Glycocalyx Studies Bring Precision Medicine to Critical Care

Massachusetts General Hospital physician-scientists are investigating the underlying mechanisms responsible for the heterogeneity of critical illnesses such as sepsis and acute respiratory distress syndrome (ARDS). Their research into the structure and function of the alveolar epithelial glycocalyx, a layer of sugars lining the surface of the airspaces of the lung, provides an opportunity to develop personalized diagnostic tools and treatments that can be practically employed in critical care settings like ICUs.

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"There are well-known clues in a patient's presentation that allow doctors to quickly diagnose critical illnesses such as sepsis and start standard supportive treatments. We now realize that these general diagnoses and standard treatments aren't enough: we need to go deeper to figure out not only what diagnosis a patient has, but what process was responsible for that diagnosis," says pulmonologist Eric Schmidt, MD, chief of the Division of Pulmonary and Critical Care Medicine at Mass General. "Identification of an individual's specific process of critical illness would allow us to personalize our care of that patient—something we call precision medicine—so that we can apply a customized treatment to that patient at the proper time. This precision medicine, however, is challenging in critical illness, as you have to act fast. We cannot wait days for test results to come back that tell us what specific treatment a patient needs. To truly personalize our care of the critically ill, we need to be able to perform a test at the bedside that will tell us within minutes exactly what disease process led to that patient's critical illness, so we can initiate personalized therapies targeted against that disease process."

From Oncology to Critical Care: Exploring the Heterogeneity of Critical Illness

Throughout his career, Dr. Schmidt has been committed to caring for patients in the ICU. Sepsis became a particular interest for him as he observed its devastating and unpredictable effects firsthand. "If two seemingly similar patients develop sepsis, why does one get better quickly while the other crashes? A patient has an infection that should be easily controlled. But for some reason, it sets into motion a chain of events that causes that patient's organs to fail. There must be a way to predict the risk of that patient, so we can intervene," Dr. Schmidt says.

One young patient who developed bacterial pneumonia had a particularly powerful impact on Dr. Schmidt. "He was a healthy, active man in his 20s. He had the flu—something thousands of healthy 20-year-olds get—yet he went on to develop terrible bacterial pneumonia as well. Trying to understand why that previously healthy patient developed such a devastating pneumonia started a whole line of research in my laboratory."

While precision medicine has been an important concept in oncology for decades, its role in critical care has only recently been explored. "We know instinctively that giving the same drug to a thousand patients with different cancers doesn't work. Generally speaking, you can't treat breast cancer like lung cancer, and even breast cancers are highly different," Dr. Schmidt says. "But with sepsis, every time we try to test promising new medicines in large studies, we tend to apply these medicines across a broad mix of patients with different causes of sepsis, and the medicine disappoints. In retrospect, we shouldn't be surprised that this generalized approach to treatment often doesn't work."

Dr. Schmidt says that conducting bedside-to-bench investigations has paved the way to a better understanding of the complexity and subtypes of critical illness, as well as the need to avoid broad classifications in illnesses like sepsis. "By setting up systems and follow-up studies that enable us to do this kind of bedside observation, we can aggressively figure out how to personalize our care," he says. "Understanding the nuance of disease allows us to discover more individualized treatments, which allows us to be much more effective in our prevention and treatment of illness."

Measuring the Concentration of Epithelial Glycocalyx Fragments to Diagnose Critical Illness

The glycocalyx is a glycosaminoglycan-rich layer that lines the surface of many cells, including the endothelium inside of blood vessels. Dr. Schmidt spent the first half of his career publishing critical care research papers that studied the structure of this endothelial glycocalyx and its impact on the function of blood vessels during health and disease. In a paper published in Nature Medicine in 2012, Dr. Schmidt's laboratory found that degradation of the pulmonary endothelial glycocalyx during sepsis was a key early event in lung dysfunction.

Inspired by the curiosity of one of Dr. Schmidt's PhD students, five years ago Dr. Schmidt's group expanded its focus beyond the blood vessels, asking if the epithelium lining the lung airspaces similarly had a glycocalyx. While the presence of such a glycocalyx was proposed more than five decades ago, little was known about its structure or function. "We discovered these airspace sugars are also important for keeping lung physiology normal," says Dr. Schmidt. "The epithelial glycocalyx forms a smooth layer necessary for surfactant function, which is important to prevent lungs from collapsing during exhalation."

Using murine models, his team demonstrated that when conditions like ARDS, pneumonia, COVID-19, or influenza damage lungs, the alveoli shed epithelial glycocalyx fragments into the airspace. In a 2022 study published in JCI Insight, Dr. Schmidt's team sought to determine if similar shedding occurred in human patients. They collected alveolar fluid from patients who were mechanically ventilated. They then developed and employed an inexpensive test to measure the concentration of alveolar epithelial glycocalyx fragments in that fluid. "If there are a lot of sugars shed into the exhaled fluid, that may hint at the kind of lung dysfunction the patient has and potentially allow us to develop a personalized treatment for it," says Dr. Schmidt. "We are now trying to create a blood test, which allows us to make similar measurements of glycocalyx degradation even in people who are not on a mechanical ventilator."

A 2022 Cell Reports study added to these discoveries by demonstrating that the risk and severity of secondary bacterial pneumonia increases as epithelial glycocalyx fragment concentration does. "That may be what happened with my young patient so many years ago—he had a viral infection, which could have released all these sugars into his airspace that bacteria exploited," Dr. Schmidt explains. "I hypothesize that if we detect these sugars early on, we can predict who is at risk for getting this devastating secondary pneumonia and intervene earlier to prevent it."

Examining Sex and Gender to Personalize ICU Interventions

In the JCI Insight study, Dr. Schmidt's team also observed an unexpected yet striking difference between the alveolar epithelial glycocalyx shedding of men and women. "We found that women's glycocalyces are much more resilient against injury than men's," Dr. Schmidt adds. "These findings have allowed me to start working with brilliant collaborators who are experts in sex and gender research. Understanding how biological sex and societal gender affects these biologic phenotypes is incredibly understudied, and it is now a major focus of ours."

Dr. Schmidt is taking advantage of multidisciplinary partnerships across Mass General for these investigations. "For example, Thomas H. McCoy, MD, the director of research at the Center for Quantitative Health, has this incredible wealth of data that could help us better understand how biology and society influence heterogeneity," he says. "Can we understand how men and women are treated differently in the ICU? Does one gender get moved to the ICU earlier? Are they managed the same way on the ventilator? Understanding this will help us better care for individuals."

Bedside-to-Bench Research Creates More Personalized Care Opportunities

Dr. Schmidt's lab also continues to study blood vessels, with the goal to investigate if and how clinical interventions in sepsis unexpectedly shapes or interferes with endothelial glycocalyx damage. "We are working to understand how what we do as clinicians—fluid resuscitation strategies, for example—may change the kind of shedding that happens. Are there ways we unwittingly worsen this shedding with our treatment choices?"

Dr. Schmidt's team has published research showing that endothelial glycocalyx fragments can travel to the brain, where they interfere with memory formation. "People who survive sepsis often experience problems with memory and clarity of thought. We need to learn so much more about how these fragments cause this and other forms of cognitive impairment."

In his role as Division Chief, Dr. Schmidt is also focused on helping Pulmonary and Critical Care Medicine's faculty members thrive through professional fulfillment and excellence in patient care. "The best part about being a physician-scientist is I have the tools to answer the important questions that inevitably arise when caring for patients," he says. "My laboratory has been lucky enough to experience a lot of success throughout my career, and at Mass General, we all have the opportunity to do it on a grander scale."

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