Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Blocking Digestive Enzymes May Reverse Shock, Stop Multiorgan Failure

25.01.2013
New research from the University of California, San Diego published in the Jan. 23 issue of Science Translational Medicine moves researchers closer to understanding and developing treatments for shock, sepsis and multiorgan failure.

Collectively, these maladies represent a major unmet medical need: they are the number one cause of mortality in intensive care units in the United States, with hundreds of thousands of deaths annually. There is currently no treatment for these conditions in spite of many clinical trials.

Most researchers agree that organ failure in shock and sepsis involves the intestine – and that it arises when the mucosal barrier of the small intestine becomes permeable. However, the mechanism by which this disrupted membrane is tied to vastly different kinds of shock, as well as multiorgan failure and death has not been understood.

In the case of sepsis (septic shock), for example, some researchers speculate that bacteria in the intestine and their toxins are responsible for organ failure. However, interventions against bacteria that are aimed at reducing mortality in patients undergoing septic shock have been unsuccessful in clinical trials.

Looking more broadly than bacteria, a team of researchers led by Geert W. Schmid-Schönbein in the Department of Bioengineering at the UC San Diego Jacobs School of Engineering has carried out several years of careful analysis of the events in shock. That research led them to investigate the powerful, concentrated digestive enzymes in the intestine, the same enzymes that are part of daily digestion.

These digestive enzymes need to be restricted to the inside of the small intestine by the mucosal barrier. Once this barrier is disrupted, which can occur for a variety of reasons including dramatic loss of blood, physical puncture or opening (as in shrapnel injury or appendicitis), or degradation by bacterial toxins, digestive enzymes leak into the wall of the intestine and begin digesting it, a phenomenon the UC San Diego researchers call “autodigestion”. Once beyond the mucosal barrier of the small intestine, the UC San Diego researchers believe the digestive enzymes damage other organs by indiscriminately starting to degrade them, which can lead to multiorgan failure and death.

The new research, published in the Jan. 23 issue of Science Translational Medicine, provides novel results linking digestive enzymes to shock, sepsis and multiorgan failure. In particular, by administering digestive enzyme blockers directly into the small intestines of rats an hour after the onset of different types of shock, the researchers led by Schmid-Schönbein reversed the often fatal conditions, reduced injury to the heart and lungs, and greatly increased long-term survival of the animals from about 16 percent to 86 percent.

* The animals that received the digestive enzyme blockers in the lumen of the intestine regained their health and survived for long periods of time after shock. (Past experimental shock studies have been limited to relatively short observation periods.)

* The researchers showed a clear connection between direct inhibition of pancreatic digestive enzymes after the onset of three different shock models in rat, reduced organ damage and long-term survival of the animals. They demonstrated improved survival with three very different inhibitors of the digestive enzymes.

* All three of the pancreatic enzyme inhibitors, when delivered directly into the small intestine, but not when delivered intravenously, stopped autodigestion brought on by shock. (One of these enzyme inhibitors is already approved for use in the United States for other purposes).

* Blockade of the digestive enzymes was successful in three widely different forms of shock. The researchers studied hemorrhagic shock, septic shock and endotoxic shock.

For the first time, these studies specifically indicate that it is possible to stop autodigestion by blocking the digestive enzymes in animals with induced shock. “We saw far less damage to organs, faster recovery of the animals, and a reduction of mortality in shock,” said Research Associate Frank DeLano, who carried out the studies with Schmid-Schönbein.

Autodigestion
The UC San Diego bioengineers have described aspects of autodigestion, as well as the potential for stopping it (and treating shock) by blocking the powerful digestive enzymes that have breached the intestine barrier, in numerous papers in the scientific literature.

This research has the potential to lead to therapies that greatly reduce fatalities, morbidity, and length of stay in intensive care units in patients undergoing various forms of shock.

“Organisms rely on full containment of the digestive enzymes in the small intestine. The moment the intestinal mucosal barrier is compromised, the digestive enzymes escape and then we are no longer digesting just our food, but we may be digesting our organs,” said Schmid-Schönbein.

A Phase 2 clinical pilot study is under way to test the efficacy and safety of a new method of administering an enzyme inhibitor for critically ill patients such as those with new-onset sepsis and septic shock, post-operative complications, and new-onset gastrointestinal bleeding.

In addition, a published clinical report points to successful treatment of a patient with severe septic shock with digestive enzyme inhibitors delivered directly into the intestine.

In shock, there is a major failure of the mucosal barrier
in the small intestine. There may also be other conditions in which the failure of this barrier is less severe, and digestive enzymes leak more slowly into the blood stream. The effect on human health of slow leakage of digestive enzymes into the body with low level of autodigestion remains to be explored, Schmid-Schönbein explained.
Funding
This research was supported by an unrestricted gift from Leading BioSciences Inc. and by National Institutes of Health (NIH) grants HL 67825 and GM 85072.
Competing interests
Geert W. Schmid-Schönbein is a scientific advisor to Leading BioSciences Inc.
David B. Hoyt, Frank A. DeLano and Geert W. Schmid-Schönbein own equity in InflammaGen, a company by Leading BioSciences Inc., which develops therapy for shock patients.

“Pancreatic Digestive Enzyme Blockade in the Intestine Increases Survival After Experimental Shock,” by Frank A. DeLano from the Department of Bioengineering, and The Institute of Engineering in Medicine at University of California, San Diego; David B. Hoyt from the American College of Surgeons; and Geert W. Schmid-Schönbein from the Department of Bioengineering, and The Institute of Engineering in Medicine at University of California, San Diego. Published in the 23 Jan. issue of Science Translational Medicine.

Daniel Kane | Newswise
Further information:
http://www.ucsd.edu

More articles from Health and Medicine:

nachricht Researchers release the brakes on the immune system
18.10.2017 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht Norovirus evades immune system by hiding out in rare gut cells
12.10.2017 | University of Pennsylvania School of Medicine

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Terahertz spectroscopy goes nano

20.10.2017 | Information Technology

Strange but true: Turning a material upside down can sometimes make it softer

20.10.2017 | Materials Sciences

NRL clarifies valley polarization for electronic and optoelectronic technologies

20.10.2017 | Interdisciplinary Research

VideoLinks
B2B-VideoLinks
More VideoLinks >>>