Targeting the NLRP3 inflammasome for the treatment of pulmonary hypertension

T. E. McConaghy^1,2, R. S. Baliga¹, A. A. Robertson³, G. R. Drummond⁴, B. K. Kemp-Harper², A. J. Hobbs¹. ¹William Harvey Research Institute, Barts & the London Medical School, Queen Mary University of London, London, United Kingdom, ²Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Melbourne, Australia, ³Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia, ⁴Department of Physiology, Anatomy & Microbiology, School of Life Sciences, La Trobe University, Melbourne, Australia.

Introduction: Pulmonary hypertension (PH) is characterised by increased pulmonary arterial pressure, vascular remodelling and right ventricular (RV) hypertrophy; the prognosis is poor and a cure elusive¹. Macrophages are key contributors to PH pathogenesis; these cells express an NLRP3 inflammasome complex, which releases pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Since NLRP3 is implicated in other cardiovascular diseases², we hypothesised that NLRP3 activation similarly contributes to PH and that pharmacological targeting of this pathway prevents disease progression.

Method: Male C57BL/6 mice (20-25g) were exposed to hypoxia- (10% O₂, 5-weeks, plus vascular endothelial growth factor inhibitor SU5416 [20mg/kg, sc.]) or bleomycin- (2mg/kg, it., 2-weeks) induced PH. Mice were randomly-assigned to receive selective NLRP3 inflammasome inhibitor MCC950 (10mg/kg/day, sc.)³ or vehicle (saline) via osmotic mini-pump at day 7 (bleomycin), or 14 (hypoxia). Indices of disease progression assessed at endpoint included: right ventricular systolic pressure (RVSP; Millar Mikro-Tip catheterisation under 2% isoflurane), RV hypertrophy (RV to bodyweight (BW) ratio), and lung weight (LW) to BW ratio) as a rudimentary index of lung fibrosis. Data are presented as mean±SEM (n animals), analysed by one-way ANOVA with Tukey’s post-test.

Results: RVSP, RV/BW and LW/BW ratios were significantly increased in SU5416/hypoxia- (SuHx) and bleomycin-treated mice compared to control animals (Table 1), confirming development of PH. MCC950 did not affect RVSP in either model, but significantly reduced the RV/BW in SuHx mice compared to controls with a similar trend in bleomycin-treated animals (Table 1). Finally, LW/BW ratio decreased in mice treated with bleomycin and MCC950 compared to bleomycin alone (Table 1).

Table 1. Effect of MCC950 treatment on Pulmonary Hypertension

*P<0.05 vs. relevant control, ^#P<0.05 vs. SuHx, ^$P=0.052 vs. bleomycin

Conclusions: These data demonstrate that MCC950 treatment reverses RV hypertrophy in experimental models of PH without affecting pulmonary artery pressure. On-going studies will confirm if MCC950 alters lung fibrotic burden and pulmonary vascular remodelling. Therefore, combination of MCC950 with pulmonary dilators (current therapy) may provide a novel therapeutic strategy for PH.

References:

1. Baliga RS et al., (2014). Br J Pharmacol 171: 3463-3475.

2. Coll RC et al., (2015). Nat Med 21: 248-255.

3. Krishnan et al., (2016). Br J Pharmacol 173: 752-765.