Brunet-Ratnasingham Elsa, Yellamilli Shivaram, Guo Ruyin, Mohanty Rashmi Prava, Duong Allen, Kolaitis Nicholas A, Hays Steven R, Shah Rupal J, Venado Aida, Maheshwari Julia A, Kleinhenz Mary Ellen, Leard Lorriana E, McDyer John, Martinu Tereza, Combes Alexis J, Calabrese Daniel R, Singer Jonathan P, Greenland John R
Department of Medicine, University of California, San Francisco, San Francisco, California.
Department of Medicine, University of California, San Francisco, San Francisco, California; UCSF CoLabs, San Francisco, California.
J Heart Lung Transplant. 2025 Apr 16. doi: 10.1016/j.healun.2025.03.010.
Acute lung allograft dysfunction (ALAD) is a clinical syndrome of forced expiratory volume in 1-second (FEV) decline concerning for chronic lung allograft dysfunction (CLAD) onset. Novel diagnostic tools are needed to identify those with ALAD who will progress to CLAD and to target appropriate therapies. We hypothesized that progressive ALAD would be associated with changes in small airway cell composition and cell-specific transcription.
We prospectively identified recipients with undifferentiated ALAD and controls with stable allograft function for small airway brushing and single-cell RNA sequencing analysis. ALAD outcome group was categorized as (1) control (n = 8), or ALAD with (2) recovered (n = 4), (3) persistent (n = 5), or (4) progressive (n = 3) FEV decline. Cell compositional changes, pseudobulk Reactome pathways, and the AI2 score, previously linked to CLAD in airway brush transcriptomes, were assessed as a function of ALAD outcome group.
Across 68,140 cells, the distribution of cell composition was linked to ALAD outcome group (PERMANOVA, p = 0.004). Worse ALAD outcomes correlated with loss of basal cells, changes in club and ciliated subsets, a loss of macrophages, and expansion of cytotoxic T cells. The AI2 gene score was positively associated with ALAD outcome group, particularly in epithelial cell subsets (p < 0.001). Pathway analysis showed increased interferon signaling and inhibition of cell proliferation in epithelial cells.
In this pilot study, persistent and progressive ALAD was associated with changes in bronchiolar cell composition and transcriptional programs. Molecular phenotyping may help identify and characterize individuals with ALAD at increased risk for progression.
急性肺移植功能障碍（ALAD）是一种临床综合征，表现为1秒用力呼气量（FEV）下降，提示慢性肺移植功能障碍（CLAD）的发生。需要新的诊断工具来识别那些将进展为CLAD的ALAD患者，并针对性地进行适当治疗。我们假设进行性ALAD与小气道细胞组成和细胞特异性转录的变化有关。
我们前瞻性地确定了未分化ALAD的受者和移植功能稳定的对照组，对其进行小气道刷检和单细胞RNA测序分析。ALAD结局组分为：（1）对照组（n = 8），或ALAD伴（2）恢复组（n = 4）、（3）持续组（n = 5）或（4）进行性组（n = 3）FEV下降。评估细胞组成变化、拟批量反应组通路以及先前与气道刷转录组中CLAD相关的AI2评分作为ALAD结局组的函数。
在68140个细胞中，细胞组成的分布与ALAD结局组相关（PERMANOVA，p = 0.004）。更差的ALAD结局与基底细胞丢失、棒状细胞和纤毛细胞亚群变化、巨噬细胞丢失以及细胞毒性T细胞扩增相关。AI2基因评分与ALAD结局组呈正相关，尤其是在上皮细胞亚群中（p < 0.001）。通路分析显示上皮细胞中干扰素信号增加和细胞增殖受到抑制。
在这项初步研究中，持续性和进行性ALAD与细支气管细胞组成和转录程序的变化有关。分子表型分析可能有助于识别和表征进展风险增加的ALAD个体。
