Inhibition of Small RNA in Lung Macrophages May Counter Pulmonary Fibrosis

Researchers at the Yale School of Medicine (YSM) who study idiopathic pulmonary fibrosis, a debilitating and fatal lung disease, designed a molecule that reverses pulmonary fibrosis in a preclinical model of the disease and in cultured human lung tissue. The drug inhibits a microRNA, called miR-33, and protects against fibrosis by improving the metabolic functions of lung macrophages. The results appeared online on January 10, 2023, in JCI Insight.

Pulmonary fibrosis refers to the condition in which normal lung tissue needed for breathing is replaced by scarred tissue, causing increased stiffening of the lung and difficulty in obtaining enough oxygen to the blood. This condition can be caused by autoimmune conditions, environmental exposures, or genetic disorders. When the cause is unknown, the condition is referred to as idiopathic pulmonary fibrosis (IPF). IPF is progressive and lethal, with close to half of the people with IPF dying within three to five years after diagnosis. The Food and Drug Administration has approved two drugs to treat IPF. While these drugs slow IPF’s progression, they do not cure the disease. They also have side effects.

“When IPF patients progress with current therapy, the only other option is lung transplantation, which is limited, ” says study lead author Farida Ahangari, MD, assistant professor of pulmonary, critical care, and sleep medicine at YSM. “This is a huge unmet need. We need better drugs for these patients.”

In search of novel drug targets, Ahangari, and colleagues, under the leadership of Naftali Kaminski, MD, Boehringer-Ingelheim Pharmaceuticals Professor of Medicine (Pulmonary) and chief of pulmonary, critical care, and sleep medicine at YSM, looked at differences between healthy lungs and those of people with IPF. Ahangari and colleagues found that lung macrophages, immune cells known to be involved in fibrosis, that normally engulf and digest microbes, dead cells, foreign particles and other substances, from IPF patients had higher levels of a microRNA, miR-33 compared to those from healthy lungs. The term microRNA refers to small RNA molecules that regulate the expression of genes and pathways.

This microRNA, miR-33, is a known regulator of macrophage metabolic function, so the researchers hypothesized that inhibiting miR-33 would reduce the profibrotic properties of macrophages and reduce fibrosis. To test that hypothesis, collaborators Carlos Fernández-Hernando, PhD, Anthony N. Brady Professor of Comparative Medicine and of Pathology; and Nathan Price, PhD, in the Yale Vascular Biology and Therapeutics Program, generated a mouse strain in which miR-33 was specifically disabled in macrophages. After inducing fibrosis in the preclinical model by administering the drug bleomycin, the researchers discovered that the miR-33 lacking lung macrophages had healthier mitochondria and greater autophagy activity and the preclinical model was protected against pulmonary fibrosis.

Next, the researchers tested the effects of a peptide nucleic acid inhibitor of miR-33 (PNA-33) designed by collaborator Raman Bahal, PhD, associate professor of pharmaceutics in the Department of Pharmaceutical Sciences at the University of Connecticut School of Pharmacy in the preclinical model. When delivered by inhalation, this novel miR-33 inhibitor protects from developing bleomycin-induced lung fibrosis.

Finally, the researchers tested the effects of PNA-33 on lung slices in the preclinical model and from humans with advanced IPF who had had lung transplants and donated their fibrotic lungs for research. The researchers showed that the lung slices treated with PNA-33 had less severe fibrosis than the controls.

While the results are promising, the road to testing the drug in humans is long, said Kaminski, the senior author on the study,

While the results are promising, the road to testing the drug in humans is long, said Kaminski, the senior author on the study, “We are very excited about our results, but are aware that there are many obstacles to overcome and milestones to reach until PNA-33 can be developed as a drug and tested in humans. I wish that the path to humans was faster, our patients are waiting.”

The work of the investigators on this study was funded by grants from the National Institutes of Health (R01HL141852, R01HL127349, U01HL145567, and U01HL122626, and R35HL135820) and a BI Discovery Award (19-004578). In addition to Ahangari, Kaminski, Fernández-Hernando, and Bahal, other contributors include Yale’s Maurizio Chioccioli, PhD; Taylor Adams; Jooyoung Kim; Shuizi Ding; Carlos Cosmos Jr.; Kadi-Ann S. Rose; John E. McDonough, PhD; Norihito Omote; Jonas C. Schupp; Giuseppe Deluliis; Lokesh Sharma, PhD; Wonnie Ryu, MD, MPH; Charles S. Dela Cruz, MD, PhD; Thomas Bärnthaler; and Xinran Liu, MD, PhD; University of Connecticut’s Shipra Malik, and Sai Pallavi Pradeep; Weill Cornell’s Nachelle R. Aurelien, MD; Life Span Medical Group’s Gabriel Ibarra, MD; Harvard Medical School’s Julian Villalba Nunez, MD; Baylor College of Medicine’s Ivan Rosas, MD; and University of Hannover’s Antje Prasse.

The Section of Pulmonary, Critical Care and Sleep Medicine is one of the eleven 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 Twitter.