Abstract Rationale Idiopathic pulmonary arterial hypertension (IPAH) and pulmonary veno-occlusive disease (PVOD) are rare and life-threatening disorders characterized by pulmonary vascular remodeling, both classified under the pulmonary arterial hypertension (PAH). Macrophages, acting as central regulators of the inflammatory response, play a critical role in the pathogenesis and progression of PAH. Furthermore, studies indicate that inflammatory responses mediated by programmed cell death (PCD) may exacerbate the condition. However, the PCD of macrophage in IPAH and PVOD are still largely unknown. Methods This study utilized single-cell RNA sequencing to systematically analyze the cellular landscape of lung tissues from patients with IPAH (n = 4), PVOD (n = 3), and healthy controls (n = 4), with a focus on the role of macrophage subsets and their PCD patterns in these diseases. Results A total of 14 major cell types were identified. Functional enrichment analysis revealed that macrophages in IPAH patients were active in processes such as autophagy and efferocytosis, while macrophages in PVOD patients were more focused on pathways like apoptosis and cellular senescence. Macrophages were further divided into 19 clusters, categorized into 4 main subtypes (alveolar macrophages, myeloid-derived macrophages, interstitial macrophages, and unknown). Based on PCD-related functions, macrophages were classified into 5 subtypes (proliferative, senescent, apoptotic, etc.), whose distribution significantly differed between disease groups and the control group. Then, compared to the control group, multiple PCD patterns (such as alkaliptosis, apoptosis, autophagy, ferroptosis, etc.) were upregulated in macrophages from IPAH patients, and PVOD patients exhibited an overlapping yet distinct upregulation of some PCD patterns (such as apoptosis, autophagy, ferroptosis, necroptosis), while alkaliptosis and lysosome-dependent cell death were downregulated. Conclusion This research unveils the significant similarities and differences in macrophage subset distribution, functional states, and PCD patterns between IPAH and PVOD. It provides a crucial molecular foundation for understanding the pathogenesis of these two diseases in terms of inflammation and cell death, and highlights potential divergent pathological processes. This abstract is funded by: None
Sun et al. (Fri,) studied this question.
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