 |
|
Ashwell receptor reduces mortality during sepsis
May 19, 2008In research that solves the longest-standing mystery in glycobiology - a field that studies complex sugar chains called glycans - researchers at the University of California, San Diego School of Medicine have discovered that a molecule in the liver of all animals, called the Ashwell receptor, is critical in helping the body fight off the abnormal and lethal blood clotting caused by bacterial infection. Until now, it was suspected that this receptor might serve to remove abnormal proteins from circulation, but it wasn't understood which proteins were affected or what biological purpose this receptor served.
The study, published online in advance of publication in the June issue of Nature Medicine, shows that the Ashwell receptor plays an essential role in reducing coagulation abnormalities during infection and sepsis, significantly improving the probability of survival.
Sepsis, a life-threatening complication of bacterial infection in the blood, remains a major cause of death worldwide, according to the study's principal investigator, Jamey Marth, Ph.D., UCSD Professor of Cellular and Molecular Medicine and Investigator with the Howard Hughes Medical Institute. One of the major factors contributing to death in patients with sepsis is a condition called disseminated intravascular coagulation, which accelerates blood clotting.
UCSD researchers discovered that a protective response, triggered by the Ashwell receptor in the liver, limits this lethal side effect by reducing the levels of circulating blood coagulation factors, including platelets.
The bacterial pathogen Streptococcus pneumoniae (pneumococcus) is a leading cause of sepsis, especially in the young, the elderly and the immuno-compromised. The pneumococcus makes an enzyme called sialidase, which removes sugar molecules called sialic acid from host cells, and helps facilitate spread of the pathogen through the body. Using a mouse model of sepsis, the researchers found that the pneumococcal sialidase also removes sialic acid from circulating host factors involved in blood coagulation, including platelets and a glycoprotein called von Willebrand Factor (vWF). When this occurs, the Ashwell receptor recognizes the change in the glycoprotein structure and removes those pro-coagulation factors from circulation before they can cause increased blood coagulation.
The researchers made a breakthrough when they discovered that platelet counts and vWF that are reduced during pneumococcal infection remained high and unchanged in the absence of the Ashwell receptor. Pivotal results came when mice lacking the Ashwell receptor developed severe tissue and organ damage due to increased coagulation and died at significantly higher frequency and more rapidly than expected.
"This finding contradicts the prevailing notion that the low platelet count of sepsis is due to the consumption of coagulation factors caused by the pathogen and is therefore harmful," said Marth. "Rather, this low platelet count is due an adaptive response by the Ashwell receptor that is beneficial by reducing tissue damage and organ failure and thereby improving the chance of survival."
More than 35 years ago, researcher Gilbert Ashwell and colleagues discovered that the liver controls the removal of proteins in the bloodstream. The Ashwell receptor -also known as the hepatic asialoglycoprotein receptor - was the first glycan-binding receptor, or lectin, ever discovered in animals.
"The Ashwell receptor is 'turned on' after birth, and this was a clue that it is needed for environmental and pathogenic challenges," said Marth.
"This research provides a whole new way of thinking about coagulation problems in sepsis produced by pneumococcus and related pathogens" said Victor Nizet, M.D., UCSD professor of pediatrics and pharmacy whose laboratory assisted in the study. "Drugs designed to support the normal capabilities of the Ashwell receptor in the liver would represent a new approach to limiting mortality in these life-threatening conditions."
University of California - San Diego
UCSD researchers discovered that a protective response, triggered by the Ashwell receptor in the liver, limits this lethal side effect by reducing the levels of circulating blood coagulation factors, including platelets.
The bacterial pathogen Streptococcus pneumoniae (pneumococcus) is a leading cause of sepsis, especially in the young, the elderly and the immuno-compromised. The pneumococcus makes an enzyme called sialidase, which removes sugar molecules called sialic acid from host cells, and helps facilitate spread of the pathogen through the body. Using a mouse model of sepsis, the researchers found that the pneumococcal sialidase also removes sialic acid from circulating host factors involved in blood coagulation, including platelets and a glycoprotein called von Willebrand Factor (vWF). When this occurs, the Ashwell receptor recognizes the change in the glycoprotein structure and removes those pro-coagulation factors from circulation before they can cause increased blood coagulation.
The researchers made a breakthrough when they discovered that platelet counts and vWF that are reduced during pneumococcal infection remained high and unchanged in the absence of the Ashwell receptor. Pivotal results came when mice lacking the Ashwell receptor developed severe tissue and organ damage due to increased coagulation and died at significantly higher frequency and more rapidly than expected.
"This finding contradicts the prevailing notion that the low platelet count of sepsis is due to the consumption of coagulation factors caused by the pathogen and is therefore harmful," said Marth. "Rather, this low platelet count is due an adaptive response by the Ashwell receptor that is beneficial by reducing tissue damage and organ failure and thereby improving the chance of survival."
More than 35 years ago, researcher Gilbert Ashwell and colleagues discovered that the liver controls the removal of proteins in the bloodstream. The Ashwell receptor -also known as the hepatic asialoglycoprotein receptor - was the first glycan-binding receptor, or lectin, ever discovered in animals.
"The Ashwell receptor is 'turned on' after birth, and this was a clue that it is needed for environmental and pathogenic challenges," said Marth.
"This research provides a whole new way of thinking about coagulation problems in sepsis produced by pneumococcus and related pathogens" said Victor Nizet, M.D., UCSD professor of pediatrics and pharmacy whose laboratory assisted in the study. "Drugs designed to support the normal capabilities of the Ashwell receptor in the liver would represent a new approach to limiting mortality in these life-threatening conditions."
University of California - San Diego
Sepsis News and Current Sepsis Events RSSScientists figure out how the immune system and brain communicate to control disease
In a major step in understanding how the nervous system and the immune system interact, scientists at The Feinstein Institute for Medical Research have identified a new anatomical path through which the brain and the spleen communicate.
Once suspect protein found to promote DNA repair, prevent cancer
An abundant chromosomal protein that binds to damaged DNA prevents cancer development by enhancing DNA repair, researchers at The University of Texas M. D. Anderson Cancer Center report online this week in the Proceedings of the National Academies of Science.
Pitt Team Receives $2.5 Million to Simulate and Analyze Brain, Immune System Activity and Apply Math to Medical Problems
In an effort to promote the application of mathematics to medical treatment, researchers in the University of Pittsburgh's Department of Mathematics will undertake a $2.5 million project to create models of how the brain and immune system function and change over time in response to certain illnesses, infections, and treatment.
Major 'missed' biochemical pathway emerges as important in virtually all cells
A new study by Duke University researchers provides more evidence that the nitric oxide (NO) system in the life of a cell plays a key role in disease, and the findings point to ways to improve treatment of illnesses such as heart disease and cancer.
CAPHOSOL relieves oral mucositis and improves quality-of-life in cancer patients
New data show that CAPHOSOL® (www.caphosol.com), an advanced electrolyte solution, relieves painful oral mucositis (OM) and improves quality of life for cancer patients undergoing chemotherapy and radiation therapy.
New discovery on role of vital protein that fights meningitis
A University of Leicester researcher has discovered how a protein in the blood - linked to defence against meningitis - plays a more vital role than previously understood in the body's immune defence system.
Researchers find possible target to treat deadly bloodstream infections
Researchers at the University of Illinois at Chicago have discovered a possible target to treat bloodstream bacterial infections.
Customized treatments for sepsis lower treatment time and reduce length of ICU stays
Using a blood test and a decision algorithm, rather than standard hospital protocols, to determine the appropriate length of antibiotic therapy in patients with severe sepsis or septic shock can reduce duration of treatments, shorten ICU stays, and lower hospital costs- all without adverse effects on patients, according to new research.
Scripps scientists studying sepsis in mice find potential drug targets for deadly disease
"We have identified a key connection of signaling pathways in the cascade of events leading to sepsis. This defines a crucial point where the immune system spirals out of control to cause severe sepsis and where there is an opportunity for therapeutic intervention," says Scripps Research Professor Wolfram Ruf, who led the research with his postdoctoral fellow Frank Niessen.
MGH study identifies enzyme that protects against intestinal bacterial toxin
A persistent mystery in human medicine is how the lining of the small intestine, through which nutrients are absorbed, also prevents intestinal bacteria and their toxins from entering the bloodstream and causing serious infections.
More Sepsis News Articles
 | Contemporary Diagnosis and Management of Sepsis by E. Wesley Ely, Gordon R. Bernard This valuable reference provides clinicians with the most up-to-date data on accurate diagnostic techniques and management of this life-threatening illness, including the latest treatment... |
 | One Step at a Time by Jennifer Smith and Bradie Kvinsland "One Step at a Time" is a book, keepsake and guide for coping with a child's hospitalization. It offers a unique way for a parent to ask the right questions, record important medical information, and express joy, fear and hope during a very difficult time. And most important, it encourages parents to take care of themselves physically, emotionally and... |
 | Mechanisms of Sepsis-Induced Organ Dysfunction and Recovery (Update in Intensive Care Medicine) There have been tremendous advances in understanding the cellular mechanisms involved in sepsis and contributing to the development of multiple organ dysfunction and mortality in this setting. The chapters in this book provide up-to-date insights into important pathways that are initiated by... |
 | Cytokines in Severe Sepsis & Septic Shock (Progress in Inflammation Research) This book deals with the central role of cytokines in the generalized inflammatory response of the host as the consequence of severe infection/endotoxin action. International specialists cover several aspects in 20 chapters starting with the agents responsible (endotoxin, superantigens) and recognition during cytokine induction. Further chapters deal with the signal transduction cascade, its... |
 | Sepsis: New Strategies for Management Sepsis is an important public health problem around the world. Severe sepsis carries significant morbidity, mortality and high costs. The incidence of sepsis is increasing because of the aging population, the growing number of immunocompromised hosts, the increasing use of invasive procedures, and, to a lesser extent, antibiotic resistance among pathogens. Despite recent advances in the... |
 | Yearbook of Intensive Care and Emergency Medicine / Annual volumes 2008 (Yearbook of Intensive Care and Emergency Medicine) The Yearbook compiles the most recent developments in experimental and clinical research and practice in one comprehensive reference book. The chapters are written by well recognized experts in the field of intensive care and emergency medicine. It is addressed to everyone involved in internal medicine, anesthesia, surgery, pediatrics, intensive care and emergency... |
 | Sepsis (Competency-Based Critical Care) Sepsis is a serious medical condition, resulting from the immune response to a severe infection. Septicaemia is sepsis of the bloodstream caused by bactemeria, which is the presence of bacteria in the bloodstream. The term septecaemia is also used to refer to sepsis in general. In the US, sepsis is the leading cause of death in non-coronary ICU patients, and the tenth most common form of death... |
 | The Sepsis Text 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... |
 | Toll-like Receptors in Inflammation (Progress in Inflammation Research) A repertoire of 10 TLRs mediate the first response to all microbes that infect mammals. They are the long sought receptors for a wide range of microbial products. Notable examples include TLR4 which recognizes LPS from gram negative bacteria, TLR3 which recognizes viral double-stranded RNA and TLR9 which recognizes CpG DNA motifs, found commonly in both viruses and bacteria. TLRs are increasingly... |
 | Sepsis, Kidney And Multiple Organ Dysfunction: 3rd International Course on Critical Care Nephrology, Vicenza, June 2004 (Contributions to Nephrology) Severe sepsis is among the most common causes of death in the United States and the most common cause of death in the Intensive Care Units worldwide, and its recognition and treatment remain the most important challenges of critical care medicine. Severe sepsis and septic shock have a profound effect on kidney function and the function of other organs through complex mechanisms, which... |
| © 2008 BrightSurf.com |