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Home » Elevated Carbon Dioxide Linked to Restricted Airway
Disease Discoveries

Elevated Carbon Dioxide Linked to Restricted Airway

By Will DossSep 21, 2018
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Jacob Sznajder, MD, the Ernest S. Bazley Professor of Asthma and Related Disorders, professor of Medicine in the Division of Pulmonary and Critical Care and of Cell and Molecular Biology and senior author of the study published in Science Translational Medicine (center). Emilia Lecuona, PhD, research associate professor of Medicine in the Division of Pulmonary and Critical Care and co-author of the study (left). Masahiko Shigemura, PhD, postdoctoral research fellow in the Sznajder laboratory and first author of the study (right).

A new study finds that excessive carbon dioxide in a patient’s bloodstream can lead to a restricted airway, calling into question current clinical practices for patients with chronic obstructive pulmonary disease (COPD).

“Currently, reducing carbon dioxide is not part of the recommendation for treating patients with COPD,” said Jacob Sznajder, MD, the Ernest S. Bazley Professor of Asthma and Related Disorders and senior author of the study published in Science Translational Medicine. “These patients can have an asthma-like effect, which can be very dangerous for them.”

The study of volatile gases like carbon dioxide interacting with the human body is only a few decades old, according to Sznajder, beginning with the 1986 discovery of nitric oxide’s involvement in cardiovascular function. As such, many gases previously considered inert may have biological effects with clinical impact.

In the current study, Sznajder and his colleagues examined the effects of carbon dioxide on smooth muscle cells that line the airways of mice.

“Patients with lung diseases often have high levels of carbon dioxide in their bloodstream, but it’s not considered harmful,” said Sznajder, who’s also a professor of Medicine in the Division of Pulmonary and Critical Care and of Cell and Molecular Biology. “In fact, some investigators felt it was even beneficial.”

Surprisingly, they found that elevated levels of carbon dioxide in the tissues and bloodstream, a condition known as hypercapnia, led to contraction in these smooth muscle cells, causing the airway to constrict. Working backwards, they painstakingly traced the signaling pathway, finding that a protein called caspase 7 served as a fork in the road.

“Usually, caspase 7 regulates apoptosis, or natural cell death,” said Masahiko Shigemura, PhD, postdoctoral research fellow in the Sznajder laboratory and first author of the study. “In this case, it has a new role during hypercapnia.”

Airway constriction in high-carbon dioxide environment. Airways in room air (left), and in high-carbon dioxide air (right) before (top) or after (bottom) agonist stimulation.

Hypercapnia leads to increased calcium, which in turn activated a different function in caspase 7: Instead of regulating cell death, caspase 7 down-regulated certain micro-RNA, which eventually led to smooth muscle contraction and bronchial constriction in mouse models.

The investigators also examined if there was a correlation between hypercapnia and airway restrictions in patients with COPD, working with collaborators in Japan and Spain. According to the study, airway resistance was increased in hypercapnic patients and decreased when carbon dioxide levels returned to normal, corroborating the scientific discoveries made in the Sznajder laboratory.

“What we showed in animals, our collaborators corroborated in patients,” Sznajder said. “Hopefully this will trigger a paradigm shift in COPD — we want to change the practice of exposing patients to high carbon dioxide levels.”

Next, Shigemura and Sznajder hope to identify the carbon dioxide “sensor,” the combination of molecular signaling and physical structures in the body that identify carbon dioxide and jump-start the signaling cascade.

“We are closing in on the sensor, which is so far undiscovered,” Shigemura said. “If we discover the sensor, that could open new scientific frontiers.”

Other Northwestern authors include Emilia Lecuona, PhD, research associate professor of Medicine in the Division of Pulmonary and Critical Care; Francisco J. Gonzalez-Gonzalez, PhD, postdoctoral fellow; Lynn Welch, research laboratory manager; Luciano Amarelle, MD, postdoctoral fellow in the Sznajder laboratory; Seok-Jo Kim, PhD, research assistant professor of Medicine in the Division of Pulmonary and Critical Care; and GR Scott Budinger, MD, chief and professor of Pulmonary and Critical Care in the Department of Medicine, the Ernest S. Bazley Professor of Airway Diseases, a professor of Cell and Molecular Biology and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

This study was supported in part by National Institutes of Health grants HL-085534, HL-071643 and HL-048129.

Cell and Developmental Biology Health and Lifestyle Pulmonology Research
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