Michael D. Woods

Introduction. Pulmonary arterial hypertension (PAH) is a rare chronic disease characterized by a mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg in the setting of pulmonary vascular disease.¹ Chronic inflammation drives the endothelium and pulmonary artery smooth muscle cells (PASMC) to resist apoptosis, proliferate, and migrate, resulting in the abolition of arterioles, muscular thickening of arteries, and formation of plexiform lesions in PAH.^1,2 In particular, elevated IL-6 is correlated with a reduction in overall survival and therefore may be a novel drug target in the treatment of PAH.^2,3 Methods. PASMC migration assays⁴ and vascular changes in monocrotaline (MCT)-PAH mouse models in the presence of IL-6 and IL-6 antagonists (ERBF and sGP130Fc) before and after PAH induction were evaluated.⁵ Genomic analysis on HL-60 differentiated neutrophils in response to IL-6 was conducted, and the amount of neutrophils in the lungs, blood, and bone marrow of chronic hypoxia (CH)-PAH mouse models with and without a homozygous CX₃CR1 deletion were measured.⁶ Lung mast cell density and IL-6 production in MCT-PAH rat models were evaluated in response to anti-IL-6 and ketotifen.⁷ Accumulation of B cells and production of autoantibodies were evaluated in response to anti-IL-6, ketotifen, and a genetic mast cell deficiency.⁷ Finally, a 6-month clinical trial in which 19 PAH patients received tocilizumab was conducted.⁸ Results. IL-6 signaling increased PASMC migration and this effect was eliminated with sGP130Fc.⁴ ERBF administration before MCT-PAH induction attenuated vascular changes and administration after induction reversed vascular changes and reduced mPAP.⁵ IL-6 upregulated CX₃CR1 in neutrophils and CX₃CR1 deletion reduced neutrophil egress from the bone marrow and attenuated PAH development.⁶ Anti-IL-6 had no effect on mast cell accumulation but ketotifen eliminated lung IL-6 production in PAH.⁷ Mast cell depletion reduced B cell accumulation identical to anti-IL-6 and ketotifen significantly reduced lung autoantibodies.⁷ 3/13 idiopathic-PAH patients and 4/6 connective tissue (CT)-PAH patients experienced a > 15% reduction in pulmonary vascular resistance following tocilizumab.⁸ Conclusion. IL-6 directly increased PASMC migration, contributed to the accumulation of neutrophils and B cells, and increased production of autoantibodies in the lungs of PAH models. In vitro blockade of IL-6 reduced vascular changes, mPAP, and right ventricular systolic pressure. Mast cells were shown to be upstream of the IL-6 signaling cascade, produced most IL-6 in PAH, and may be an additional therapeutic target. Despite robust preclinical support, IL-6 blockade failed to effectively treat PAH in humans but shows promise in CT-PAH populations.

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