Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Scripps Research Scientists Discover New Key to Pulmonary Edema in Respiratory Distress Syndrome


Physiology is sometimes a crossroads where many different paths converge. Such is the case with acute respiratory distress syndrome, a severe and often fatal condition also known as adult respiratory distress syndrome or simply "shock lung."

Acute respiratory distress syndrome can be caused by a number of underlying conditions, including smoke inhalation, a severe blow to the chest, bad pneumonia, septic shock, severe blood loss, or drug overdose. Although the causes vary greatly, the situation for a patient who arrives at an emergency room with acute respiratory distress syndrome is largely the same—critical. Adult respiratory distress syndrome leads to the filling of the lung’s airways with fluids, a condition known as pulmonary edema. This leads to a reduction of oxygen intake, which can rapidly degenerate into complete respiratory failure.

"It’s a serious complication that often results in death," says Professor Hugh Rosen, M.D., Ph.D., of The Scripps Research Institute.

Adult respiratory distress syndrome is usually treated by ventilation that increases the oxygen available to the lungs, as well as by antibiotics, muscle relaxers, pain relievers, heart stimulants, and other drugs that address some of the related problems. According to the U.S. National Heart, Blood, and Lung Institute, these therapies have helped greatly. While in the past fewer than half of all people who developed acute respiratory distress syndrome survived, now as many as seven out of ten receiving critical care in a hospital do.

Now, hoping to improve matters further, Rosen and his Scripps Research colleagues are reporting a new molecular mechanism that controls how the lungs are kept dry and under what conditions they permit fluids to enter. The mechanism involves a protein called the S1P3 receptor expressed on the surface of the cells lining the lung’s air sacs. When the receptor is activated, the lungs become leaky, causing pulmonary edema.

Because the S1P3 receptor is involved in pulmonary edema, blocking this receptor may be a way to improve the prognosis for people with acute respiratory distress syndrome.

Gas Exchange and What Goes Wrong When Lungs Are Wet

The lung is a remarkable piece of anatomy that enables the exchange of gaseous molecules from the environment with molecules in the bloodstream. Though the lungs are compact enough to fit inside our rib cages, lung tissue is a series of airways and air sacs so elaborate that the air cavities inside the lungs encompass an area about 40 times larger than the surface area of the entire body.

These air cavities play a crucial role for the body because they let oxygen into the bloodstream, where it is picked up by erythrocytes, or red blood cells, and carried to the rest of the tissues throughout the body. The cavities are also where carbon dioxide, a waste product, is removed from the blood stream and expelled from the body.

With each breath you take, air flows in your mouth or through your nasal passageways and down your throat. It goes past the epiglottis, the flap that keeps the food and drink you have consumed from spilling into your lungs. Then, the air flows into the larynx, past your vocal cords, and down the trachea, which splits into the two primary bronchi—one feeding each lung. From there, the air continues to the ends of the bronchi, which bifurcate like thousands of stems branching from a trunk into about 30,000 tiny terminal "bronchioles" in each lung. At the ends of the bronchioles are tiny grape-like clusters of air sacs known as the alveoli. It is in the alveoli that the gas exchange with blood occurs.

The alveoli are elastic cavities lined with a tiny amount of fluid and a molecule called surfactant, which prevents these airways from collapsing in on themselves. Surrounding the alveoli are networks of tiny capillaries that carry oxygen-depleted blood around the outside of the alveoli. When a tiny portion of air reaches the alveoli, gasses are easily dissolved into the fluid, and then exchanged with molecules in the adjacent bloodstream.

One physiology that enables this exchange is the lung epithelium, the specialized layer of cells immediately lining the air sacs. The epithelium is held together via what are known as tight junctions. These tight junctions are made up of proteins that insert through the membranes of adjacent cells and link the cells together so tightly that they prevent salt and other small molecules from passing through the gaps between the cells.

In the airways of the lung, tight junctions are critical because there are only two layers of cells between the air and the blood it is supplying with oxygen—a layer of epithelial cells lining the alveoli and a layer of endothelial cells forming the walls of the blood vessels. The total space between the bloodstream and the air at this interface is only about one five-thousandth of a millimeter. This thinness is essential because oxygen and carbon dioxide molecules have to be able to pass through this space during gas exchange, and the further the molecules have to go, the harder it is for oxygen to reach the blood.

When fluid leaks into the lungs, the distance the gas molecules must travel to reach the blood increases, and this impedes gas exchange. In acute respiratory distress syndrome, pulmonary edema can be so severe that the lungs become heavy and stiff, which is why acute respiratory distress syndrome has also been called "wet lung" or "stiff lung."

Physiologically, pulmonary edema can be caused by conditions other than acute respiratory distress syndrome, for example congestive heart failure, which leads to an increase in pressure in the capillaries surround the lung sacs and a leaking of fluid in the lungs. But in acute respiratory distress syndrome, there is not necessarily too much pressure in the capillaries. So why the fluid-filled lungs?

One reason, Rosen and his colleagues have reported in an upcoming issue of the journal Proceedings of the National Academy of Sciences, may be because of the signaling of a small lipid called sphingosine 1-phosphate (S1P), that is produced at sites of inflammation. The activation of S1P3 receptors in the lung by S1P may be what causes pulmonary edema to arise by causing a breakdown of the epithelial barrier.

Breakdown of the Tight Junctions

The work started as a collaboration between Rosen and his Scripps Research colleague Professor Jerold Chun, M.D., Ph.D., both of whom have spent several years studying various lipids and lipid receptor systems in the body including sphingosine 1-phosphate and the lysophosphatidic acid receptors. Sphingosine 1-phosphate is produced or secreted throughout the body, including in the lungs, where it has been found in the lung fluid taken from patients with asthma. The production of sphingosine 1-phosphate is induced as a response to the presence of pro-inflammatory chemicals such as type-1 interferons and tumor necrosis factor, which are both produced during septic shock, one of the exact conditions that lead to edema.

Wanting to know what effect sphingosine 1-phosphate has on edema, the Rosen lab looked at the effect of the lipid on the cells lining the lung and the blood vessels surrounding the lungs. Chun’s group had created mutant mice deficient for the S1P3 receptor, which allowed a clean assessment of its role in the lung.

On the blood vessel side, the "endothelial" cells lining the capillaries express a type of protein known as S1P1 receptors. Activation of these S1P1 receptors with the sphingosine 1-phosphate leads to the tightening of junctions between the endothelial cells and the stoppage of potential leakage—the opposite of what happens in edema.

However, the epithelial cells on the lung side express a slightly different type of S1P receptor called the S1P3 receptor protein. Yasuhiro Gon, M.D., Ph.D., found that when sphingosine 1-phosphate is administered into lung sacs, it activates the S1P3 receptors on the airway side of these epithelial cells and induces pulmonary edema. Significantly, they found that a mouse model that has no receptors of this type is protected against pulmonary edema when exposed to sphingosine 1-phosphate.

Why does the sphingosine 1-phosphate induce lung leakage? To answer this, Rosen and Gon turned to their collaborators Malcolm Wood, Ph.D., and William Kiosses, Ph.D., in Scripps Research’s Core Microscopy facility. They applied fluorescence microscopy to sections of tissue that had been exposed to sphingosine 1-phosphate and showed that the leakage occurs because the activation of S1P3 receptor signaling causes disruptions in the integrity of the tight junctions between epithelial cells. Electron microscopy revealed that certain proteins normally found in the tight junctions had been lost.

These results suggest that a chemical antagonist (something that blocks activation) of the sphingosine 1-phosphate receptors in the lung airways might be protective against pulmonary edema and might lead to a therapy to address acute respiratory distress syndrome.

The article, "S1P3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF" by Yasuhiro Gon, Malcolm R. Wood, William B. Kiosses, Euijung Jo, M. Germana Sanna, Jerold Chun, and Hugh Rosen will appear in an upcoming issue of the journal Proceedings of the National Academy of Sciences. The article was published June 20, 2005 on the PNAS Early Edition website. See:

This work was supported by grants from the National Institute of Allergy and Infectious Disease, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke—all three components of the NIH. Additional support was provided by Kyorin Pharmaceutical Company, Ltd.

About The Scripps Research Institute and Scripps Florida

The Scripps Research Institute in La Jolla, California, and Palm Beach County, Florida, is one of the world’s largest, independent, non-profit biomedical research organizations. It stands at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development.

The Scripps Research Institute employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel in 14 buildings overlooking the Pacific Ocean in La Jolla, a part of the City of San Diego.

Scripps Florida will be a 350,000 square-foot, state-of-the-art biomedical research facility to be built on 100 acres of undeveloped land in Palm Beach County. Scripps Florida will focus on basic biomedical science, drug discovery, and technology development, employing more than 500 researchers and support staff by 2010. Palm Beach County and the State of Florida have provided start-up economic incentives for development, building, staffing, and equipping the campus.

Scripps Florida is now operating with more than 100 researchers and technicians at a 40,000 square-foot facility on the campus of Florida Atlantic University in Jupiter.

Jason Bardi | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute

nachricht Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

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...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>



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

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

More VideoLinks >>>