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 fo llowing 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.