Science Current Events | Science News | Brightsurf.com
 

Lack of a key enzyme dramatically increases resistance to sepsis

April 24, 2006
Findings could lead to new therapeutic approaches to a major disease

According to the new study, the presence of caspase-12, which appears to modulate inflammation and innate immunity in humans, increases the body's "vulnerability to bacterial infection and septic shock" while a deficiency confers strong resistance to sepsis. This new discovery suggests that caspase-12 antagonists could be a potentially useful in the treatment of sepsis and other inflammatory and immune disorders.

The study was published in the April 20 edition of the journal Nature (Volume 440, Number 7087).

Richard Ulevitch, chair of the Scripps Research Immunology Department and an author of the paper, says, "The results of the study make clear that caspase-12 plays a critical role in the elimination of bacterial pathogens, and that a deficiency allows systemic and abdominal infections to be better resolved. It's known that the presence of caspase-12 as a full length protein occurs in a small percentage of people of African descent. As a result, some of these individuals are far more susceptible to severe sepsis and have a significantly increased risk of dying from it."

Sepsis, the body's inflammatory response to severe infection, is one of the leading causes of death in the United States, killing more than 200,000 people each year, according to the Society of Critical Care Medicine. A 2003 study by The Centers for Disease Control and Emory University School of Medicine showed that the incidence of sepsis in the United States has increased almost nine percent a year since 1979.

The new study showed that caspase-12 deficient mice were resistant to peritonitis and septic shock and were able to clear pathogenic bacteria more efficiently than mice with the enzyme. The presence of caspase-12 also reduced production of several pro-inflammatory cytokines, increasing vulnerability to bacterial infection and septic mortality.

"Without the experimental model of peritonitis perfected by John Mathison from Scripps Research, we would not have been able to differentiate between the two mouse phenotypes," Ulevitch said. "Because of his work, we were able to use a surgically implanted stent in the colon that allowed a gradual occurrence of sepsis and easy identification."

A majority of mice with caspace-12 died from sepsis within the first 48 hours after onset, while 60 percent of the caspase-12 deficient mice survived. The deficient mice also showed a significantly lower number of bacterial colony-forming units per milliliter of blood, suggesting that more efficient bacterial clearance occurs in the absence of caspase-12.

Caspase-12 is also an inhibitor of caspase-1, a related enzyme involved in the inflammation process. Caspase-1 deficient mice are two-to-three times more susceptible to lethal Escherichia coli infection than normal mice. Consequently, the study said, sepsis resistance in caspase-12 deficient mice was most likely due to an initial hyper-production of cytokines that fight the infection.

"The resulting beneficial effect of cytokine hyper-production runs contrary to some of the current thinking in sepsis research," Ulevitch said. "The general thinking is that this initial cytokine 'storm' is harmful, and that belief has been the basis of a number of unsuccessful clinical studies. In our study, cells containing caspase-12 appear to weaken the activity of caspase-1 that is normally essential for bacterial clearance and sepsis survival."

In another finding, researchers showed that both mouse models had similar levels of stress-induced apoptosis or programmed cell death. While caspase-12 was previously thought to be a key mediator of endoplasmic reticulum apoptosis, the new study found that the presence or absence of caspase-12 had no effect on apoptotic sensitivity whatsoever.

Others authors of the study include Maya Saleh (currently with McGill University), Melissa K. Wolinski, Steve J. Bensinger, Patrick Fitzgerald, Nathalie Droin, Douglas R. Green (La Jolla Institute of Allergy and Immunology and St. Jude Children's Research Hospital); Donald W. Nicholson of Merck Research Laboratories, and; John C. Mathison of Scripps Research.

Scripps Research Institute


Related Sepsis Current Events and Sepsis News Articles


Geisel Researchers Contribute to Study of Trained Immunity
A study published in the journal Science provides support for a new-and still controversial-understanding of the immune system.

Critically ill ICU patients lose almost all of their gut microbes and the ones left aren't good
Researchers at the University of Chicago have shown that after a long stay in the Intensive Care Unit (ICU) only a handful of pathogenic microbe species remain behind in patients' intestines.

Research evaluates neurodevelomental and medical outcomes in single family room NICU
The prevalence of preterm birth - the birth of an infant prior to 37 weeks of pregnancy - is a significant health problem that has increased over the past two decades.

In mice, vaccine stops urinary tract infections linked to catheters
The most common type of hospital-associated infection may be preventable with a vaccine, new research in mice suggests.

Blood-cleansing biospleen device developed for sepsis therapy
Things can go downhill fast when a patient has sepsis, a life-threatening condition in which bacteria or fungi multiply in a patient's blood -- often too fast for antibiotics to help.

Bone Cancer Surgical Team Sees Success in New Application of Surgical Aid
An ortho-oncology team at Dartmouth-Hitchcock Norris Cotton Cancer Center successfully adapted a shoulder surgical aid (the Spider Limb Positioner) to conduct a left hip disarticulation on a melanoma patient as described in a case report published online in Medical Devices.

To admit or not to admit: Variation in hospitalizations from ER costs billions
It sounds like the setup for a joke: Two identical patients go to two different hospital emergency entrances, complaining of the same symptoms.

Penn study: Sepsis patients fare better in hospitals with higher case volumes
Patients with sepsis, one of the most time-sensitive and hard-to-detect illnesses in medicine, are more likely to survive the life-threatening condition when treated at a hospital that sees a higher volume of sepsis cases.

Long antibiotic treatments: Slowly growing bacteria to blame
Whether pneumonia or sepsis - infectious diseases are becoming increasingly difficult to treat. One reason for this is the growing antibiotic resistance.

Treatment with lymph node cells controls dangerous sepsis in animal models
An immune-regulating cell present in lymph nodes may be able to halt severe cases of sepsis, an out-of-control inflammatory response that can lead to organ failure and death.
More Sepsis Current Events and Sepsis News Articles

Sepsis and Septic Shock

Sepsis and Septic Shock


Sepsis and Septic Shock

Last updated: 9/30/12, 5/21/13
Number of questions: 12

Gyroscope- A Survival of Sepsis

Gyroscope- A Survival of Sepsis
by Gary Black (Author)


Gyroscope is a compelling and inspiring true story about a miraculous survival of sepsis. It reveals and illustrates the innermost traumas and triumphs of a journey through this devastating illness.

Actual book size is 6 x 9

Sepsis: Diagnosis, Management and Health Outcomes (Allergies and Infectious Diseases)

Sepsis: Diagnosis, Management and Health Outcomes (Allergies and Infectious Diseases)
by Nancy, M.D., Ph.D. Khardori (Editor)




Gyroscope: A Survival of Sepsis

Gyroscope: A Survival of Sepsis
by Infinity Publishing


Gyroscope is a compelling, revealing, and inspiring true story about a miraculous survival of sepsis. From onset to recovery, this book takes you on an in-depth perilous journey through this devastating illness, which includes near-death and out-of-body experiences, desperation in the ICU, Divine intervention and healing, and soul-searching personal transformations.

The extensive art work explores dreams, delirium, visits to the dark void, sadness, depression, terror, and love and hope. It offers a profound, introspective portal to view the innermost traumas and triumphs. Gyroscope opens our eyes to the magnitude of sepsis, and the aftermath of physical, mental, and spiritual recovery.

The Sepsis Text

The Sepsis Text
by Jean-Louis Vincent (Editor), Jean Carlet (Editor), Steven M. Opal (Editor)


This textbook is written at the dawn of a new era in the management of sepsis. Recent achievements in the clinical management of septic shock are the culmination of decades of basic and applied research by innovative researchers and clinical investigators worldwide. The contributing authors to this book have spearheaded much of this research and the Editors have endeavored to create a textbook that is comprehensive in nature while maintaining a specific focus upon the multitude of work that constitutes the spectrum of sepsis research including: pathophysiology; monitoring systems; general support; microbial aspects; complications; and anti-sepsis therapies.

Sepsis

Sepsis
by Springer


Sepsis or septic shock is a type of condition/infection which represents one of the leading post-surgical or post-traumatic complications. Sepsis is the major cause of morbidity and mortality in intensive care units worldwide. Also, sepsis is the leading cause of death in non-coronary patients, with pulmonary sepsis accounting for most cases as it relates to lung dysfunction.
This is a concise, practical softcover volume devoted to covering only the most practical information for physicians. Charts, tables, and other figures are used to illustrate easy-to-follow treatment guidelines for those professionals who regularly treat patients in the ICU.

Sepsis

Sepsis
by Guillermo Ortiz-Ruiz (Editor), Marco A. Perafan (Editor), Eugen Faist (Editor), Carmelo DueƱas Castell (Editor)


Sepsis (or septic shock) is one of the leading post-surgical or post-traumatic complications in today's hospitals. This pervasive condition is the major cause of morbidity and mortality in intensive care units worldwide, as well as the leading cause of death in non-coronary patients. This is a concise, practical soft cover volume devoted to covering only the most practical information for physicians. Charts, tables, and other figures are used to illustrate easy-to-follow treatment guidelines for those professionals who regularly treat patients in the ICU.

Sepsis and Multiorgan Failure

Sepsis and Multiorgan Failure
by Alan M. Fein (Author), Fink (Author), Bone (Author)


This reference provides guidelines for management of infections in critically ill patients. It provides disease mechanisms of sepsis as well as clinical diagnosis, treatment and management, and the authors also explain the proper guidelines for assessment and treatment protocols in the ICU. They have designed this resource specifically to handle the common infectious problems. Included are evolving concepts from multiple pertinent disciplines such as: basic microbiology, outcome measures, pharmacology and epidemiology statistics.

ABC of Sepsis

ABC of Sepsis
by Ron Daniels (Editor), Tim Nutbeam (Editor)


The importance of early prevention and treatment of sepsis has never been greater. In the UK alone sepsis contributes to more deaths than lung cancer, from bowel cancer and breast cancer combined, and approximately one third of patients who suffer from severe sepsis die. The ABC of Sepsis provides a much needed introduction and an invaluable aid in the increasing efforts to reduce hospital infection and improve patient safety.As growing numbers of junior medical staff experience emergency medicine, critical care and acute medicine as part of the Foundation Programme, there is an increasing need to develop the skills required to treat severe sepsis. The editors are involved with the Survive Sepsis campaign - developed to improve the recognition, diagnosis and treatment of sepsis - and are...

Sepsis and Non-infectious Systemic Inflammation: From Biology to Critical Care

Sepsis and Non-infectious Systemic Inflammation: From Biology to Critical Care
by Jean-Marc Cavaillon (Editor), Christophe Adrie (Editor)


Providing definitions, clinical features and epidemiology, this handbook and reference adopts a comprehensive approach, describing in detail the various physiological systems involved. As such, it is the first to combine sepsis and non-infectious SIRS, reviewing both the biological and medical aspects of these two important syndromes. The whole is rounded off with a discussion of past, present and future therapies.

© 2014 BrightSurf.com