Pseudomonas aeruginosa Induced Airway Epithelial Injury Drives Fibroblast Activation: A Mechanism in Chronic Lung Allograft Dysfunction

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.

Pseudomonas aeruginosa and acute rejection independently increase the risk of donor-specific antibodies after lung transplantation

“…Our data indicate that this relationship is unique to Pseudomonas aeruginosa , as we did not detect an association between other bacteria, fungi, or viruses and DSA in our cohort. Several reports have demonstrated that Pseudomonas aeruginosa stimulates potent innate immune responses, including airway neutrophilia . Our group has also shown that Pseudomonas aeruginosa infection in a mouse model of lung transplantation promotes neutrophilia through a granulocyte‐colony stimulating factor‐dependent mechanism that prevents established tolerance .…”

“…18,22,37,38 Over half of those who had Pseudomonas aeruginosa isolation after transplantation were culture negative for Pseudomonas aeruginosa before transplantation. Moreover, the association between [39][40][41] Our group has also shown that Pseudomonas aeruginosa infection in a mouse model of lung transplantation promotes neutrophilia through a granulocyte-colony stimulating factor-dependent mechanism that prevents established tolerance. 39 Notably, we also observed that Pseudomonas aeruginosa infection induced allograft-infiltrating neutrophils to upregulate the B7 molecules CD80 and CD86, which in turn could drive alloantigen-specific T cell responses through providing B7:CD28 costimulation in trans.…”

Inflammation: A Double-Edged Sword in the Response to <b><i>Pseudomonas aeruginosa</i></b> Infection

“…Fibroblast activation can be driven by products of P. aeruginosa -injured epithelial cells such as IL-1α, and may underlie the development of BOS in lung transplant patients infected with P. aeruginosa . These individuals show increased levels of IL-1α, elevated IL-8 levels, and higher neutrophil percentages in bronchoalveolar lavage (BAL) fluid collected shortly before the diagnosis of BOS, as compared to post-transplant patients without BOS, and inflammation is temporally correlated with P. aeruginosa growth in BAL [56]. …”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…While in vitro models of OB have utility in showing how individual populations, such as bronchial epithelial cells, mesenchymal stromal cells, and airway smooth muscle cells, may contribute to disease (95)(96)(97)(98), animal models can provide a window into the events from transplant to the final fibrotic obliteration of small airways and is key to investigating the pathogenesis of OB and conducting preclinical studies of potential therapeutic interventions. Utilized models of post-lung-transplant OB are based on allogeneic lung tissue transplantation with a goal of reproducing fibrotic airway remodeling.…”