Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cox-2 enzyme plays important role regulating acute pancreatitis and associated lung injury

18.12.2002


New study identifies an enzyme associated with pancreatic inflammation



Bethesda, MD – Clinical acute pancreatitis can present with varying degrees of severity The chief causes of this disorder are gallstones, gallbladder-related disease and alcohol use. Viral infection, mumps, and certain medications such as corticosteroids, diuretics, and tetracycline are other causes. In adults, the disorder is frequently associated with lung injury, manifesting itself as adult respiratory distress syndrome.

Background


While the catalyst for pancreatitis is not well known, it is thought that enzymes normally secreted by the pancreas in an inactive form become activated inside the pancreas and start to digest the pancreatic tissue. This process is called autodigestion and causes swelling, hemorrhage, and damage to the blood vessels. An attack may last for 48 hours, and damage to the Cyclooxygenase-2 (COX-2), a widely distributed enzyme, plays an important role in pancreatic inflammation.

The initiation of prostanoid synthesis from arachidonic acid involves the enzyme cyclooxygenase (COX), an enzyme that is also referred to as PGH synthase or PG endoperoxide synthase, because it is also the rate limiting enzyme for PGE2 synthesis.

Two COX isoforms have been identified; first, as a constitutive form (COX-1), which is thought to have an important housekeeping function; and second, as an inducible form (COX-2), which has been implicated as an important pro-inflammatory mediator. COX-2 is up-regulated in response to a variety of pro-inflammatory stimuli including IL-1, TNF, and bacterial lipopolysaccharide. COX-2 mRNA and protein levels are increased during experimental pancreatitis, but the role of COX-2 in pancreatitis has heretofore not been well defined.

The Study

A new study has explored the role of COX-2 in acute pancreatitis and pancreatitis-associated lung injury. The protocols entailed pretreating selected mice with COX-2 inhibitors, whereas other mice were bred with genetic deletion of COX-2. Pancreatitis was induced via supramaximal secretagogue stimulation.

The authors of "Inhibition Of Cyclooxygenase-2 Ameliorates the Severity Of Pancreatitis And Associated Lung Injury," are Albert M. Song, Lakshmi Bhagat, Vijay P. Singh, G. D. Van Acker, Michael L. Steer, and Ashok K. Saluja, all from the Department of Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. Their findings appear in the November, 2002 edition of the American Journal of Physiology – Gastrointestinal and Liver Physiology. The journal is one of 14 publications published each month by the American Physiological Society (APS).

Methodology

Pancreatitis was induced in the mice with COX-2 inhibitors, and those bred with genetic deletion of COX-2 by 12 hourly injections of cerulein. The severity of pancreatitis was assessed by measuring serum amylase, pancreatic trypsin activity, intrapancreatic sequestration of neutrophils, and acinar cell necrosis. The severity of lung injury was evaluated by measuring lactate dehydrogenase levels in the bronchoalveolar lavage fluid and by quantitating neutrophil sequestration in the lung.

Two groups of studies were performed to evaluate the role of COX-2 in pancreatitis. The first involved use of genetically altered mice that do not express COX-2, whereas the second involved administration, to wild-type mice, of agents known to inhibit COX-2. Both groups of studies yielded similar results. Either genetic deletion or pharmacological inhibition of COX-2 resulted in a marked reduction in the severity of secretagogue-induced pancreatitis. Both approaches also resulted in a marked reduction in the severity of pancreatitis-associated lung injury.

Results

The researchers found that:

· pancreatic COX-2 mRNA levels rose within 15 minutes of the start of cerulein administration and that pancreatic COX-2 protein levels were increased within four hours of cerulein administration; and
· these observations suggest that COX-2 might play an important role in regulating the severity of pancreatitis and, possibly, of pancreatitis-associated lung injury as well.

This reduction in pancreatitis and lung-injury severity, brought about by interfering with COX-2, led to a conclusion that COX-2 plays an important pro-inflammatory role in both pancreatitis and its associated lung injury.

The mechanisms by which COX-2 might promote inflammation in pancreatitis are not immediately obvious. The researchers considered the possibility that it might modulate the early intra-acinar cell events that characterize this model of pancreatitis. These include activation of trypsinogen and NF-ÊB, two temporally and mechanistically parallel events that occur within 30 min of the start of cerulein administration. The findings revealed that neither cerulein-induced trypsinogen activation nor cerulein-induced early NF-ÊB activation were altered by COX-2 deletion after 30 minutes of cerulein administration.

Conclusions

These studies indicate that COX-2 plays an important pro-inflammatory role in pancreatitis and pancreatitis-associated lung injury. COX-2 appears to regulate the severity of pancreatitis via mechanisms that are downstream to the early cell events. The pro-inflammatory effects of COX-2 in this model of pancreatitis may be multifactorial and involve, among other things, alterations in various enzyme expressions, specifically HSP70, iNOS, and neutrophil function.

Further studies will clearly be needed to identify those mechanisms, but regardless of the results of those studies, the observations reported in this study indicate that pharmacological interventions that inhibit COX-2 may prove beneficial in the prevention and/or treatment of acute pancreatitis.


Source: November 2002 edition of the American Journal of Physiology – Gastrointestinal and Liver Physiology.

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

Donna Krupa | EurekAlert!

More articles from Health and Medicine:

nachricht TSRI researchers develop new method to 'fingerprint' HIV
29.03.2017 | Scripps Research Institute

nachricht Periodic ventilation keeps more pollen out than tilted-open windows
29.03.2017 | Technische Universität München

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: A Challenging European Research Project to Develop New Tiny Microscopes

The Institute of Semiconductor Technology and the Institute of Physical and Theoretical Chemistry, both members of the Laboratory for Emerging Nanometrology (LENA), at Technische Universität Braunschweig are partners in a new European research project entitled ChipScope, which aims to develop a completely new and extremely small optical microscope capable of observing the interior of living cells in real time. A consortium of 7 partners from 5 countries will tackle this issue with very ambitious objectives during a four-year research program.

To demonstrate the usefulness of this new scientific tool, at the end of the project the developed chip-sized microscope will be used to observe in real-time...

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Researchers shoot for success with simulations of laser pulse-material interactions

29.03.2017 | Materials Sciences

Igniting a solar flare in the corona with lower-atmosphere kindling

29.03.2017 | Physics and Astronomy

As sea level rises, much of Honolulu and Waikiki vulnerable to groundwater inundation

29.03.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>