Chronic Aspiration of Gastric Fluid Induces the Development of Obliterative Bronchiolitis in Rat Lung Transplants

Abstract

Long-term survival of a pulmonary allograft is currently hampered by obliterative bronchiolitis (OB), a form of chronic rejection that is unique to lung transplantation. While tracheobronchial aspiration from gastroesophageal reflux disease (GERD) has clinically been associated with OB, no experimental model exists to investigate this problem. Using a WKY-to-F344 rat orthotopic left lung transplant model, the effects of chronic aspiration on pulmonary allograft were evaluated. Recipients received cyclosporine with or without 8 weekly aspirations of gastric fluid into the allograft. Six (66.7%) of 9 allografts with aspiration demonstrated bronchioles with surrounding monocytic infiltrates, fibrosis and loss of normal lumen anatomy, consistent with the development of OB. In contrast, none of the allografts without aspiration (n = 10) demonstrated these findings (p = 0.002). Of the grafts examined grossly, 83% of the allografts with chronic aspiration but only 20% without aspiration appeared consolidated (p = 0.013). Aspiration was associated with increased levels of IL-1a , IL-1b , IL-6, IL-10, TNF-a and TGF-b in BAL and of IL-1a , IL-4 and GM-CSF in serum. This study provides experimental evidence linking chronic aspiration to the development of OB and suggests that strategies aimed at preventing aspiration-related injuries might improve outcomes in clinical lung transplantation.

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

“…An intriguing model of lung transplantation in ferrets also develops OB-like lesions (112). Finally, the role of innate immune activation in augmenting OB has also been evaluated using the rat lung transplant model with intratracheal gastric fluid challenge (113).…”

Macrophage activation by gastric fluid suggests MMP involvement in aspiration-induced lung disease

“…Further, we have shown that chronic aspiration can exacerbate asthmalike hypersensitivity in mice (Barbas et al 2008). The wide range of pulmonary pathology that can be influenced by chronic aspiration is further demonstrated by the observations that chronic aspiration can induce either accelerated acute rejection (Hartwig et al 2006) or the development of obliterative bronchiolitis (Li et al 2008) in rat lung transplant models. The studies described in this manuscript are intended to provide the first in vitro investigations aimed at elucidating the mechanisms associated with chronic aspiration in the pathogenesis of pulmonary disease.…”

Histological Examination of the Relationship between Respiratory Disorders and Repetitive Microaspiration Using a Rat Gastro-Duodenal Contents Reflux Model

“…These lesions may play an important role in exacerbation of FEV 1 subsequent to COPD exacerbations, unlike true constrictive BO that is fused to the bronchiolar wall and obliterates the lumen. In a recent experimental study, Li et al [29] reported histological evidence consistent with BO development in lung allografts after inducing chronic gastric fluid aspiration in a rat model that utilized immunosuppression to avoid acute rejection. However, the BO-like lesions observed in the present reflux animal lungs did not result from lung transplants or cyclosporine treatments.…”