Modifying macrophages in the lung could head off pulmonary hypertension

In the 1980s, when Stella Kourembanas, MD, began her career in neonatology, she cared for newborns with pulmonary hypertension, a disease that results in abnormally high blood pressure in the lung arteries and can lead to heart failure. Since then, treatments like inhaled nitric oxide, new vasodilators, new modalities of mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) have reduced mortality from about 85 percent to 10 percent. But pulmonary hypertension still persists.

“There’s amelioration, improved survival, but no cure,” says Kourembanas, chief of the Division of Newborn Medicine at Boston Children’s Hospital.

As more infants survive premature births and develop bronchopulmonary dysplasia (BPD), a chronic lung disease, more are developing pulmonary hypertension. It’s believed that BPD arrests the development of blood vessels in the lungs and prevents normal lung growth.

Inflammatory vs. anti-inflammatory macrophages

About 25 years ago, Kourembanas and her colleagues started testing new therapeutic approaches in animal models of BPD and hypoxia-induced pulmonary hypertension. In the process, they uncovered critical pathological mechanisms and new cellular targets. They showed that lung vascular disease is preceded by inflammation. Later, they found that specific subtypes of macrophages (a class of white blood cells), recruited to the lung during hypoxia, release inflammatory factors that cause vascular disease to progress.

They further showed that other macrophage subtypes could resolve inflammation and inhibit the development of pulmonary hypertension. Finally, in their model of hypoxia, they showed that interfering with early inflammation prevents pulmonary hypertension from developing.

In new work recently published in Arteriosclerosis, Thrombosis, and Vascular Biology, Kourembanas’s team, led by Angeles Fernandez-Gonzalez, PhD, modified macrophages to have an anti-inflammatory profile by incubating them with specific cytokines. When they administered the modified macrophages into the lungs of mice via the trachea, they saw reduced inflammation caused by hypoxia. And monocyte recruitment was halted.

Four weeks after treatment, the team saw decreased cardiac pathology. Right ventricular hypertrophy, right ventricular systolic pressure, and vascular remodeling — all complications of pulmonary hypertension — were reduced as compared with controls that did not receive modified macrophages.

“The key is to halt inflammation at an early time point and eliminate triggers that switch on in the beginning,” says Fernandez-Gonzalez. “After activation of inflammatory factors, crosstalk leads to production of more inflammatory factors, thickening of the vessel walls, and vascular remodeling that makes vessels resistant to blood flow. This forces the heart to work harder.”

Possible directions for therapy

Kourembanas believes focusing on manipulating macrophages could prevent pulmonary hypertension in clinically deteriorating infants with BPD, without harming normal lung development.

“Today we give steroids, which halt inflammation but also halt normal lung development,” she says. She believes that focusing on macrophages and early inflammation could also curb exacerbations of pulmonary hypertension in older children and adults. 

In her mind, a macrophage-focused therapy could take different forms — cell therapy delivering the anti-inflammatory macrophages themselves, delivery of products derived from macrophages, or delivery of factors that modify macrophages or the lung environment. It’s a question that academic and industry labs are actively investigating.

Fernandez-Gonzalez notes that “good” macrophages can be altered by signals in their environment after being put in the lung, losing their anti-inflammatory properties.

To avoid this from happening, “it may turn out not to be cells, but something derived from them that could have long-lasting effects, but we don’t know yet,” Kourembanas says. “Active research and future clinical trials will give us the answer.”

Learn how we care for infants with BPD