Severe inflammatory response syndrome, or SIRS, occurs when the body's response to an overwhelming infection becomes uncontrolled. The very immune response meant to clear the pathogen and its toxins actually causes damage to the host's own tissues when it goes into overdrive, releasing too many immune signals. Thus, the immune response must be carefully controlled to prevent damage to the host.
Damazo et al. studied this balancing act by analyzing the effects of the bacterial toxin LPS on normal and annexin 1 knockout mice. Annexin 1 was chosen because it appears to be involved in the resolution phase of the immune response: its expression on white blood cells impairs their ability to bind blood vessel walls, preventing their transit from the blood to other organs.
When normal mice were treated with LPS, the immune system induced a steady migration of white blood cells from the blood into affected tissues. However, mice deficient for annexin 1 exhibited a dramatic release of white blood cells from blood vessels, ultimately leading to 100% mortality by 48 hours.
The researchers characterized the expression of annexin 1 and found that the gene was activated as early as 1.5 and 6 hours after LPS administration, with levels returning to normal by 24 hours. Higher levels of markers of inflammation, and of organ injury, were measured in annexin 1 deficient animals. Altogether, these findings implied that the protective effects of the annexin 1 pathway were activated in the first few hours following toxin administration. In fact, when annexin 1 knockout mice were given small doses of human recombinant annexin 1 in the first 24 hours following LPS treatment, survival increased to 60%.
These results, obtained in the lab of Dr. Mauro Perretti, highlight the delicate balance between the "pro-inflammatory/detrimental vs. anti-inflammatory/protective phases" of the immune response. Dr Perretti explained, "For too long, we have ignored anti-inflammatory/counter-regulatory mediators and the impact they have on pathology outcome; studying the way our body controls responses to infections can allow the modeling of new therapeutics with lower side effects."
The importance of this work is underscored by the fact that bacterial sepsis ranked among the top ten causes of death in both adults and neonates in 2002 in the United States (Natl Vital Stat Rep 2005, 53:1-89). The patients at greatest risk of developing sepsis and SIRS are those with impaired immune systems. When such patients are unable to control the underlying bacterial infection, their immune systems overcompensate and trigger a dangerous cascade of tissue damage.
Thus, to prevent death from sepsis, physicians must not only control the bacterial infection but better control the detrimental effects of the immune system. Dr. Perretti's lab is further investigating these immune pathways: "The ultimate goal is to use these new targets (e.g., a receptor for a given anti-inflammatory mediator) to develop better and safer drugs." The data for annexin 1 provide a new direction for such therapeutics that delicately balances removal of bacterial toxins and damage to host tissues.
Research was funded by the Arthritis Research Campaign UK, FAPESP, Centro Nationale de la Pesquisa, the Nuffield Foundation UK, CAPES, the Wellcome Trust, and the Medical Research Council UK.
This work involved collaborators at the William Harvey Research Institute, Queen Mary, University of London, UK; The Department of Morphology, UNIFESP-EPM, São Paulo, Brazil; and the Department of Biology, IBILCE-UNESP, São José do Rio Preto, Brazil.
AS Damazo, S Yona, F D'Acquisto, RJ Flower, SM Oliani, M Perretti: Critical protective role for annexin 1 gene expression in the endotoxemic murine microcirculation. Am J Pathol 2005, 166:1607-1617
Commentary: A Gewirtz: A most important annexation: Am J Pathol 2005, 166:1581-1583
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The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.
William Harvey Research Institute--Based in central London, the Institute is part of Barts and The London, Queen Mary's School of Medicine and Dentistry. It was established in 1985 by the Nobel Laureate Sir John Vane, and is today one of the leading centres for pharmacological research in the UK. The Institute ranks among the top 20 pharmacological research institutions in the world (The Scientist, 2004), and is world-renowned as a centre of excellence for cardiovascular and inflammation research. Its major research programmes have been funded by pharmaceutical companies in Europe, the USA and Japan. A number of the Institute's senior scientists are among the 100-leading pharmacologists in the world (www.williamharvey.co.uk).
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