Dual Roles of Cela1 and AAT Open Doors for Emphysema Research

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.”

An image of a western blot and a bar chart.

Click image to learn more.

An image of lung tissue slides.

Click image to learn more.

A photo of Brian Varisco, MD.

Brian Varisco, MD

Citation

Joshi R, Heinz A, Fan Q, Guo S, Monia B, Schmelzer CEH, Weiss AS, Batie M, Parameshwaran H, Varisco BM. Role for Cela1 in Postnatal Lung Remodeling and Alpha-1 Antitrypsin-Deficient Emphysema. Am J Respir Cell Mol Biol. 2018 Aug;59(2):167-178.