Scientists discovered new types of cells in the respiratory system's epithelial lining that could shed new light on the mysterious sudden infant death syndrome.

Pulmonary neuroendocrine cells, or PNECs, help govern communication between the central nervous system and the respiratory system. A study published April 20 in Cell Reports describes three individualized types of these cells — two more than previously believed to exist. 

The neurotransmitter activity of some groups of these cells could change how doctors view SIDS and neuroendocrine hyperplasia of infancy, or NEHI, a rare respiratory disorder usually found in children 2 years old and younger.

"Conventionally, people are fixated on serotonergic neurons in the brain stem," said co-lead author Xingbin Ai, an associate professor of pediatrics at Harvard Medical School and director of basic research in neonatology at Massachusetts General Hospital. "We believe we have a new arm of the disease that may also be a very important pathogenic event, in addition to what's going on in the brain."

Serotonergic neurons create serotonin. Ai's lab studies the development of the nervous system in the respiratory system. According to Ai, the function of the nervous system in other organs, such as the heart or the gastrointestinal tract, is well documented, while neurological research devoted to the respiratory system tends to focus on the central nervous system, specifically the brain stem, because there are few neurons in the respiratory system itself. 

Instead, axons following the neurons outside the respiratory tract provide this neurologic input. But this lack of neurons makes studying more difficult, according to Ai. 

While researching human lung innervation, or nervous activity regulating lung function, one of Ai's graduate students found that some of the epithelial cells lining the airway expressed a neuromarker called tubulin beta 3 class III, or TUBB3. This discovery surprised Ai, but it led her and her colleagues to investigate what diseases could be connected to changes in these types of epithelial cells. 

"The study was helped by a complete lack of understanding of pathogenic mechanisms in [SIDS and NEHI]," Ai said in an interview with The Academic Times. "So that motivates our study further to understand how these neuroendocrine cells differ or not differ from your traditional endocrine cells."

Doctors generally hypothesize that SIDS, a syndrome where infants suddenly die in their sleep, occurs when the brain deregulates breathing, resulting in death. According to the U.S. Centers for Disease Control and Prevention, roughly 1,300 infants died of SIDS in 2018.

Drawing on 10 SIDS-related autopsy samples, Ai and her colleagues found that samples with high levels of serotonin also had high levels of the TUBB3-expressing cells. 

Serotonin created by neurons just outside the respiratory system helps govern communication between the lungs and the brain stem. But because these TUBB3-expressing cells also produce serotonin, the process behind SIDS and NEHI may be slightly different than what scientists once believed.   

According to Ai, PNECs help mediate environmental changes to cells in the body, so the ones that produce TUBB3 may overreact in SIDS cases during a pathogenic infection, for example. These cells may then flood the respiratory system with serotonin, a potent vasoconstrictor that narrows blood vessels. 

Ai cannot say for sure how many TUBB3-expressing cells appear in the epithelial lining. Counting them all within an entire respiratory system would be impossible, but Ai describes how in SIDS cases, they tend to cluster like large "meatballs" around the airway. These clusters may show that the TUBB3-expressing cells outnumber normal cells by 10 or even 20 to one in SIDS deaths. 

With these new findings, Ai believes doctors could eventually start measuring babies' blood serotonin levels to identify those who could be at risk of SIDS or NEHI, as well as looking for other neuromarkers similar to TUBB3.

"If these can serve as a marker, I think that is a great advancement in terms of preventing this from happening, or saving the babies who might otherwise die because of this sudden disease," Ai said.

The study, "Airway basal stem cells generate distinct subpopulations of PNECs," published April 20 in Cell Reports, was authored by Hongmei Mou and Juliana Barrios, Massachusetts General Hospital for Children; Ying Yang and Wellington V. Cardoso, Columbia University Medical Center; Molly A. Riehs, Sara O. Vargas and Robin L. Haynes, Boston Children's Hospital; Manjunatha Shivaraju, Kimberly Gilmore, Jayaraj Rajagopal, Massachusetts General Hospital; Adam L. Haber, Harvard University; Daniel T. Montoro, Broad Institute of MIT and Harvard; Elisabeth A. Haas, Rady Children's Hospital; Brankica Paunovic, San Diego County Office of the Medical Examiner; Alan Fine, Boston University; and Xingbin Ai, Harvard University and Massachusetts General Hospital.