Editors' ChoicePulmonary Hypertension

Blocking IL-6 signaling deflates pulmonary arterial hypertension

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Science Translational Medicine  23 May 2018:
Vol. 10, Issue 442, eaat8534
DOI: 10.1126/scitranslmed.aat8534


IL-6 signaling contributes to the pathogenesis of pulmonary arterial hypertension by orchestrating pulmonary arterial smooth muscle cell expansion.

Pulmonary arterial hypertension is a devastating disease characterized by progressive narrowing and obliteration of the pulmonary vasculature. There are few effective treatment options other than lung transplantation; current therapies provide symptomatic relief but only modestly improve survival. Over the past decade, important insights into the pathophysiology of pulmonary arterial hypertension have emerged, implicating the expansion of pulmonary vascular smooth muscle cells as a key pathogenic factor common to many etiologies of pulmonary arterial hypertension.

Tamura et al. build on the observation that circulating interleukin 6 (IL-6) is increased in patients with pulmonary arterial hypertension and is associated with poor quality of life and mortality. Through integrative assessment of human lung tissues and using three rodent models of pulmonary hypertension, the authors revealed that pulmonary vascular smooth muscle cells ectopically express the IL-6 receptor in patients with hereditary and idiopathic pulmonary arterial hypertension and that IL-6 signaling contributes to the pathogenesis of pulmonary arterial hypertension by promoting the growth and survival of pulmonary arterial smooth muscle cells. They further demonstrated that pharmacological inhibition of IL-6 receptor signaling reduced smooth muscle cell accumulation within the pulmonary vascular wall and improved outcomes in rodent models of pulmonary hypertension.

This study provides evidence that IL-6 signaling is central to the pathogenesis of pulmonary arterial hypertension and suggests that IL-6 signaling may be a new therapeutic target for this devastating disease. It is intriguing to postulate that inhibition of IL-6 signaling might be efficacious across the spectrum of pulmonary hypertension etiologies since smooth muscle expansion represents a common pathological hallmark of the disease. The mechanistic basis by which the IL-6 receptor becomes up-regulated in the pulmonary smooth muscle cells remains an area of open investigation. Today, there are several IL-6 and IL-6 receptor antagonists (such as tocilizumab, siltuximab, sarilumab) approved by the U.S. Food and Drug Administration for the treatment of autoimmune conditions. Future clinical studies will be needed to delineate the efficacy of IL-6 blockade in pulmonary arterial hypertension. Nonetheless, these observations are exciting and provide hope for a new class of pulmonary hypertension therapies.

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