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 Using DNA origami to build nanodevices of the future
31.08.2015 | Institute for Integrated Cell-Material Sciences at Kyoto University

nachricht An ounce of prevention: Research advances on 'scourge' of transplant wards
28.08.2015 | University of Wisconsin-Madison

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: An engineered surface unsticks sticky water droplets

The leaves of the lotus flower, and other natural surfaces that repel water and dirt, have been the model for many types of engineered liquid-repelling surfaces. As slippery as these surfaces are, however, tiny water droplets still stick to them. Now, Penn State researchers have developed nano/micro-textured, highly slippery surfaces able to outperform these naturally inspired coatings, particularly when the water is a vapor or tiny droplets.

Enhancing the mobility of liquid droplets on rough surfaces could improve condensation heat transfer for power-plant heat exchangers, create more efficient...

Im Focus: Increasingly severe disturbances weaken world's temperate forests

Longer, more severe, and hotter droughts and a myriad of other threats, including diseases and more extensive and severe wildfires, are threatening to transform some of the world's temperate forests, a new study published in Science has found. Without informed management, some forests could convert to shrublands or grasslands within the coming decades.

"While we have been trying to manage for resilience of 20th century conditions, we realize now that we must prepare for transformations and attempt to ease...

Im Focus: OU astrophysicist and collaborators find supermassive black holes in quasar nearest Earth

A University of Oklahoma astrophysicist and his Chinese collaborator have found two supermassive black holes in Markarian 231, the nearest quasar to Earth, using observations from NASA's Hubble Space Telescope.

The discovery of two supermassive black holes--one larger one and a second, smaller one--are evidence of a binary black hole and suggests that supermassive...

Im Focus: What would a tsunami in the Mediterranean look like?

A team of European researchers have developed a model to simulate the impact of tsunamis generated by earthquakes and applied it to the Eastern Mediterranean. The results show how tsunami waves could hit and inundate coastal areas in southern Italy and Greece. The study is published today (27 August) in Ocean Science, an open access journal of the European Geosciences Union (EGU).

Though not as frequent as in the Pacific and Indian oceans, tsunamis also occur in the Mediterranean, mainly due to earthquakes generated when the African...

Im Focus: Self-healing landscape: landslides after earthquake

In mountainous regions earthquakes often cause strong landslides, which can be exacerbated by heavy rain. However, after an initial increase, the frequency of these mass wasting events, often enormous and dangerous, declines, in fact independently of meteorological events and aftershocks.

These new findings are presented by a German-Franco-Japanese team of geoscientists in the current issue of the journal Geology, under the lead of the GFZ...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Networking conference in Heidelberg for outstanding mathematicians and computer scientists

20.08.2015 | Event News

Scientists meet in Münster for the world’s largest Chitin und Chitosan Conference

20.08.2015 | Event News

Large agribusiness management strategies

19.08.2015 | Event News

 
Latest News

Siemens sells 18 industrial gas turbines to Thailand

01.09.2015 | Press release

An engineered surface unsticks sticky water droplets

01.09.2015 | Materials Sciences

New material science research may advance tech tools

01.09.2015 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>