Pulmonary fibrosis is a condition that causes scarring of the lungs. It is often accompanied by shortness of breath, cough, rapid loss of lung function, and respiratory failure.
Currently, there are only two FDA-approved medications for treating the chronic fibrotic lung disease. These drugs slow down the progression of the disease, but do not improve patients' quality of life or reverse the fibrosis.
“The clinical benefits of these drugs are modest, and they have significant side effects that some patients cannot tolerate,” says Genta Ishikawa, MD, MPH, instructor of medicine in the Section of Pulmonary, Critical Care and Sleep Medicine (Yale PCCSM). “At this point, there is no cure for pulmonary fibrosis except lung transplantation.”
As a physician-scientist, Ishikawa says patient care motivates him to find the missing link in pulmonary fibrosis treatments. Recently, he was awarded a Parker B. Francis Fellowship in Pulmonary Research for his groundbreaking studies of pulmonary fibrosis neurobiology.
Ishikawa began his medical career in Tokyo, Japan, where he worked as a board-certified pulmonologist treating patients with Interstitial Lung Disease (ILD) in Tokyo.
“Patients died because there was no treatment for lung fibrosis,” says Ishikawa. “This devastating experience made me want to save more and more patients.”
Patients died because there was no treatment for lung fibrosis. This devastating experience made me want to save more and more patients.
Genta Ishikawa, MD, MPH
After six years, he wanted to make a bigger impact as a physician-scientist. That’s what brought him to the U.S., and eventually to Yale School of Medicine in 2020 for postdoctoral training on Yale PCCSM’s NHLBI funded T32 Training in Translational Lung Biology and Pathobiology training grant. He joined the laboratory of Erica Herzog, MD, PhD, John Slade Ely Professor of Medicine (Pulmonary) and professor of pathology.
Around the time Ishikawa came to Yale, Herzog and team had discovered that sympathetic nerves were growing into peripheral lung regions in patients with pulmonary fibrosis. Ishikawa’s responsibility as a postdoc was to determine the mechanism for observation and answer the question, “Why?”
Ishikawa’s research is focused on the interaction between the sympathetic nerves and myofibroblasts, key effector cells in pulmonary fibrosis.
In the Herzog lab, he first discovered increased expression of alpha-1 adrenoreceptors—primary receptors for nerve-derived noradrenaline—in myofibroblasts in mouse models, along with enriched sympathetic innervation. Herzog and lab members surmised that abrogation of signaling through this receptor would improve lung fibrosis.
This led to the discovery that inhibiting the receptor–both in vivo and in vitro–mitigated pulmonary fibrosis.
Dr. Ishikawa is a visionary scientist whose research skills facilitated our discovery of a fibrogenic unit comprised of sympathetic nerves and effector myofibroblasts in pulmonary fibrosis. His ability to combine fundamental discovery work with patient-relevant translational studies has advanced this project to bring the science closer to helping the patients we serve.
Erica Herzog, MD, PhD
“Dr. Ishikawa is a visionary scientist whose research skills facilitated our discovery of a fibrogenic unit comprised of sympathetic nerves and effector myofibroblasts in pulmonary fibrosis. His ability to combine fundamental discovery work with patient-relevant translational studies has advanced this project to bring the science closer to helping the patients we serve,” says Herzog, Ishikawa’s mentor.
The team also found myofibroblasts in fibrotic human lungs from both patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) express alpha-1 adrenoreceptors, along with evidence of increased downstream signaling.
“While we found that abrogation of nerve-derived signaling improves fibrosis, we need more detail on the characteristics of these nerve-associated fibroblasts and their interactions with other cell types, such as immune and structural cells. We believe there is complex neuronal involvement in the pathogenesis of lung fibrosis that needs to be unveiled,” Ishikawa says.
“This is a superb testament to the benefit NIH training grants provide, “says Naftali Kaminski, MD, section chief of Yale PCCSM and principal investigator of the T32 grant. “We were able to bring Dr. Ishikawa from a different institution, match him with a superb physician-scientist mentor like Dr. Herzog, and train him in translational biology, and work on discoveries that we believe will help our patients.”
In the next few years, Ishikawa plans to further explore the neurobiology of fibrotic lung diseases and become an independent principal investigator. He’s hopeful the research will lead to clinical trials for therapeutic options for patients.
The research reported in this news article was supported by the National Institutes of Health (awards T32HL007778 and R01HL163984) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The Section of Pulmonary, Critical Care and Sleep Medicine is one of the ten sections within Yale School of Medicine’s Department of Internal Medicine. To learn more about Yale PCCSM, visit PCCSM's website, or follow them on Facebook and X/Twitter.