期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 178, 期 1, 页码 187-202出版社
WILEY
DOI: 10.1111/bph.14945
关键词
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资金
- National Institutes of Health [HL142776, HL144085, R01 HL142776, K08 HL144085]
- University of Florida Gatorade Trust
- American Lung Association
- Martha Q. Landenberger Research Foundation
- Gilead Sciences Research Scholars Program in Pulmonary Arterial Hypertension
The study investigated the impact of myeloid cell proliferation induced by emergency myelopoiesis on the development of pulmonary hypertension, as well as the therapeutic effect of PD-L1 in preventing pulmonary vascular remodeling. The results showed that PD-L1 could be a viable therapeutic target in pulmonary hypertension by acting through a signaling axis involving myeloid-derived suppressor cells.
Background and Purpose Pulmonary hypertension (PH) secondary to chronic lung disease (World Health Organization Group 3 PH) is deadly, with lung transplant being the only available long-term treatment option. Myeloid-derived cells are known to affect progression of both pulmonary fibrosis and PH, although the mechanism of action is unknown. Therefore, we investigated the effect of myeloid cell proliferation induced by emergency myelopoiesis on development of PH and therapy directed against programmed death-ligand 1 (PD-L1), expressed by myeloid cells in prevention of pulmonary vascular remodelling. Experimental Approach LysM.Cre-DTR (mDTR) mice were injected with bleomycin (0.018 U center dot g(-1), i.p.) while receiving either vehicle or diphtheria toxin (DT; 100 ng, i.p.) to induce severe PH. Approximately 4 weeks after initiation of bleomycin protocol, right ventricular pressure measurements were performed and tissue samples collected for histologic assessment. In a separate experiment, DT-treated mice were given anti-PD-L1 antibody (alpha PD-L1; 500 mu g, i.p.) preventive treatment before bleomycin administration. Key Results Mice undergoing induction of emergency myelopoiesis displayed more severe PH, right ventricular remodelling and pulmonary vascular muscularization compared to controls, without a change in lung fibrosis. This worsening of PH was associated with increased pulmonary myeloid-derived suppressor cell (MDSC), particularly polymorphonuclear MDSC (PMN-MDSC). Treatment with alpha PD-L1 normalized pulmonary pressures. PD-L1 expression was likewise found to be elevated on circulating PMN-MDSC from patients with interstitial lung disease and PH. Conclusions and Implications PD-L1 is a viable therapeutic target in PH, acting through a signalling axis involving MDSC.
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