ADENOVIRUS-MEDIATED TRANSFER OF A GENE ENCODING ACYLOXYACYL HYDROLASE(AOAH) INTO MICE INCREASES TISSUE AND PLASMA AOAH ACTIVITY

Although the host response to gram-negative bacterial infection follow s largely from the interactions of bacterial lipopolysaccharides (LPS or endotoxin) with host cells, little information is available concern ing the mechanisms by which the host eliminates or detoxifies LPS. Acy loxyacyl hydrolase (AOAH) is an enzyme, found in phagocytic cells, tha t catalyzes the enzymatic deacylation of the lipid A moiety of LPS. En zymatically deacylated LPS is much less potent than LPS at inducing re sponses in human cells, and it can antagonize the ability of LPS to ac tivate human macrophages, neutrophils, and endothelial cells. Despite these observations, the physiologic role of LPS deacylation remains un defined. To investigate the ability of AOAH to carry out LPS deacylati on in vivo, we produced a recombinant adenovirus carrying a gene encod ing AOAH (Ad.CMV-AOAH) and employed this vector to elicit transient ov erexpression of AOAH in mice. Mice infected with Ad.CMV-AOAH expressed high levels of the enzyme in plasma, liver, spleen, and kidney. Altho ugh adenovirus-induced hepatitis reduced hepatic uptake of intravenous ly injected [H-3]LPS, animals expressing the transgene deacylated a la rger fraction of the [3H]LPS taken up by their livers than did mice in fected with a control adenovirus. These studies indicate that AOAH can catalyze the deacylation of LPS in vivo, and they provide evidence th at the rates of hepatic LPS uptake and deacylation are not closely lin ked.