Inflammatory Protein Study Suggests Treatment Strategies for Pulmonary Hypertension

Most of the time, our immune system does a great job of protecting us from infections and keeping our bodies functioning. However, sometimes the immune system can make the situation worse. As an example, a recent study by Japanese scientists showed that a naturally occurring immune system protein may play a key role in the development of an incurable form of lung disease.

In a study published last month in the journal PNAS, researchers from the National Institute of Cardiovascular Research (NCVC) reported that an inflammatory protein called IL-6 activates certain immune cells in pulmonary hypertension, worsening associated symptoms.

Pulmonary hypertension is a rare and debilitating condition in which the arteries in the lungs become narrowed or blocked. It causes symptoms such as difficulty breathing, fatigue, fainting, and in later stages, even heart failure and death.

"There is currently no cure for pulmonary hypertension, so available treatments aim to reduce symptoms and improve quality of life," explains lead author Tomohiko Ishibashi.

"Recent studies have shown that IL-6 plays a role in the progression of pulmonary hypertension and may be a useful target for treatment; however, conflicting results have been obtained using different mouse models, raising uncertainty about the effectiveness of this approach."

To address this issue, the researchers used a mouse model in which a component of the IL-6 receptor is thought to be disrupted only in smooth muscle cells, but can also be deactivated in other cell types, to find out which specific cells were affected by IL-6 signaling.

“Surprisingly, we found that the expression of the IL-6 receptor component was disrupted in a wide range of blood cell precursors,” explains senior author Yoshikazu Nakaoka.

"Under normal conditions, the receptor is most highly expressed by CD4-positive T cells, and its ablation in these cells significantly inhibited the development and progression of pulmonary hypertension in mice."

The researchers then deleted the gene that codes for IL-6 in the rats. The team found that regardless of whether pulmonary hypertension in rats was caused by hypoxia, chemicals, or a combination of both, removing IL-6 rendered the rats resistant to the pathological changes associated with pulmonary hypertension.

Inadvertent Cre recombination in all cells of the hematopoietic lineage in SM22α-Cre mice. Source: Proceedings of the National Academy of Sciences (2024). DOI: 10.1073/pnas.2315123121

Treating IL-6-deficient rats with drugs currently used to treat patients with pulmonary hypertension further improved symptoms and reduced damage to both the lungs and heart.

"Our results suggest that combining IL-6 inhibitors with current medications for the treatment of pulmonary hypertension may reduce symptoms and improve patients' quality of life," says Ishibashi.

Given the current lack of effective treatments for pulmonary hypertension, the results of this study provide hope for the development of new therapeutic strategies in the future. Although a recent clinical trial of an anti-IL-6 receptor antibody yielded disappointing results, targeting IL-6 in specific cell types and interfering with the end effects of IL-6 signaling remain potential approaches.