When sprinters gasp for breath at the end of a run and air rushes into their lungs, it passes through a branching network of bronchial tubes. To really bring the oxygen in, the airway smooth muscle (ASM) that surrounds these tubes loosen up. But that’s not something people with healthy lungs need to worry about; the process occurs automatically.
“When I take that big breath and stretch, my muscle fluidizes,” said Rama Krishnan, a bioengineer at Harvard University. “In an asthmatic on the other hand, a deep breath does not provide them relief.”
People with asthma have more ASM, and that tissue squeezes their airways more forcefully in response to the signaling molecules released when allergies, illnesses, or physical stimuli cause inflammation in the lungs. A puff of albuterol or another beta-agonist can disrupt the cell signaling pathways that promote ASM contraction, relaxing the bronchi. However, overuse of beta-agonists can lead to desensitization, so researchers, including Krishnan, are looking for other therapeutic targets.

Rama Krishnan studies the machinery that drives airway smooth muscle contraction and bronchial constriction in asthma.
Credit: Rama Krishnan
That search has led Krishnan to the protein neuronal (N)-cadherin. He and his team found that it plays an essential role in ASM contraction and that inhibiting it prevents bronchial constriction, according to a study they recently published in Science Advances (1).
Krishnan has been studying the mechanical properties of ASM cells for decades, but discovering N-cadherin’s role in contraction and force generation still came as a surprise. He had been collaborating with Kirk Druey, an immunologist at the National Institute of Allergy and Infectious Diseases, when they found that mice with fungus-induced asthma symptoms had higher levels of N-cadherin protein in their lungs.
“Then, my interest in mechanical transduction, force generation, and muscle got us thinking about the contractility itself,” said Krishnan.
In the present study, Krishnan and his team showed that human ASM cells also express N-cadherin. The protein was especially prevalent in the lung sections of patients who had died from acute asthma attacks.
To learn more about the role of N-cadherin in ASM cells and asthma, Krishnan’s team generated mice whose ASM cells lacked one copy of the N-cadherin gene. The researchers then exposed both N-cadherin-deficient and wild type mice to a mold, causing the animals to develop allergic asthma. When the mice later breathed in mold, their lungs became inflamed, regardless of how much N-cadherin they expressed.
Despite this initial similarity, the N-cadherin-deficient mice did not develop severe airway constriction in response to mold exposure while wild type mice did. However, the wild type asthmatic mice experienced relief from bronchial constriction when Krishnan’s team injected them with ADH-1, an experimental drug that inhibits N-cadherin and is currently in clinical trials as a cancer therapeutic. These results suggest that disrupting N-cadherin could keep airways open even when patients with asthma are experiencing inflammation in their lungs.
“That’s not surprising,” said Dale Tang, a molecular biologist at Albany Medical College who was not involved in the present study. “Inflammation is upstream of contraction.”
While the classical approach to treating asthma has long emphasized steroids that suppress the immune response, Tang, Krishnan, and others in the field are increasingly turning their attention to downstream targets that are directly responsible for airway constriction. “If you can inhibit muscle contraction to occur in the first place, you can then inhibit the asthmatic attack,” said Krishnan.

Contraction of the airway smooth muscle cells drives severe bronchial constriction in patients with asthma.
Credit: iStock.com/ttsz
To investigate N-cadherin’s role in ASM force production, Krishnan’s team cultured human ASM cells on a soft substrate that allowed them to measure contraction via physical changes to the substrate. Treating the ASM cells with ADH-1 reduced the substrate movement, showing that inhibiting N-cadherin reduced the force the cells could produce.
But being the engineer that he is, Krishnan wasn’t satisfied knowing that N-cadherin plays some role in ASM force production; he wanted to know its precise contribution. So, Krishnan and his team decided to investigate the interaction between N-cadherin and F-actin, the polymeric form of the actin protein through which myosin can transmit force. Inhibiting N-cadherin reduced the presence of these rigid filaments, making the ASM cells more fluid and less capable of developing force.
Tang appreciated the novelty of Krishnan’s finding. “Smooth muscle contraction can be viewed as the moving of a car,” said Tang. He explained that most people focus their attention on myosin, which serves as the motor in his analogy. “They focused on the transmission system, which is new,” said Tang.
The existence of ADH-1 as a drug than can inhibit N-cadherin also excited him, although he acknowledged there is still work required to develop it into a therapeutic for asthma. Once it’s injected, ADH-1 only remains active in the body for a couple of hours, and its effects rapidly wear off.
If you can inhibit muscle contraction to occur in the first place, you can then inhibit the asthmatic attack.
- Rama Krishnan, Harvard University
In addition, ADH-1 currently exists in an injectable form, which makes sense for treating cancer, but not asthma. “Another interesting and important change would to be turn it into an inhalable,” said Krishnan. But Krishnan noted that there are many compounds that can inhibit N-cadherin, so even if ADH-1 doesn’t work, there are other options to explore.
For now, though, Krishnan is focused on another question. While his team did find evidence that inhibiting N-cadherin promoted airway dilation in beta-agonist-desensitized mice, Krishnan wants to try this treatment strategy in a variety of mouse models before he’s confident moving toward human trials. “What we need to show is: Will this N-cadherin antagonist overcome that desensitized effect?” said Krishnan.
Reference
1. Pereira, N. L. et al. N-cadherin antagonism is bronchoprotective in severe asthma models. Sci Adv 10, eadp8872 (2024).