During her fellowship training, Christina M. Eckhardt, MD, MS, a pulmonologist and researcher in the Division of Pulmonary, Allergy, and Critical Care Medicine at NewYork-Presbyterian/Columbia, quickly realized that timeliness of diagnosis is vital in order to optimize treatment and outcomes for patients with chronic lung diseases. “I began thinking more closely about ways to identify patients earlier in their course so that we can start treating them earlier,” says Dr. Eckhardt. “It became very apparent that once the horse has left the barn, there are few treatments that can repair existing damage in the lungs. I started to think, how do we keep the horse in the barn?”
Dr. Christina Eckhardt
Dr. Eckhardt’s research interests led her to work closely with Andrea Baccarelli, MD, PhD, the Leon Hess Professor and Chair of the Department of Environmental Health Sciences at Columbia and Dr. Eckhardt’s mentor. “We started looking at extracellular vesicles, which are nano-sized vesicles that arise naturally from cells in the lung and contain biologically active cargo, including EV-encapsulated microRNAs, or EV-miRNAs for short,” says Dr. Eckhardt. “Emerging research suggests EV-miRNAs may provide a mechanistic link between inhaled exposures and the pathogenesis of chronic lung diseases. They can create a systemic inflammatory response that seems to contribute to lung damage and early changes in the lungs that precede chronic lung diseases. We began investigating these potential biomarkers that can help identify signs of early lung damage at a point in time where we can possibly intervene.”
As Dr. Eckhardt explains, most diseases stem from an interplay of genetic makeup and the environment. “Some diseases are much more driven by genes, such as cystic fibrosis. Other diseases, such as COPD, are much more driven by the environment and whether you smoked or had certain inhaled exposures over your lifetime,” she says. “MicroRNAs are important in that they are biologically active. There is evidence that if you expose lung cells to particulate matter air pollution, for example, those lung cells release these extracellular vesicles that contain microRNAs. Those EVs containing this miRNA cargo are released into the systemic circulation where they are then taken up by recipient cells. The miRNAs then degrade mRNA transcripts in the recipient cell, thereby altering the biology in that cell.”
Dr. Eckhardt and her colleagues in the Baccarelli Laboratory have focused their research on inhaled exposures such as smoking and air pollution that trigger a proinflammatory signaling cascade that is linked to remodeling and damage in the lungs. This cascade can potentially be the precursor to more chronic diseases, including COPD.
“We are looking to characterize miRNA expression in people who already have chronic lung diseases,” says Dr. Eckhardt. “If we can identify dysregulated miRNA expression in a patient with COPD, can we then in the future re-engineer EVs and their miRNA cargo to either carry miRNAs that are deficient in COPD or block miRNAs that are in excess? Can that potentially represent a precise way to treat or prevent COPD? That is our next question and next area of focus. It is not currently possible, but we hope that this research will build the foundation for that type of work.”
“This is the first extracellular vesicle-wide association study to evaluate associations of global plasma EV-miRNAs with lung function in humans. The study suggests that EV-miRNAs may represent a viable biomarker of subclinical lung injury and may help identify individuals at risk of developing lung function impairment.” – Dr. Christina Eckhardt and study co-authors
Dr. Eckhardt recently led a National Institute of Environmental Health Sciences-funded multicenter study to evaluate associations of plasma EV-miRNAs with lung function. The study involved individuals enrolled in the U.S. Veterans Affairs Normative Aging Study (NAS). The NAS cohort consisted of 2,280 men in New England aged 21 to 80 years who were free of chronic disease at the time of entry. In the current study, participants’ EV-miRNAs were measured at baseline from 1996 to 2015 and spirometry every 3 to 5 years through 2019. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the Health Effects of Arsenic Longitudinal Study (HEALS). The results, which were published in the January 1, 2023, issue of the American Journal of Respiratory and Critical Care Medicine, showed:
- In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function, 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort
- A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample
- Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity
“The results from our research suggest that these EV-encapsulated miRNAs may represent a robust biomarker of early lung injury and may help identify individuals who are at risk of developing lung function impairment and lung diseases in the future,” says Dr. Eckhardt. “More research is needed to delve deeper into these markers and their biological roles. Our goal is to develop potential strategies to change expression of these markers to further unlock a potentially rich resource for improving prevention and treatment of chronic lung diseases.”
“I think that the next phase of our understanding of each person’s individual risk will be based on the interplay of their genes and the environmental exposures that they’ve encountered throughout their life,” adds Dr. Eckhardt. “Developing a deeper understanding of the interplay between those two factors will shed light on understanding disease risk and identifying new strategies to prevent chronic diseases.”