Simone Juel Dragsbaek, Andreas Overgaard, Mathilde Emilie Kirk, Cecilie Dahl Baltsen, Christina Carøe Ejlskov Pedersen, Anushree Burade, Mannudeep K Kalra, Julie Nelly Christensen, Bettina Hansen, Xiaoke Pan, Jurjan Aman, Harm Jan Bogaard, Joanna Kalucka, Mads Dam Lyhne, Asger Andersen
In this porcine model, repetitive PE combined with local cGAMP exposure increased lung tissue CXCL10 without inducing pulmonary hypertension over 30 days, suggesting that selective activation of the immune system at clot level alone is insufficient to drive a more advanced chronic thromboembolic phenotype.
BACKGROUND: Chronic thromboembolic pulmonary disease (CTEPD) is a long-term complication of pulmonary embolism (PE) and can occur with pulmonary hypertension. Inflammation is implicated but its causal role remains unclear.
OBJECTIVES: Investigate whether local immune activation modifies haemodynamic, inflammatory, and thromboembolic responses after repetitive PE.
METHODS: In a 30-day prospective study, six pigs underwent repetitive autologous PE containing cyclic GMP-AMP (cGAMP) to induce local immune activation and were compared with six pigs receiving repetitive PE and tranexamic acid-mediated inhibition of endogenous fibrinolysis (TXA). Animals underwent haemodynamic assessment, blood sampling, computed tomography pulmonary angiography (CTPA), lung tissue cytokine quantification, and histological analysis.
RESULTS: Repetitive embolisation induced acute transient increases in mean pulmonary arterial pressure in both groups, but no animals developed pulmonary hypertension at follow-up (18 ± 3 mmHg in cGAMP-group and 16 ± 2 mmHg in TXA-group, p = 0.20). CTPA demonstrated persistent vascular obstruction in both groups, with comparable obstruction percentages (85 [75-87] % vs. 72 [50-80] %, p = 0.29). Systemic leukocyte, neutrophil, and lymphocyte counts remained within porcine reference intervals. Lung tissue CXCL10 levels were higher in the cGAMP-group than in the TXA-group (9120 ± 5027 vs. 3763 ± 1904 pg/g, p = 0.035), whereas IL-1β, TNF-α, and IL-8 did not differ. Immunohistochemistry demonstrated CXCL10-positive inflammatory cell infiltration within organised thrombi.
CONCLUSIONS: In this porcine model, repetitive PE combined with local cGAMP exposure increased lung tissue CXCL10 without inducing pulmonary hypertension over 30 days, suggesting that selective activation of the immune system at clot level alone is insufficient to drive a more advanced chronic thromboembolic phenotype.