Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.
Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction.
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DOI：
10.1111/ajt.13690
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发表时间：
2016-06
期刊：
影响因子：
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通讯作者：
Fisher AJ
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文献类型：
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作者：
Borthwick LA;Suwara MI;Carnell SC;Green NJ;Mahida R;Dixon D;Gillespie CS;Cartwright TN;Horabin J;Walker A;Olin E;Rangar M;Gardner A;Mann J;Corris PA;Mann DA;Fisher AJ
肺移植后细菌感染导致气道上皮损伤，并与闭塞性细支气管炎综合征发生风险增加相关。受损的上皮细胞是激活先天免疫系统的警报素的来源，但尚未评估它们在闭塞性细支气管炎综合征发展中激活成纤维细胞的能力。两个上皮alarmins纵向测量支气管肺泡灌洗液从肺移植受者谁开发闭塞性细支气管炎综合征，并进行了比较，以稳定的控制。此外，将来自感染铜绿假单胞菌的人气道上皮细胞的条件培养基应用于肺成纤维细胞，并测定炎症反应。白细胞介素-1 α（IL-1α）在生长铜绿假单胞菌的肺移植受者的支气管肺泡灌洗液中升高（11.5 [5.4-21.8] vs. 2.8 [0.9-9.4] pg/mL，P < 0.01），并在发展为闭塞性细支气管炎综合征的3个月内显著升高（8.3 [1.4-25.1] vs. 3.6 [0.6-17.1] pg/mL，p < 0.01），而高迁移率族蛋白B1保持不变。IL-1α与支气管肺泡灌洗液IL-8水平（r2 = 0.6095，p < 0.0001）和中性粒细胞百分比（r2 = 0.25，p = 0.01）升高呈正相关。来自铜绿假单胞菌感染上皮细胞的条件培养基通过IL-1α/IL-1 R依赖性信号传导途径诱导成纤维细胞中的强效促炎表型。总之，我们认为IL-1α可能是限制肺移植后假单胞菌相关同种异体移植物损伤的一个新的治疗靶点。本研究表明，肺上皮细胞的铜绿假单胞菌激发导致肺成纤维细胞释放IL-1α并诱导炎症表型，并提供了铜绿假单胞菌感染、支气管肺泡灌洗液中IL-1α水平与肺移植后闭塞性细支气管炎综合征发生之间相关性的证据。
Bacterial infections after lung transplantation cause airway epithelial injury and are associated with an increased risk of developing bronchiolitis obliterans syndrome. The damaged epithelium is a source of alarmins that activate the innate immune system, yet their ability to activate fibroblasts in the development of bronchiolitis obliterans syndrome has not been evaluated. Two epithelial alarmins were measured longitudinally in bronchoalveolar lavages from lung transplant recipients who developed bronchiolitis obliterans syndrome and were compared to stable controls. In addition, conditioned media from human airway epithelial cells infected with Pseudomonas aeruginosa was applied to lung fibroblasts and inflammatory responses were determined. Interleukin‐1 alpha (IL‐1α) was increased in bronchoalveolar lavage of lung transplant recipients growing P. aeruginosa (11.5 [5.4–21.8] vs. 2.8 [0.9–9.4] pg/mL, p < 0.01) and was significantly elevated within 3 months of developing bronchiolitis obliterans syndrome (8.3 [1.4–25.1] vs. 3.6 [0.6–17.1] pg/mL, p < 0.01), whereas high mobility group protein B1 remained unchanged. IL‐1α positively correlated with elevated bronchoalveolar lavage IL‐8 levels (r2 = 0.6095, p < 0.0001) and neutrophil percentage (r2 = 0.25, p = 0.01). Conditioned media from P. aeruginosa infected epithelial cells induced a potent pro‐inflammatory phenotype in fibroblasts via an IL‐1α/IL‐1R‐dependent signaling pathway. In conclusion, we propose that IL‐1α may be a novel therapeutic target to limit Pseudomonas associated allograft injury after lung transplantation. This study demonstrates that a Pseudomonas aeruginosa challenge of lung epithelial cells causes the release of IL‐1α and the induction of an inflammatory phenotype in lung fibroblasts, and provides evidence of an association between infection with P. aeruginosa, IL‐1α levels in bronchoalveolar lavage fluid, and the development of bronchiolitis obliterans syndrome following lung transplantation.