Bihari Chhagan, Baweja Sukriti, Shasthry Seggere Murlaikrishna, Lal Deepika, Negi Preeti, Thangariyal Swati, Tripathi Dinesh Mani, Sarin Shiv Kumar
Department of Pathology and Hematology, Institute of Liver and Biliary Sciences, D1, Vasant Kunj, New Delhi, India.
Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, D1, Vasant Kunj, New Delhi, India.
J Clin Transl Hepatol. 2022 Feb 28;10(1):53-62. doi: 10.14218/JCTH.2021.00331. Epub 2022 Jan 4.
Cirrhosis patients exhibit cytopenia, and, at times refractory neutropenia to granulocyte colony-stimulating factor (G-CSF), which acts through the CSF3-receptor (CSF3R), and changes in CSF3R can affect the response. We conducted this study to assess the CSF3R status and its relevance in cirrhotic patients.
Cirrhotic patients (=127) and controls (=26) with clinically indicated bone marrow (BM) examination were studied. BM assessment was done by qRT-PCR and immunohistochemistry (IHC) for . Circulating G-CSF, CSF3R, and carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1) were measured. BM hematopoietic precursor cells and their alterations were examined by flow cytometry. The findings were validated in liver cirrhosis patients who received G-CSF for severe neutropenia.
The mean age was 48.6±13.4 years, and 80.3% were men. Circulatory CSF3R reduction was noted with the advancement of cirrhosis, and confirmed by qRT-PCR and IHC in BM. CSF3R decline was related to decreased hematopoietic stem cells (HSCs) and downregulation of CSF3R in the remaining HSCs. Cocultures confirmed that CEACAM1 led to CSF3R downregulation in BM cells by possible lysosomal degradation. Baseline low peripheral blood-(PB)-CSF3R also predisposed development of infections on follow-up. Decreased CSF3R was also associated with nonresponse to exogenous G-CSF treatment of neutropenia.
Advanced liver cirrhosis was associated with low CSF3R and high CEACAM1 levels in the BM and circulation, making patients prone to infection and inadequate response to exogenous G-CSF.
肝硬化患者存在血细胞减少，有时对通过CSF3受体（CSF3R）起作用的粒细胞集落刺激因子（G-CSF）难治性中性粒细胞减少，且CSF3R的变化会影响反应。我们开展本研究以评估肝硬化患者的CSF3R状态及其相关性。
对有临床指征进行骨髓（BM）检查的127例肝硬化患者和26例对照进行研究。通过qRT-PCR和免疫组织化学（IHC）对 进行BM评估。检测循环中的G-CSF、CSF3R和癌胚抗原细胞粘附分子-1（CEACAM1）。通过流式细胞术检查BM造血前体细胞及其变化。在因严重中性粒细胞减少接受G-CSF治疗的肝硬化患者中验证这些发现。
平均年龄为48.6±13.4岁，80.3%为男性。随着肝硬化进展，循环中CSF3R降低，BM中的qRT-PCR和IHC证实了这一点。CSF3R下降与造血干细胞（HSCs）减少以及剩余HSCs中CSF3R下调有关。共培养证实CEACAM1可能通过溶酶体降解导致BM细胞中CSF3R下调。基线外周血（PB）-CSF3R低也易导致随访中感染的发生。CSF3R降低还与对外源性G-CSF治疗中性粒细胞减少无反应相关。
晚期肝硬化与BM和循环中低CSF3R及高CEACAM1水平相关，使患者易发生感染且对外源性G-CSF反应不足。
