Reversal of the myocardial dysfunction of meningococcal septicaemia through targeted blockade of interleukin 6.
Dr Nazima Pathan, Professor Michael Levin, Professor Sian Harding
- Start Date:
01 January 2003
Imperial College School of Medicine at St Mary's Hospital, London, UK
Myocardial dysfunction is a major component in the pathophysiology of meningococcal septic shock, and is the principal cause of death. The development of specific treatments for myocardial failure in septic shock has been hampered by a lack of understanding of the pathophysiology of the disorder. Over the past four years, we have undertaken a programme of work to identify the factors responsible for myocardial depression in meningococcal shock. Using a combination of gene microarray technology and conventional immunochemical methods, we have established that Interleukin 6 (IL-6) is a major myocardial depressant factor in the plasma of children with meningococcal sepsis. This discovery now opens the way to the development of specific treatments to block the myocardial depressant effects of IL-6.
Through a collaborative programme of work, linking the expertise in Professor Sian Harding's laboratories at the National Heart and Lung Institute, expertise in small animal physiology in Dr Masao Takata's laboratories, and the extensive expertise in the inflammatory consequences of meningococcal sepsis in the department of Paediatrics at Imperial College London, we plan to elucidate mechanisms through which IL-6 causes myocardial depression and identify candidate pharmacological agents to block different stages of its action. We will test these candidates using in vitro models of myocardial function, and in animal models. Candidate agents that are able to block the myocardial effects of IL-6 will be taken forward for future clinical trials.
Results from this study have been published in scientific journals as follows:
Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE, McCabe C, Welch SB, Whitney A, O'Gara P, Nadel S, Levin M.
Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock.
Lancet 2004 Jan 17;363(9404):203-9.
Pathan N, Williams EJ, Oragui EE, Stephens AC, Levin M.
Changes in the interleukin-6/soluble interleukin-6 receptor axis in meningococcal septic shock.
Crit Care Med 2005 Aug;33(8):1839-44.