Disabling the smoke detector

smoke-detector

In 2013 Eisai, a Japanese firm performed a phase 3 clinical trial of Eritoran, a drug that was supposed to make the company millions.

It did not work out that way.

Just another failed pharma R&D venture?

Or was this predictable with a little knowledge of evolutionary medicine and a cursory understanding of selection and host defenses?

Maybe its not a good idea to disable the smoke detector.

[Eritroran works by blocking the toll-like receptor TLR-4. TLR 4 is a pathogen-associated recognition receptor that is a key immune detector of dangerous pathogens. The main ligand for TLR-4 is lipopolysaccharide (LPS), the cell wall constituent of gram negative bacteria, such as E. coli. Previous trials using antibodies directed at lipopolysaccharide failed to improve infectious outcomes. Gene knockout mice lacking TLR-4 promptly die of overwhelming sepsis. Human patients with sepsis are more likely to die if they have reduced expression of TLR-4. So why should we think that Eritroran would be helpful in sepsis? Because the conventional wisdom of sepsis holds that septic shock represents a dangerous over-reaction of the innate immune system. Injury and death is thought to result from a cascade of  inflammatory products that damage the microvasculature and cause multi organ failure. The flip side is that handicapping the immune system – in this case by blocking pathogen detection by toll like receptors – is likely to interfere with key innate host defenses. Understanding the “smoke detector” function of TLRs can illuminate their physiologic role.  Appreciation of the “smoke detector principle”  would suggest that blocking TLR-4 in sepsis would be a bad idea. Perhaps so]

Toll like receptor 4 illustrated below:

F7.large

(citation: http://circ.ahajournals.org/content/126/11_suppl_1/S222/F7.expansion.html)

Joe Alcock MD

2 thoughts on “Disabling the smoke detector

  1. Pingback: Sepsis – what have we learned? | Evolutionary Medicine

  2. Pingback: Food, an early warning system? | Evolutionary Medicine

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