Fasudil reduces airway smooth muscle contractility and lung resistance in ex vivo sheep lungs

The airways inside our lungs are lined with a layer of muscle that acts like a flexible ring, capable of tightening or loosening to control the flow of air. In a healthy person, this muscle relaxes to let air in and out freely. However, in conditions like asthma, these muscles can become overactive, squeezing the airways shut and making it difficult to breathe. Scientists have long known that a specific chemical pathway inside these muscle cells, involving a protein called Rho-kinase, acts as a switch that tells the muscle to contract and stay tight. If this switch is stuck in the "on" position, the airways remain constricted. While researchers have found that blocking this switch can relax the muscle, there has been a gap in our knowledge: most evidence comes from tiny animals like mice, whose lungs are very different in size and structure from human lungs. To truly know if a drug could work for people, it must be tested in a large animal model that more closely resembles the human respiratory system.

A team of researchers at St. Paul's Hospital in Vancouver decided to bridge this gap by testing a drug called fasudil on sheep lungs. Fasudil is already approved and widely used in Japan and China to treat a different condition involving blood vessels in the brain, so its safety profile is well established. The researchers wanted to see if this existing drug could be repurposed to treat asthma by relaxing the airway muscles in a large, living lung model. They worked with freshly removed sheep lungs and tracheas, keeping the tissue alive in a laboratory setting that mimicked the body's temperature and chemical environment. Their goal was twofold: first, to understand exactly how the drug relaxed the muscle at a molecular level, and second, to see if they could deliver the drug effectively through a nebulizer, the same kind of misting device used for human asthma inhalers.

In the first part of their investigation, the researchers took strips of muscle from the sheep's windpipe and placed them in a bath of nutrient-rich fluid. They used a chemical to force the muscle strips to contract tightly, simulating a severe asthma attack. Once the muscle was fully squeezed, they added fasudil in increasing amounts. They observed that the drug worked like a key turning off the lock: as the concentration of fasudil rose, the muscle strips gradually relaxed. The team found that the drug was highly effective, reducing the force of the contraction in a predictable way. To understand the mechanism behind this relaxation, they looked inside the muscle cells at a specific protein called myosin light chain. This protein acts like a molecular switch; when it is phosphorylated, meaning a small chemical tag is attached to it, the muscle contracts. When the tag is removed, the muscle relaxes. The researchers measured the amount of this tag on the protein and found that fasudil removed the tag, returning the muscle to a relaxed state. The reduction in the chemical tag matched the reduction in muscle force almost perfectly, suggesting that the drug works primarily by turning off this specific switch.

The study then moved to a more complex test using whole sheep lungs. The researchers placed a lung inside a sealed chamber and connected it to a machine that could breathe for it, pushing air in and out. They set up a scenario where the lung was breathing with very small breaths and no deep inhales, a condition known to cause the airways to slowly tighten on their own over time. In the control group, where the lung breathed only a plain mist, the resistance to airflow increased steadily, and the lung became stiffer, mimicking the worsening of an asthma attack. However, when the researchers nebulized fasudil into the lung before this period of shallow breathing, the airways stayed open. The drug prevented the natural tightening of the airways, keeping the lung flexible and the airways clear. This effect was seen even when the drug was delivered as a mist, proving that it could reach the deep, narrow airways where it is needed most without needing to be injected into the bloodstream.

The results suggest that fasudil is a potent tool for relaxing airway muscles and preventing them from closing up, working through a clear and direct mechanism of turning off the chemical signal that causes contraction. Because the drug was already known to be safe for humans and because it worked effectively in a large animal model that closely resembles human lung mechanics, the findings offer a strong reason to consider testing it in people with asthma. The study did not claim to cure asthma or solve the entire disease, but it provided concrete evidence that a drug currently used for blood vessel problems could be repurposed to help the lungs breathe more easily. By showing that the drug works in a large, realistic lung model and explaining exactly how it relaxes the muscle, the researchers have laid a solid foundation for future clinical trials that could bring a new treatment option to patients.