Calming the Storm – learning from research

In recent years we have become all too aware of the danger posed by viruses avian H5N1 influenza and SARS.  The high death rate associated with such infections is due to the infection causing acute respiratory distress syndrome (ARDS), where the infected individuals own immune system overreacts to the presence of the virus in what is termed a “cytokine storm”.  This cytokine storm does terrible damage to the lungs and is believed to have been responsible for killing over 20 million people during the 1918 Spanish flu pandemic.

While considerable effort has gone into developing vaccines and anti-viral drugs that may help prevent infection there is also an awareness that it will be difficult to roll out enough of these treatments in time in the event of a pandemic, so researchers have also turned their attention to trying to prevent or lessen the cytokine storm that actually kills most patients.

In a paper published this week in Cell (1) a multinational team led by Joseph Penninger have identified a key pathway that is involved in triggering the cytokine storm.  Penninger and his colleagues knew that ARDS is a problem common to many species infected with influenza or SARS, so they carried out a series of experiments with knockout mice in order to identify genes required for severe lung damage in an experimental model of ARDS.  They observed that deletion of a gene for the cell surface receptor TLR4 resulted in less damage to the lungs. Next a particular pathway mediated by the adaptor protein TRIF was discovered to lead from activation of TLR4 to increased production of the Interleukin-6 (IL-6), a cytokine previously associated with ARDS in humans (2).

So what activates TLR4 to set the chain of events in motion?  The researchers examined a series of possible agents, and identified oxidized phospholipids (OxPLs) as the activators of TLR4. The amount of OxPLs was greatly increased in the lungs of mice with experimentally induced ARDS and mice exposed to H5N1 flu virus.  Blocking TLR4 lessened the damage to the lungs of mice exposed to H5N1.

The relevance of this research to humans with ARDS was supported by analysis of tissues taken from SARS patients, which showed greatly increased levels of OxPLs, and by in vitro experiments showing that exposing human lymphocytes to H5N1 triggers oxidative stress and consequently increased OxPLs.

This study, which ably demonstrates how animal research helps make sense of clinical observations in humans, should lead to the development of new treatments for ARDS that target the TLR4 mediated inflammatory pathway.  While these treatments will not stop the spread of a new pandemic they should help to reduce the toll of death and injury that follows in its wake.


Paul Browne

1)  *Yumiko Imai et al “*Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury” Cell Volume 133, Issue 3, Pages 235-249 (2008) doi:10.1016/j.cell.2008.2.043
2)  Madhav Bhatia and Shabbir Moochhala “Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome” J. Pathol. Volume 202, Issue 2, Pages145-156. (2004) doi:10.1002/path.1491