Pulmonary arterial hypertension (PAH) is an umbrella term describing diseases characterized by an increase in mean pulmonary artery pressures, with a normal left heart. Pulmonary veno-occlusive disease (PVOD) is a rare and deadly form of PAH, characterised by the progressive obliteration of small pulmonary veins and venules by fibrous intimal thickening. Patients experience worsening breathlessness as the increasing pulmonary vascular resistance results in right heart failure. Comparatively little is known about the pathophysiology of PVOD and patients are generally treated with medications licensed for PAH, with particularly poor outcomes. Most patients with PVOD die within 2-3 years from diagnosis without lung transplantation.
The disease is caused by mutations in EIF2AK4, Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2). However, the mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. In this study, Elaine Soon and colleagues developed two mouse models to investigate this link: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction.
They showed that loss of GCN2 results in mild pulmonary hypertension and exaggerated interleukin-6 (IL-6) responses to lipopolysaccharide (LPS). Chronic exposure to LPS in GCN2-deficient mice worsens the pulmonary hypertensive phenotype. Single cell RNA sequencing and immunofluorescence studies identified adventitial fibroblasts as both a source of IL-6 and a responding cell type. A regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signalling was established. Together, they show that interleukin-6 is a critical mediator of both Gcn2 deficiency–associated and mitomycin C–triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways and the ISR as potential therapeutic targets.