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 Cholesterol-lowering drugs may fight infectious disease
22.08.2017 | Duke University

nachricht Once invincible superbug squashed by 'superteam' of antibiotics
22.08.2017 | University at Buffalo

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: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

What the world's tiniest 'monster truck' reveals

23.08.2017 | Life Sciences

Treating arthritis with algae

23.08.2017 | Life Sciences

Witnessing turbulent motion in the atmosphere of a distant star

23.08.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>