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 Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

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: Shape matters when light meets atom

Mapping the interaction of a single atom with a single photon may inform design of quantum devices

Have you ever wondered how you see the world? Vision is about photons of light, which are packets of energy, interacting with the atoms or molecules in what...

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

IHP presents the fastest silicon-based transistor in the world

05.12.2016 | Power and Electrical Engineering

InLight study: insights into chemical processes using light

05.12.2016 | Materials Sciences

High-precision magnetic field sensing

05.12.2016 | Power and Electrical Engineering

VideoLinks
B2B-VideoLinks
More VideoLinks >>>