Virulence factors, including lipopolysaccharide (LPS) of gram-negative bacteria, play a pivotal role in severe sepsis, for the generation of inflammatory cytokines that lead to a decrease in total peripheral resistance and, in severe cases, impaired myocardial function. LPS uses the TLR4/CD14 complex from the TLR (toll like receptor family) for the induction of inflammatory cytokines. Ehrentraut and colleagues at the Institute of Physiology II, Universitätsklinikum Bonn, Wilhelmstrasse, Bonn, Germany, have reported (Arteriosclerosis, Thrombosis, and Vascular Biology, 2007) that Eritoran (E5564 | Eisai Research), a synthetic lipid-A analog which inhibits LPS at TLR4/CD14, effectively antagonizes LPS-induced attenuation of smooth muscle contractility.
The team studied the effects of LPS on LPS-responsive and LPS-unresponsive (point mutation in TLR4) mice. The mice were injected with LPS and were euthanized 6 hours later. Explanted abdominal aortic ring preparations were then used for the ex-vivo recordings. The preparations were incubated with E.coli LPS or LPS plus Eritoran, and the contractile responses to phenylephrine were recorded. The results showed that the co-incubation of Eritoran and LPS completely prevented the attenuation of vascular contractility caused by LPS. Interestingly, when Eritoran was used in concentrations greater than double that of LPS (2 micrograms/ml), it also blocked the LPS-associated cardiac depression. The results indicate that the LPS-induced relaxation of vessel walls is dependent on TLR4.
In addition to Eritoran, the team evaluated the effect of inducible nitric oxide synthase (iNOS)-inhibitors on the ex-vivo preparations. L-NG-nitro-arginine methylester (L-NAME), a competitive NOS inhibitor, and S-methylisothiourea hemisulfate (SMT), an iNOS inhibitor, both led to significant increase in contractility of vessels, proving that vascular relaxation is nitric oxide dependent. It has been previously shown that iNOS inhibitors prevent hypotension during sepsis (Biochem Biophys Res Commun, 1990). LPS has the ability to induce iNOS expression and cytokine expression (via TLR4 stimulation) in both smooth muscle and endothelial cells. Baumgarten et al had previously demonstrated that Eritoran is useful in maintaining myocardial function during endotoxemia (Shock, 2006).
Septic shock is an important cause of mortality in intensive care units. Treatment of catecholamine-resistant hypotension and cardiac dysfunction prove to be a challenge in patients with septic shock, and patients who are resistant to the usual drug repertoire. In the future, novel therapeutic agents like Eritoran may prove useful in this context. However, in-vivo experimental studies are required to fully elucidate its actions.
References
1. Ehrentraut S, Frede S, Stapel H, et al. Antagonism of Lipopolysaccharide-Induced Blood Pressure Attenuation and Vascular Contractility. Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2170-2176.
2. Kilbourn RG, Jubran A, Gross SS, et al. Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, an inhibitor of nitric oxide synthesis. Biochem Biophys Res Commun. 1990; 172: 1132–1138.
3. Baumgarten G, Knuefermann P, Schuhmacher G, et al. Toll-like receptor 4, nitric oxide, and myocardial depression in endotoxemia. Shock. 2006; 25: 43–49.
