA.
First, in addition to Fe overload, the baseline CVD of the SH and SHHF rats may play a role in susceptibility to LA.