05:16pm Sunday 17 November 2019

Drug reduces risk of pneumonia in newborn mice

May lead to new way to protect premature infants from pneumonia

The underdeveloped lungs and immune systems of premature babies put them at high risk of potentially deadly pneumonia. Now, a study from Washington University School of Medicine in St. Louis has found, in mice, that an inhaled drug promotes the development of lung immunity and reduces the risk of pneumonia.

The findings, published Aug. 14 in Science Advances, suggest that the drug – an inhalable form of a normal immune protein called GM-CSF – could reduce the risk of life-threatening lung infections common among premature infants. Senior author S. Celeste Morley, MD, PhD, an associate professor of pediatrics, and of pathology and immunology, discussed the study.

Why did you start exploring whether GM-CSF could prevent pneumonia?

Immune cells called macrophages are critical for controlling lung infections, and they appear in the lungs in the first day or two after birth. We know that newborn mice naturally experience a burst of GM-CSF in their lungs in the first 24 to 48 hours after birth that triggers the development of specialized lung macrophages. We don’t know for sure whether the same thing happens in babies. But we think that full-term babies also get a burst of GM-CSF, and preemies might not. If so, the macrophages in the lungs of premature infants would not develop normally, which could explain why preemies are at such high risk of pneumonia.

What happened when you gave mice GM-CSF?

We used mice with a genetic defect that prevents their lung macrophages from maturing normally. We couldn’t study premature mice – they’re just too small to work with. But full-term newborn mice with this genetic defect are very susceptible to bacterial infection and pneumonia, like human preemies, so we used them instead. We gave these newborn mice GM-CSF intranasally for the first 24 hours after birth. The number of lung macrophages increased immediately, and since they are very long-lived cells, the mice were protected from pneumonia even into adulthood.

GM-CSF has been tried before as a way to protect preemies from pneumonia. Why didn’t it work then, and why do you think it will work now?

People have tried giving premature infants GM-CSF intravenously or subcutaneously. When you give GM-CSF this way, it mobilizes neutrophils, a different immune cell that is also very important for fighting off infections in general, but is not the crucial immune cell type in the lungs. So it wasn’t a bad idea, but the clinical trials have been disappointing. GM-CSF injections did not lower the risk of pneumonia. What we did differently is we administered the drug to the lungs directly, by inhalation, which triggered the development of lung macrophages instead of neutrophils. And then we saw long-lasting protection against pneumonia.

Could inhaled GM-CSF help protect premature infants from pneumonia?

I hope so. The key point is that it has to be given within the first day after birth. These specialized macrophages are only made in the first couple of days after birth. After that, the maturation window is over and you’ve missed your chance to intervene. And you have to give it through inhalation so it gets directly to the lungs. GM-CSF is an FDA-approved drug, and it has been used safely in previous clinical trials in premature infants. We still have some questions to answer, but I hope we can take this into clinical trials soon.


Todd EM, Ramani R, Szasz TP, Morley SC. Inhaled GM-CSF in neonatal mice provides durable protection against bacterial pneumonia. Science Advances. Aug. 14, 2019. DOI: 10.1126/sciadv.aax3387
This study was supported by the National Institutes of Health (NIH), grant numbers R01 AI104732 and R21 AI142723; the National Institute of Arthritis and Musculoskeletal and Skin Diseases, grant number P30-AR048335; the Hope Center Transgenic Vectors Core; and the Speed Congenics Facility of the Rheumatic Diseases Core Center.
Washington University School of Medicine’s 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Originally published by the School of Medicine

 

 


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