In This Article
- Pulmonary vascular clotting is common in acute respiratory distress syndrome (ARDS) and is associated with worse outcomes, but existing anticoagulant and antiplatelet therapies have not improved outcomes in patients with ARDS
- A Massachusetts General Hospital pulmonary and critical care physician has found that hypoxia upregulates the expression of a protein called NEDD9 in the pulmonary vasculature, which promotes clotting by binding activated platelets
- NEDD9 is significantly increased in the pulmonary vasculature of patients with ARDS, especially when due to COVID-19
- A national foundation award for underrepresented junior faculty will support testing a novel antibody to inhibit NEDD9-platelet interactions in animal models, a potential future therapy for patients with ARDS
A pulmonologist at Massachusetts General Hospital has won a national four-year foundation award to continue his research into the role of the protein NEDD9 in mediating pulmonary vascular dysfunction in acute respiratory distress syndrome (ARDS). The grant will help build on his body of work showing that NEDD9 could be a therapeutic target in patients with pulmonary thromboembolic disorders.
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"ARDS is a heterogeneous disorder, and to this point, blanket treatment with anticoagulant and antiplatelet medications hasn't worked. Some patients with ARDS have significant pulmonary blood vessel clotting, which puts them at higher risk of death. This high-risk subgroup could potentially benefit from targeted treatment," says George Alba, MD, a critical care physician and pulmonologist at Mass General. "My goal is to test whether inhibiting interactions between NEDD9 and platelets could serve as a potential therapy."
Research Finds Relationship Among NEDD9 Protein, Platelets, and Clotting
NEDD9 is a known protein relevant to cancer biology. Recently, Dr. Alba's mentor, Bradley Maron, MD, of the Heart and Vascular Center at Brigham and Women's Hospital, identified its role in pulmonary vascular fibrosis. Now, they are studying its potential role in potentiating acute lung injury by promoting platelet-endothelial adhesion.
Dr. Alba became interested in pulmonary vascular disease and lung injury during his pulmonary and critical care fellowship at Mass General. "Certain patients with pulmonary embolism have incomplete resolution of their blood clots, which can lead to significant remodeling and severe pulmonary hypertension," Dr. Alba says. "I became interested in this form of pulmonary hypertension called chronic thromboembolic pulmonary hypertension, or CTEPH. It is the only form of pulmonary hypertension that can be cured surgically with pulmonary thromboendarterectomy [PTE]."
Mass General is a major CTEPH referral center and receives a large volume of CTEPH patients referred for treatment of this rare condition, including PTE. Dr. Alba said the relatively rare patient population with access to precious surgical samples provided a unique opportunity to study his question in greater detail. He partnered with Dr. Maron's laboratory to examine surgical specimens, endothelial cells, and platelets from patients in combination with transgenic animal models to understand mechanisms relevant to the development of CTEPH. "I was interested in understanding why some patients develop pulmonary hypertension and persistence of blood clots while others do not."
"We discovered that hypoxia causes an upregulation of NEDD9 in the pulmonary vascular endothelial cells lining the blood vessels in the lungs. We also found that patients with pulmonary hypertension, including CTEPH, had higher blood levels of NEDD9," Dr. Alba says. "We then dug down into the cells themselves, trying to understand where NEDD9 is located and what role it may have. We identified that a portion of NEDD9 is expressed on the surface of the cells and directly interacts with activated platelets to promote platelet-endothelial binding."
The researchers developed a novel antibody that successfully inhibited pulmonary endothelial NEDD9 and decreased platelet-endothelial adhesion and pulmonary vascular clotting in animal models. Dr. Alba's work was published in the American Journal of Respiratory and Critical Care just as the COVID-19 pandemic was about to change everything.
NEDD9's Role in COVID-19 Lung Injury
As SARS-CoV-2 spread, Mass General cared for hundreds of patients with ARDS due to COVID-19. "Laboratory operations shut down, and I was taking care of patients in the ICU with significant lung injury, low oxygen levels, and frequent clotting complications. I began to investigate whether upregulation of NEDD9 in the lung blood vessels is also evident in patients with ARDS due to COVID-19 and whether it was associated with increased clotting in the lungs," says Dr. Alba.
Dr. Alba also serves as associate director of the Mass General Pulmonary Coronavirus Recovery (CORE) Clinic which follows patients with persistent pulmonary symptoms following COVID-19, many of whom survived ICU stays for ARDS. Using autopsy specimens, he showed that NEDD9 is upregulated in the lung blood vessels of patients with COVID-19-related ARDS and is associated with increased blood clots in the lung. Those results were published in Pulmonary Circulation in April 2022.
Alba Wins National Award for Research by Underrepresented Junior Faculty
Dr. Alba is now poised to continue his NEDD9 antibody research with a career development award from the Harold Amos Medical Faculty Development Program. He is the inaugural recipient of the jointly funded award supported by the CHEST foundation, American Thoracic Society, and American Lung Association. The program is designed to increase the number of faculty from historically disadvantaged backgrounds and to support the careers of those who can achieve senior rank in academic medicine and other health fields.
Through this award, Dr. Alba aims to rigorously study the role of inhibiting platelet-endothelial adhesion in animal models of ARDS using transgenic mice and anti-NEDD9 antibody-treated mice. In doing so, Dr. Alba hopes to determine whether inhibiting pulmonary endothelial NEDD9, and consequent platelet adhesion and clotting, is a viable potential therapeutic option for patients with ARDS.
He will continue to work closely with several mentors whom he credits with helping him to establish his line of inquiry and advance his career development: his long-standing research mentor, Dr. Maron; Eric P. Schmidt, MD, chief of the Division of Pulmonary and Critical Care Medicine and a leading expert in the interrogation of animal models of ARDS; Kathryn A. Hibbert, MD, director of the Mass General Medical ICU and academic role model; and Sherri-Ann Burnett-Bowie, MD, MPH, associate director of the Mass General Center for Diversity and Inclusion and long-time career advisor.
"My clinical work in the ICU and post-ARDS clinic serves as my inspiration for the research questions that I pursue," Dr. Alba says. "I'm lucky to be in a place that is outstanding clinically, has a robust research environment, provides access to a variety of mentors throughout Boston, and is committed to developing a pipeline of diverse junior faculty."
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