Breaking News
November 16, 2018 - High school students less likely to select milk, fruit for lunch when fruit juice is available
November 16, 2018 - Football coaches with great emotional competence are more successful
November 16, 2018 - Researchers awarded $10 million grant to address root causes of asthma in Puerto Rico
November 16, 2018 - Health Tip: Manage Morning Sickness
November 16, 2018 - Immunotherapy combination and chemotherapy show encouraging results in Phase II acute myeloid leukemia study
November 16, 2018 - ACC Latin America Conference brings experts to discuss latest cardiovascular science
November 16, 2018 - Pooled analysis of Intersect ENT’s steroid releasing implants in patients after frontal sinus surgery to be published
November 16, 2018 - Expectations about pain intensity can become self-fulfilling prophecies
November 16, 2018 - NIH awards $3.4 million to UC researchers to study gastrointestinal lymphatic system
November 16, 2018 - Scientist Dr David Taylor of MR Solutions is a finalist in the BMW i UK Tech Founder Awards
November 16, 2018 - Earlier treatment could help reverse autistic-like behavior in tuberous sclerosis
November 16, 2018 - Vegetables and salad may include bacteria that are resistant to antibiotics
November 16, 2018 - Endocrine Society chooses four Diabetes Caucus leaders as winners of Diabetes Champion Award
November 16, 2018 - Brain and muscle cells found within kidney organoids
November 16, 2018 - Person’s sex hormones may play key role in trauma survival, finds study
November 16, 2018 - PTEN Genetic Test: MedlinePlus Lab Test Information
November 16, 2018 - Toxic metal pollution linked with development of autism spectrum disorder
November 16, 2018 - Calcified nodules in the retina increase risk for progression to late stages of AMD
November 16, 2018 - ZEISS teams up with arivis AG to offer complete 3D imaging solutions
November 16, 2018 - Georgia State professor receives $1.2 million grant to study how the brain controls eating behavior
November 16, 2018 - Specific bacterial toxins reduce number of cells suppressing immune response
November 16, 2018 - Review by ID physician improves outcomes for outpatient parenteral antimicrobial therapy
November 16, 2018 - Conditions that produce signs similar to arthritis
November 16, 2018 - New artificial intelligence-based method predicts treatment effectiveness
November 16, 2018 - AHA: Dapagliflozin Noninferior to Placebo for MACE in T2DM
November 16, 2018 - Surgery remains best treatment for appendicitis, Stanford study finds
November 16, 2018 - Non-surgical fistula creation system Ellipsys becomes key focus of attention at CiDA
November 16, 2018 - Researchers find no link between ‘allergy friendly’ dogs and lower risk of asthma
November 16, 2018 - Researchers elucidate new rules of connectivity of neurons in the neocortex
November 16, 2018 - Treating children with ‘bubble baby disease’
November 16, 2018 - Nexus announces availability of Arsenic Trioxide Injection in the US
November 16, 2018 - Researchers find metabolite shuttle between cells in the liver that may combat tissue fibrosis
November 16, 2018 - AHA: PTSD Common Among Those Who Suffer Tear in the Aorta’s Wall
November 16, 2018 - Many RA patients’ pain related to central nervous system
November 16, 2018 - Changes in Himalayan gut microbiomes linked to diet
November 16, 2018 - Inhibition of prostaglandin E2 enhances ability to combat infectious colitis
November 16, 2018 - Chronic dry eye can slow reading rate and disrupt day to day tasks
November 16, 2018 - Researchers develop new drug molecule that inhibits inflammation
November 16, 2018 - Dementia symptoms peak in winter and spring, study finds
November 16, 2018 - Stanford tobacco researcher weighs in on JUUL
November 16, 2018 - Increasing omega-3 fatty acid intake during pregnancy reduces risk of premature birth, review finds
November 16, 2018 - Researchers find no link between infants waking up at night and later developmental problems
November 16, 2018 - Both parents and children agree about confidential medical services
November 16, 2018 - FDA warns against use of unapproved pain medications with implanted pumps
November 16, 2018 - Precision medicine-based approach to slow or reverse biologic drivers of Alzheimer’s disease
November 16, 2018 - Study provides new insight into norovirus outbreaks, may help guide efforts to develop vaccines
November 16, 2018 - Inexpensive, portable air purifier could help protect the heart from pollution
November 16, 2018 - New 15-minute scan could help diagnose brain damage in babies up to two years old
November 16, 2018 - Deep brain stimulation not effective for treating early Alzheimer’s
November 16, 2018 - Traditional chemotherapy superior to new alternative for oropharyngeal cancers | News Center
November 16, 2018 - What This Pond Protist Does With Its Genome Will Astound You
November 15, 2018 - Researchers develop tool that speeds up analysis and publication of biomedical data
November 15, 2018 - Scientists identify mechanism used by lung cancer cells to obtain glucose
November 15, 2018 - Abnormalities in development of the brain could be involved in onset of autism, finds new study
November 15, 2018 - Soy protein equally effective as animal protein in building muscle strength
November 15, 2018 - American Academy of Pediatrics, Nov. 2-6
November 15, 2018 - Dopamine drives early addiction to heroin
November 15, 2018 - Variance in gut microbiome in Himalayan populations linked to dietary lifestyle | News Center
November 15, 2018 - Reducing Cardiovascular Disease: The Amish Way
November 15, 2018 - King’s researchers launch charter to guide organizations to engage abuse survivors in research
November 15, 2018 - Enable Injections enters into development agreements with UCB and Apellis Pharmaceuticals
November 15, 2018 - TGen North collaborates with NARBHA Institute to advance human health
November 15, 2018 - Researchers discover molecular basis for therapeutic actions of an African folk medicine
November 15, 2018 - Human Cell Atlas study of early pregnancy shows how mother’s immune system is modified
November 15, 2018 - New guidelines for detecting and managing sarcopenia to be launched in the UK
November 15, 2018 - Researchers explore role of dietary composition on energy expenditure
November 15, 2018 - Elsevier launches Entellect™ Platform, unlocking value by creating AI-ready life sciences data
November 15, 2018 - Now that cannabis is legal in Canada, let’s use it to tackle the opioid crisis
November 15, 2018 - In the Spotlight: At the intersection of tech, health, and ethics
November 15, 2018 - Traditional Glaucoma Test Can Miss Severity of the Disease
November 15, 2018 - Researchers directly connect activities of genes with instinctive behavior in male cichlids
November 15, 2018 - Salk researchers report new methods to identify AD drug candidates with anti-aging properties
November 15, 2018 - St. Jude Hospital announces availability of largest collections of leukemia samples
November 15, 2018 - Attenua Announces First Patient Treated in Phase 2 Clinical Trial in Chronic Cough with Bradanicline
November 15, 2018 - Designing a novel cell-permeable peptide chimera to promote wound healing
November 15, 2018 - NEI investigators combine two imaging modalities to view the retina in unprecedented detail
November 15, 2018 - Determining how hearts develop to better understand congenital heart defects
November 15, 2018 - Maverick immune cells can act independently to identify and kill cancer cells, finds research
November 15, 2018 - Advanced AI and big data methods to tackle dementia
November 15, 2018 - Report reveals increase in pancreatic cancer death rates across Europe
Molecular pathway offers treatment targets for pulmonary fibrosis, related conditions

Molecular pathway offers treatment targets for pulmonary fibrosis, related conditions

image_pdfDownload PDFimage_print
A chest radiograph of a patient with Idiopathic Pulmonary Fibrosis (IPF). Credit: Wikipedia/CC BY-SA 3.0

A study led by investigators at Massachusetts General Hospital (MGH) and University Health Network (UHN) in Toronto has identified a molecular pathway that appears to be critical to the development of fibrosis – scarring and excessive tissue deposition that result from abnormal healing responses and can compromise the function of vital organs. In their report that has received advance online publication in Nature Medicine, the researchers describe a series of molecular interactions that are essential for the induction of lung and skin fibrosis in a mouse model and appear to be active in human fibrotic lung disease.

“The ability of organs to regenerate following injury declines with age, so aberrant healing in response to chronic tissue injury in aged individuals can result in fibrosis – which contributes to 45 percent of deaths in the developing world,” explains David Lagares, PhD, director of the Matrix and Mechanobiology Program at the MGH Fibrosis Research Center, co-corresponding author of the report. “Fibrosis is a component of chronic kidney disease, liver cirrhosis and pulmonary fibrosis; and the pathway we have identified could be a therapeutic target for halting the process and for restoring organ function.”

Normal healing requires the interaction of many cell types – immune cells, stem cells, and the connective tissue cells called fibroblasts. Activated fibroblasts are called myofibroblasts and orchestrate many aspects of the healing process. But severe or repetitive injury can cause myofibroblasts to become hyperactive, setting off an out-of-control tissue buildup that leads to fibrosis. The molecular mediators underlying fibroblast activation are poorly understood, and their identification was a primary focus of the current study.

“We specifically wanted to identify factors that could control profibrotic activity without affecting normal wound healing,” says co-corresponding author Mohit Kapoor, PhD, director of Arthritis Research in the Krembil Research Institute at UHN. “Identifying these factors will not only further enhance our understanding of the pathogenesis of fibrosis but will also provide new antifibrotic targets for multiple diseases.”

The investigators first searched a gene expression database for genes that were upregulated in fibroblasts from patients with two important fibrotic diseases – idiopathic pulmonary fibrosis (IPF) and systemic sclerosis or scleroderma – compared with healthy individuals. One of the genes they identified codes for the cell membrane protein ephrin-B2, which binds to receptors on adjacent cells. During normal development ephrin-B2 regulates the formation and assembly of blood vessels, and its activity has been associated with the development of new blood vessels within and around malignant tumors.

After confirming increased ephrin-B2 expression in a set of lung fibroblasts from patients with IPF, the team found that suppressing ephrin-B2 expression blocked the development of lung fibrosis in a mouse model. Further investigation revealed that the attraction of additional fibroblasts to sites of lung injury and their activation into myofibroblasts was set off when the portion of the ephrin-B2 protein that extends outside the cell membrane was clipped off by an enzyme called ADAM10, releasing a molecule called sEphrin-B2.

“Finding that this extracellular portion of ephrin-B2 was cleaved from the cell surface and secreted into the airspace following lung injury was totally unexpected and led us to hypothesize that this soluble form of ephrin-B2 may contribute to lung fibrosis,” says Lagares, a principal investigator in the MGH Division of Pulmonary and Critical Care Medicine and faculty member at Harvard Medical School. “While ephrin-B2 typically interacts with receptors on different types of cells, both ephrin-B2 and its receptors are expressed on the surface of myofibroblasts, where their interaction usually suppresses the process leading to the overaccumulation of fibrotic tissue. In the novel mechanism we have discovered, the release of sEphrin-B2 prevents that inhibitory interaction and activates the receptors, leading to the amplification of tissue fibrosis.”

In their mouse model of lung fibrosis, the inhibition of ADAM10 prevented the shedding of sEphrin-B2 and reduced fibrosis and death. Increased ADAM10-sEphrin-B2 signaling was also found in lung fibroblasts from IPF patients, and the enzyme’s inhibition reduced sEphrin-B2 shedding in cells from both IPF patients and healthy volunteers. Suppression of ADAM10-sEphrin-B2 signaling also reduced the expression of several fibrosis-associated proteins in myofibroblasts from patients with IPF, and levels of sEphrin-B2 were higher in both lung fluid and plasma from patients than from healthy volunteers.

“Myofibroblasts are absent in healthy tissues, but their numbers and activity are markedly increased in fibrotic diseases,” says Kapoor, a senior scientist at UHN. “Our identification of the ADAM10-sEphrin-B2 pathway as a promoter of myofibroblast activation gives us a number of attractive therapeutic targets for pulmonary and other fibrotic diseases.” The team is continuing to investigate the fibrogenic program induced by ephrin-B2 signaling in activated myofibroblasts and testing the potential efficacy of neutralizing ephrin-B2 antibodies in tissue fibrosis.

A guiding force behind this work was the late Andrew Tager, MD, of the MGH Pulmonary and Critical Care Medicine, who founded what is now the Andrew Tager Fibrosis Research Center. “Andy was a giant in pulmonary fibrosis research and one of the most influential scientific minds in the field. His vision and insight were crucial to the discovery of the ADAM10-sEphrin-B2 pathway in pulmonary fibrosis” says Lagares. A co-author of this Nature Medicine paper and an associate professor of Medicine at Harvard Medical School, Tager passed away in August 2017.


Explore further:
Newly identified growth factor inhibitors selectively target the cells that cause fibrosis

More information:
David Lagares et al, ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis, Nature Medicine (2017). DOI: 10.1038/nm.4419

Journal reference:
Nature Medicine

Provided by:
Massachusetts General Hospital

Tagged with:

About author

Related Articles