Washington University in St. Louis

New strategy blocks chronic lung disease in mice

Research involving cytokines and how they’re packaged sheds light on inflammation in asthma, COPD, COVID-19

Newswise — Inflammatory lung diseases such as asthma, COPD and, most recently, COVID-19, have proven difficult to treat. Current therapies reduce symptoms and do little to stop such diseases from continuing to damage the lungs. Much research into treating chronic inflammatory diseases has focused on blocking chemicals called cytokines, which trigger cascades of molecular events that fuel damaging inflammation.

Now, scientists at Washington University School of Medicine in St. Louis have found that such cytokines can drive inflammation in more ways than previously understood, perhaps revealing new routes to potential treatments for chronic inflammatory conditions.

A new study demonstrates that in addition to raining down directly into tissues and triggering damaging events, cytokines can come packaged in tiny compartments called exosomes, making the packaged cytokines extremely difficult to detect and nearly impossible to study without specialized instruments. Not being able to study these exosomes means scientists could be missing important strategies to treat or prevent inflammatory disease.

The study, in JCI Insight, also demonstrates that understanding how these inflammatory cytokines are packaged can reveal new ways to block them, preventing lung disease from developing, at least in mice.

“In trying to understand and better treat inflammatory disease in patients, scientists have focused heavily on blocking cytokines, which we know are key players in setting off inflammatory processes and keeping them smoldering,” said senior author Jennifer Alexander-Brett, MD, PhD, an assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine. “How a particular family of cytokines gets out of cells to trigger inflammation has been a mystery that has stymied the field for a long time. At the same time, people started to recognize that these structures called exosomes are doing something, though it was unclear what. They’re small, difficult to isolate and easily overlooked. But with new technology, we’re starting to understand that key cytokines can be packaged in exosomes in ways that completely change the way we would target them to develop anti-inflammatory therapies.”

Based on prior work from Alexander-Brett, Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, and other investigators at Washington University, it has long been known that a specific cytokine called IL-33 is a central player in the development of chronic lung diseases, such as COPD and asthma. Indeed, this cytokine also is implicated in arthritis, inflammatory bowel disease, hepatitis, heart failure, inflammation of the central nervous system and cancer. But how it triggers inflammation was unknown. The new research shows that IL-33 is released into the airway, packaged with an exosome. Complicating matters further, IL-33 doesn’t travel inside the exosome; it piggybacks on the outside.

With a new understanding of the packaging, the researchers tried a different method to block the inflammatory signaling of IL-33. They studied mice that develop lung disease due to inhaling a type of fungus; the disease, mimics, for example, the development of asthma due to an inhaled allergen. The researchers showed that they could block airway disease from developing in mice exposed to the fungus by treating them with a compound that blocks exosome secretion, rather than IL-33 directly.

“This study opens up many new questions about how cytokine signaling might be different when the cytokine is bound to an exosome,” Alexander-Brett said. “It’s possible exosome packaging is a key feature of cytokines that are not secreted in the classical way. This new understanding of cytokine signaling could lead to completely different ways of targeting it to treat diseases such as COPD. At the moment, we have no treatments that reverse or even slow COPD. We can only treat symptoms.”

Alexander-Brett said that until recently, this type of exosome activity would have been extremely difficult to detect. Her lab has a relatively new instrument called a single-particle interferometric reflectance imaging system (SP-IRIS) that lets her team study exosomes using very small amounts of biological samples.

For asthma and COPD, Alexander-Brett said her lab is seeking more precise ways to block specific exosomes, since a strategy that blocks all of them across the board, as in this mouse study, likely would stop some beneficial processes as well.

“We need more research to find an inhibitor that might block IL-33 from even being incorporated into the exosome, which would theoretically stop the initial trigger of chronic lung disease,” Alexander-Brett said. “Ideally, we would like to find something that we could deliver as an inhaled drug that would target the effects to the airway, where it’s needed.”

###

This work was supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), grant numbers K08 HL121168, R01 HL152245 and T32 HL007317; an Early Career Investigator Award from the American Thoracic Society; a career award for medical scientists from the Burroughs Wellcome Fund; and the fund to retain clinical scientists from the Doris Duke Foundation. Additional support and services were provided by the Washington University Digestive Diseases Research Core, grant number NIDDK P30 DK052574; the Siteman Center Flow Cytometry Core; the Washington University Center for Cellular Imaging, grant number ORIP OD021629; the Washington University Genome Engineering and iPSC Center; and the Pulmonary Morphology Core.

Katz-Kiriakos E, et al. Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease. JCI Insight. Feb. 22, 2021.

Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.



Filters close

Showing results

110 of 5855
Released: 22-Jun-2021 12:30 PM EDT
Political Variables Carried More Weight Than Healthcare in Government Response to COVID-19
Binghamton University, State University of New York

Political institutions such as the timing of elections and presidentialism had a larger influence on COVID-19 strategies than the institutions organizing national healthcare, according to a research team led by a professor at Binghamton University, State University of New York.

22-Jun-2021 12:00 PM EDT
Study Testing How Well COVID-19 Vaccine Prevents Infection and Spread of SARS-CoV-2 Among University Students Now Expands to Include Young Adults Beyond the University Setting
Covid-19 Prevention Network (CoVPN)

The Prevent COVID U study, which launched in late March 2021 to evaluate SARS-CoV-2 infection and transmission among university students vaccinated with the Moderna COVID-19 Vaccine, has expanded beyond the university setting to enroll young adults ages 18 through 29 years and will now also include people in this age group who choose not to receive a vaccine.

Newswise: First Wave COVID-19 Data Underestimated Pandemic Infections
18-Jun-2021 8:30 AM EDT
First Wave COVID-19 Data Underestimated Pandemic Infections
American Institute of Physics (AIP)

Two COVID-19 pandemic curves emerged within many cities during the one-year period from March 2020 to March 2021. Oddly, the number of total daily infections reported during the first wave is much lower than that of the second, but the total number of daily deaths reported during the first wave is much higher than the second wave.

Newswise: PNNL AI Expert Harnesses Open-Source Data to Understand Human Behavior
Released: 22-Jun-2021 9:55 AM EDT
PNNL AI Expert Harnesses Open-Source Data to Understand Human Behavior
Pacific Northwest National Laboratory

PNNL researchers used natural language processing and deep learning techniques to reveal how and why different types of misinformation and disinformation spread across social platforms. Applied to COVID-19, the team found that misinformation intended to influence politics and incite fear spreads fastest.

Released: 22-Jun-2021 8:30 AM EDT
Engineering Nanobodies As Lifesavers When SARS-CoV-2 Variants Attack
Ohio State University

Scientists are pursuing a new strategy in the protracted fight against the SARS-CoV-2 virus by engineering nanobodies that can neutralize virus variants in two different ways.

Released: 21-Jun-2021 3:45 PM EDT
Rare Neurological Disorder Documented Following COVID-19 Vaccination
American Neurological Association (ANA)

In two separate articles in the Annals of Neurology, clinicians in India and England report cases of a rare neurological disorder called Guillain-Barré syndrome after individuals were vaccinated against COVID-19.

Newswise: New Analysis reveals link between birthdays and COVID-19 spread during the height of the pandemic
17-Jun-2021 12:10 PM EDT
New Analysis reveals link between birthdays and COVID-19 spread during the height of the pandemic
Harvard Medical School

Risk of SARS-CoV-2 infection increased 30 percent for households with a recent birthday in counties with high rates of COVID-19 Findings suggest informal social gatherings such as birthday parties played role in infection spread at the height of the coronavirus pandemic No birthday-bash infection jumps seen in areas with low rates of COVID-19 Households with children’s birthdays had greater risk of SARS-CoV-2 infection than with adult birthdays

Newswise: COVID-19 dual-antibody therapies effective against variants in animal study
Released: 21-Jun-2021 10:05 AM EDT
COVID-19 dual-antibody therapies effective against variants in animal study
Washington University in St. Louis

A study from Washington University School of Medicine in St. Louis suggests that many, but not all, COVID-19 therapies made from combinations of two antibodies are effective against a wide range of virus variants, and that combination therapies appear to prevent the emergence of drug resistance.

13-Jun-2021 12:05 PM EDT
COVID-19 Pandemic Drinking: Increases Among Women, Black Adults, and People with Children
Research Society on Alcoholism

Risky drinking has been a public health concern in the U.S. for decades, but the significant increase in retail alcohol sales following COVID-19 pandemic stay-at-home orders in particular raised red flags for alcohol researchers. New research has assessed changes in alcohol drinking patterns from before to after the enactment of stay-at-home orders. These results and others will be shared at the 44th annual scientific meeting of the Research Society on Alcoholism (RSA), which will be held virtually this year from the 19th - 23rd of June 2021 due to the COVID-19 pandemic.

13-Jun-2021 1:05 PM EDT
The Impact of the COVID-19 Pandemic on Alcohol Consumption Is Far From ‘One Size Fits All’
Research Society on Alcoholism

An ongoing analysis of the effects of the COVID-19 pandemic on alcohol and related outcomes shows that COVID-related stressors experienced by study participants – including work-, financial-, and family-related stressors – are having a varied impact on individuals with and without alcohol use disorders (AUDs). These results will be shared at the 44th annual scientific meeting of the Research Society on Alcoholism (RSA), which will be held virtually this year from the 19th - 23rd of June 2021 due to the COVID-19 pandemic.


Showing results

110 of 5855

close
1.86439