Quantitative trait loci modulate neutrophil infiltration in the liver during LPS-induced inflammation

A crucial aspect of the inflammatory response is the recruitment of activat ed neutrophils (PMN) to the site of damage. Lytic enzymes and oxygen radica ls released by PMN are important in clearing an infection or cellular debri s, but can also produce host tissue damage. Failure to properly regulate th e inflammatory response contributes to a variety of human diseases like sep sis and multiple organ dysfunction syndrome, the leading cause of morbidity and mortality in surgical intensive care units. Many aspects of human dise ase pathology, including hepatic PMN infiltration, can be recapitulated in mice using an endotoxic shock model. Six quantitative trait loci that predi spose to high infiltration of PMN in hepatic sinusoids after high-dose endo toxin administration were provisionally identified. Two of these loci, Hpi1 and Hpi2 on mouse chromosomes 5 and 13, were mapped to the significant and highly significant level using a lo cv-resolution genome scan on 122 inter cross animals. These loci interact epistatically to produce a high degree o f PMN infiltration. Intercross and recombinant inbred strain mice with a sp ecific genotype at these loci always had a high infiltration response, indi cating that genotype analysis at just these two loci can accurately predict a high PMN infiltration response. Genetic predisposition to the degree of PMN infiltration in the inflammatory response in mice suggests that analogo us genetic mechanisms occur in human beings that could be used for diagnost ic purposes.-Matesic, L. E., Niemitz, E. L., De Maio, A., Reeves, R. H. Qua ntitative trait loci modulate neutrophil infiltration in the liver during L PS-induced inflammation.