Abstract
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.
Highlights
Chronic lung allograft dysfunction (CLAD) causes significant loss of function to the transplanted lung and is the major factor limiting long-term survival after lung transplant [1]
Chronic P. aeruginosa infection can lead to persistent inflammation and damage of the respiratory epithelium [15,16], and damaged epithelial cells may be a source of danger signals referred to as alarmins or damage-associated molecular patterns (DAMPs) [17,18,19]
The association between P. aeruginosa in the lung allograft and an increased risk of bronchiolitis obliterans syndrome (BOS) has been demonstrated in numerous studies
Summary
Chronic lung allograft dysfunction (CLAD) causes significant loss of function to the transplanted lung and is the major factor limiting long-term survival after lung transplant [1]. When this process affects the small- and medium-sized airways resulting in airflow limitation, it is referred to as bronchiolitis obliterans syndrome (BOS). BOS is characterized by progressive loss of bronchial epithelium, neutrophil influx, chronic inflammation, and fibroproliferation causing small airway obliteration [1,2,3,4]. Alarmins are a diverse class of molecules serving many important intracellular functions
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Schedule a callMore From: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
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