New therapy protects lungs from runaway inflammation

March 12, 2009

A novel anti-inflammatory therapy designed by Vanderbilt University Medical Center investigators prevents acute lung injury in mice exposed to an inflammation-causing toxin, the researchers report in the journal Molecular Therapy.

The new therapy may offer a way to protect the lungs from the "runaway inflammation" that can accompany bacterial or viral pneumonia, said Jacek Hawiger, M.D., Ph.D., the leader of the research team that has pioneered the new approach.

"Lung inflammation is an extremely perplexing problem," noted Hawiger, chair of the Department of Microbiology & Immunology.

The immune system sometimes overreacts to lung infection and produces excessive concentrations of inflammatory signals (cytokines and chemokines), which can damage the fine architecture of the lungs and lead to life-threatening acute respiratory distress syndrome (ARDS). Such damage is most likely when pneumonia has both viral and bacterial causes - for example from combined influenza and Staphylococcus aureus infections.

"We believe that in addition to controlling the infection with antibacterial and antiviral agents, we need therapies that reduce this inflammation-induced collateral damage to the lung tissue," Hawiger said. "This would allow both faster clearance of the infecting organisms and faster healing of the lung."

Several years ago, Hawiger and colleagues began searching for new targets for anti-inflammatory therapy. They reasoned that a protein called NF-kappa-B - the "master regulator" of genes that encode mediators of inflammation - might make a good target.

The researchers knew that NF-kappa-B moves from the cell cytoplasm to the nucleus (where it is active) in response to cellular injury or microbial agents, and they decided to try to block this nuclear translocation.

They designed a small protein fragment - a peptide - that mimicked the nuclear transport "signal," hoping that it would compete with, and block, NF-kappa-B's movement to the nucleus. To get the peptide into cells, the team took advantage of the cellular mechanism that proteins use to cross membranes and engineered a membrane-crossing motif onto the therapeutic peptide.

"To our delight, we found that this peptide crossed the cell membrane and stopped NF-kappa-B in its tracks, blocking it from going to the nucleus in response to conditions which cause inflammation," Hawiger said.

It turned out that the inhibitor worked even more broadly than the researchers expected. The peptide blocks a "shuttle" that ferries not only NF-kappa-B to the nucleus, but also a group of additional stress-responsive proteins. The nuclear shuttle protein represents a new intracellular target for anti-inflammatory therapy, Hawiger said.

The researchers tested the effectiveness of this cell-penetrating peptide therapy against inflammation in a mouse model of acute lung injury.

They exposed mice to staphylococcal enterotoxin B (SEB), an immunotoxin produced by methicillin-resistant S. aureus (MRSA). SEB generates a "storm" of inflammatory signals that damages the lungs and causes ARDS and multiple organ dysfunction. Airborne SEB caused fatal ARDS in non-human primates.

Treatment of SEB-exposed mice with the nuclear transport inhibitor suppressed the inflammatory storm in the lungs. Inflammatory cells, whose numbers increase 2.5-fold after SEB exposure, remained normal in peptide-treated mice. Peptide therapy also suppressed the levels of chemokines and cytokines and prevented injury to the lung's blood vessels.

"It's very reassuring to us that this single agent, which targets the nuclear import shuttle, suppressed the production of all of these harmful mediators of excessive inflammation," Hawiger said.

The investigators are pursuing pre-clinical studies of the peptide therapy with hopes that it will lead to improved adjunctive therapies for life-threatening pneumonia caused by multiple germs.

Vanderbilt University Medical Center

---

---

	Anti-Inflammatory Foods for Health: Hundreds of Ways to Incorporate Omega-3 Rich Foods into Your Diet to Fight Arthritis, Cancer, Heart Disease, and More (Healthy Living Cookbooks) by Barbara Rowe (Author), Lisa M Davis (Author) Great food for inflammation sufferers.Cut your finger accidentally and the area will swell, redden, and heat up. This type of acute inflammatory response is the body's reaction to trauma, and it's an essential part of the healing process. But inflammation can be harmful when it hangs around too long and refuses to leave. When the inflammation switch refuses to turn off, the body operates as if it is always under attack (the older we get, the more likely this is to happen). White blood cells flood the system for weeks, months, and even years.Researchers are now linking low-grade, persistent inflammation to premature aging, heart disease, M.S., diabetes, Alzheimer's, psoriasis, arthritis, and cancer. While anti-inflammatory drugs do exist, they can injure the stomach or suppress the...
	Fish Oil: The Natural Anti-inflammatory by Joseph C. Maroon (Author), Jeffrey Bost (Author) Did you know that the root cause of serious chronic diseases such as heart disease, Alzheimer's disease, cancer, arthritis, and asthma has been identified as chronic inflammation? Although numerous studies have confirmed these findings, few physcians are aware of or consider the fact that the battle against inflammation is at the forefront of the fight for health and well-being of the global population. Authors Joseph Maroon and Jeffrey Bost have set out to reverse that trend with "Fish Oil: The Natural Anti-Inflammatory." Pharmaceujtical companies have spent billions of dollars in an attempt to understand the bio-chemistry of inflammation. Unfortunately, pharmaceutical anit-inflammatories such as Celebrex, Vioxx, and Bextra have been shown to greatly increase the risk of heart attack,...
	Natural Antioxidants and Weight Loss: Anti-Obesity and Anti-Inflammatory Effects of Polyphenol Extracts from Fruits and Herbs (Journal of Personalized and Systems Medicine) by PharmTao.com Polyphenols are chemicals found in many plants. Polyphenols are usually antioxidants that can protect cells from oxidative damage caused by free radicals. Polyphenols include tannins, lignins, and flavonoids. Many polyphenols have anti-obesity activities and are beneficial for weight loss. Aging and obesity may lead to inflammatory and oxidative conditions. Inflammation and oxidative stress are also important pathological factors in obesity-related diseases such as diabetes, fatty liver, cardiovascular diseases, and cancer. Polyphenol extracts from fruits and herbs such as apples and green tea can inhibit inflammation, lower blood cholesterol and glucose levels, and reduce risks of heart diseases. These natural antioxidants can be used as dietary supplements without evident adverse...
	Novel Molecular Approaches to Anti-Inflammatory Therapy (Agents and Actions Supplements) by Waldemar Pruzanski (Editor), Peter Vadas (Editor) Major advances have recently been made in our understanding of inflammatory mechanisms. These advances serve as the basis for a new generation of therapeutic agents which may potentially alter our approach to inflammatory processes and infectious diseases. In this volume scientists of international repute describe in detail novel approaches to the study of inflammation. Topics discussed include chemokines and their role in human disease, mediation of inflammation by cyclooxygenase-2, leukocyte adhesion and the anti-inflammatory effects of leukocyte adhesion and the anti-inflammatory effect of leukocyte integrin blockade, anti-inflammatory lipocortin-derived peptides, and the use of anti-PECAM and other agents in the control of inflammation. An up-to-date collection of recent...
	Asthma: Epidemiology, Anti-Inflammatory Therapy and Future Trends (Respiratory Pharmacology and Pharmacotherapy) by Mark A. Giembycz (Editor), Brian J. O'Connor (Editor) This book features an up-to-date analysis of the epidemiology of asthma in children and adults, the role of steroids in asthma management and new and novel asthma therapies. The book addresses clinicians and basic scientists with an interest in asthma epidemiology, steroids and future therapies. It is also of interest to clinical and non-clinical teachers in academic disciplines relating to respiratory disease.
	Symposium on Ocular Anti-Inflammatory Therapy by Herbert E. Kaufman (Author)
	The Anti-Inflammation Diet and Recipe Book: Protect Yourself and Your Family from Heart Disease, Arthritis, Diabetes, Allergies - and More by Jessica K. Black (Author) The connection between inflammation and heart disease, arthritis, and other chronic ailments has become increasingly clear. Many food allergies and poor dietary choices over stimulate the immune system and cause inflammatory responses that erode the body’s wellness and pave the path for ill health. Based on her naturopathic practice, Jessica Black has devised a complete program for how to eat and cook to minimize and even prevent inflammation and its consequences. The first part of the book explains the benefits of the anti-inflammatory diet with an accessible discussion of the science behind it. The second half contains 108 recipes. The author offers many substitution suggestions and includes a healthy ingredient tip with each recipe. Most of the dishes can be prepared quickly and...
	The Inflammation-Free Diet Plan by Monica Reinagel (Author) A revolutionary diet to help you lose weight and control disease-causing inflammation The Inflammation-Free Diet Plan will help you achieve your ideal weight--without fad dieting--while also reducing pain and allergies, slowing the aging process, and dramatically reducing your risk for dozens of medical problems. This flexible, easy-to-follow program is the ideal nutritional solution for every member of the family. At the heart of the program is the revolutionary IF Rating system that, for the first time, tells you the inflammatory or anti-inflammatory effects of all of the foods you eat. The IF Rating integrates more than twenty different nutritional factors, including essential fatty acids, glycemic index, vitamins, minerals, antioxidants, and anti-inflammatory compounds into...
	The Complete Idiot's Guide to the Anti-Inflammation Diet by Christopher P. Cannon M.D. (Author), Elizabeth Vierck (Author) New research shows that abnormal inflammation may be linked to a variety of diseases and conditions. In this book, you will find what diseases and conditions are caused by inflammation, which foods reduce inflammation and which foods contribute to inflammation, and how to tweak today’s diets to make them anti-inflammatory. Over 60 million Americans suffer from cardiovascular disease and over 20 million Americans suffer from asthma - two conditions thought too be affected, if not caused, by inflammation Many Newsweek articles have been dedicated to this topic, including "Quieting a Body's Defenses," by Anne Underwood, in 2005 New York Times best-selling author Andrew Weil dedicated a portion of his new book, Healthy Aging, to a discussion of inflammation, its role in diseases,...
	Natural Alternatives to Vioxx, Celebrex & Other Anti-Inflammatory Prescription Drugs: What to Use to Help Relieve Arthritis Pain and Inflammation by Carol N. Simontacchi (Author) Written by health professionals who are well recognized in their respective fields, these concise, easy-to-read books focus on a wide range of important health concerns. From migraine headaches to high cholesterol, each title looks at a specific problem; each provides a clear explanation of the disorder, its causes, and its symptoms; and each offers natural solutions that can either greatly reduce or completely eliminate the problem. Some titles also focus on natural alternatives to drugs with serious side effects—alternatives that in many cases can be used in conjunction with prescription medications. This growing series of titles can be counted on to provide safe and sensible solutions to all-too-common health problems.