Background: The lung macrophage (LM) is involved in most inflammatory processes of the human lung by clearance of dying cells and by wound repair. Upon cellular stress by oxidant challenge in vivo lysosomes may rupture in LMs and leakage of cellular content and cell debris may trigger airway inflammation and fibrosis, which may lead to chronic airflow limitation (CAL).
Objective: The aim of this study was to determine whether lysosomal membrane permeabilization (LMP) in LMs challenged to oxidants ex vivo is associated with airway inflammation and CAL, the latter assessed as the reduced forced expiratory volume in one second (FEV₁) expressed as % of predicted.
Materials and Methods: Twenty-eight subjects were investigated; 13 lung-healthy subjects and 15 subjects with a variety of inflammatory disorders, demonstrating CAL on dynamic spirometry (defined as an FEV₁/FVC ratio < 0.70). LMs were harvested by broncho-alveolar lavage (BAL) and challenged ex vivo by oxidants. LMP in oxidant-exposed LMs was assessed as the emitted acridine orange (AO) green fluorescence from oxidant-exposed LMs (using macrophage-like murine J774 cells as positive controls). Inflammatory cells in BAL were counted and lung volumes were recorded.
Results: Oxidant-induced LMP in LMs was significantly greater among subjects with CAL and particularly among those with ongoing inflammation. Previous tobacco history did not influence LMP. Among subjects with CAL, oxidant-induced LMP correlated negatively with FEV₁% of predicted.
Conclusion: Lysosomes of LMs harvested from patients with CAL demonstrate an increased sensitivity to oxidants, which may trigger mechanisms behind CAL, eg, chronic airway inflammation and fibrotic re-modelling. The study suggests a mechanistic role for LMP in LMs on airway inflammation, suggesting an anti-inflammatory effect by drugs that prevent increased LMP.



中文翻译：

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人肺巨噬细胞在体外受到氧化剂的挑战：溶酶体膜致敏与炎症和慢性气流受限有关

背景：肺巨噬细胞 (LM) 通过清除垂死细胞和伤口修复参与人肺的大多数炎症过程。在受到氧化剂挑战的细胞应激时，体内溶酶体可能在 LMs 中破裂，细胞内容物和细胞碎片的泄漏可能引发气道炎症和纤维化，这可能导致慢性气流受限 (CAL)。
目的：本研究的目的是确定在体外受到氧化剂挑战的 LM 中的溶酶体膜通透性 (LMP) 是否与气道炎症和 CAL 相关，后者评估为一秒用力呼气量 (FEV ₁ ) 减少，表示为预测的百分比。
材料和方法：调查了 28 名受试者；13 名肺部健康受试者和 15 名患有各种炎症性疾病的受试者，在动态肺活量测定中显示 CAL（定义为 FEV ₁ /FVC 比率 < 0.70）。LMs 通过支气管肺泡灌洗液 (BAL) 收获，并通过氧化剂离体挑战。暴露于氧化剂的 LMs 中的 LMP 被评估为来自暴露于氧化剂的 LMs 发出的吖啶橙 (AO) 绿色荧光（使用巨噬细胞样小鼠 J774 细胞作为阳性对照）。计数 BAL 中的炎症细胞并记录肺体积。
结果：在患有 CAL 的受试者中，尤其是在持续炎症的受试者中，LMs 中氧化剂诱导的 LMP 显着增加。既往吸烟史不影响 LMP。在患有 CAL 的受试者中，氧化剂诱导的 LMP 与 FEV ₁ % 的预测值呈负相关。
结论：从 CAL 患者身上采集的 LMs 的溶酶体表现出对氧化剂的敏感性增加，这可能触发 CAL 背后的机制，例如慢性气道炎症和纤维化重塑。该研究表明 LMP 在 LMs 中对气道炎症的机制作用，表明防止 LMP 增加的药物具有抗炎作用。