Published August 2018 | American Journal of Respiratory Cell and Molecular Biology

The interplay between the digestive protease chymotrypsin-like elastase (Cela1) and the lung-protective protein alpha-1 antitrypsin (AAT) in prenatal lung development not only plays a causal role in emphysema but also opens the door for potential treatments for a specific form of the breathing disorder.

Emphysema is the fourth-leading indication for lung transplants in adults. An in-depth study led by researchers from the Division of Critical Care Medicine found that Cela1 is entirely responsible for physiologic and pathologic stretch-dependent remodeling processes in the postnatal lung, and that its expression increases in AAT deficiency-related lung disease (AAT-RLD), a disorder the strikes in middle age.

Led by Brian Varisco, MD, the division’s clinical researcher, the team used CRISPR technology to create a Ce-la-1 knockout mouse. They regulated AAT by exposing it to a known oligonucleotide that affects RNA synthesis and release.

The team found that in the absence of AAT, continued lung remodeling leads to characteristic AAT-deficient emphysema, creating therapeutic potential for Cela-1 targeting in follow-up studies that his team currently is conducting.

“Current treatments for this type of emphysema are symptom-based, with no therapy that addresses the lung destruction involved in emphysema,” Varisco explains. “Cela1 is potentially an accessible and specific target for the treatment of AAT-RLD. This finding opens the door to therapies that target the structural basis of emphysema.”