Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation

Toronto Lung Transplant Program, University of Toronto, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4.
Journal of Thoracic and Cardiovascular Surgery (Impact Factor: 4.17). 06/2005; 129(5):1144-52. DOI: 10.1016/j.jtcvs.2004.10.035
Source: PubMed


Aspiration of gastroesophageal refluxate may contribute to lung transplant bronchiolitis obliterans syndrome (BOS). We investigated bile acids in bronchoalveolar lavage fluid (BALF) and studied its role in BOS.
Surveillance pulmonary function tests and BALF were evaluated in 120 lung recipients. BOS-(0p-3) was diagnosed after 6 months' survival. BOS was defined as "early" if diagnosed within 12 months after a transplant. BALF was assayed for differential cell count, bile acids, and interleukins 8 and 15. Bile acids were considered elevated if greater than normal serum levels ( or =8 micromol/L).
Elevated BALF bile acids were measured in 20 (17%) of 120 patients. BOS was diagnosed in 36 (34%) of 107 patients and judged "early" in 21 (57%) of 36. Median BALF bile acid values were 1.6 micromol/L (range, 0-32 micromol/L) in BOS patients and 0.3 micromol/L (range, 0-16 micromol/L) in non-BOS patients ( P = .002); 2.6 micromol/L (range, 0-32 micromol/L) in early BOS patients and 0.8 micromol/L (range, 0-4.6 micromol/L) in late BOS patients, ( P = .02). Bile acids correlated with BALF IL-8 and alveolar neutrophilia (r = 0.3, P = .0004, and r = 0.3, P = .004, respectively), but not with IL-15. Freedom from BOS was significantly shortened in patients with elevated BALF bile acids (Cox-Mantel test, P = .0001).
Aspiration of duodenogastroesophageal refluxate is prevalent after lung transplantation and is associated with the development of BOS. Elevated BALF bile acids may promote early BOS development via an inflammatory process, possibly mediated by IL-8 and alveolar neutrophilia.

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    • "These may show profibrotic mechanism and pulmonary fibrosis due to acid aspiration (8). Aspiration due to duodenal-gastroesophagial reflux is prevalent after lung transplantation and this is recognized with an incidence of bronchiolitis obliterans along with fibrosis and inflammatory cell infiltration around small airways (9). In asthmatic patients, GERD has been known as an important factor in asthma attacks (10) and oxidative stress intensification (11). "
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    ABSTRACT: Objective(s): Gastroesophageal Reflux Disease (GERD) is one of the most common digestive disorders that frequently lead to pulmonary complications due to gastric fluid aspiration. In the present experimental study, chronic aspiration of gastric fluid, its components and bile salts in rat lung was performed to find out the main factor(s) causing pulmonary complications of gastric fluid aspiration. Materials and Methods: Forty eight male rats weighted 250-300 g were selected in six groups. After anesthesia and tracheal cannulation, the animals received 0.5 ml/kg normal saline, 0.5 ml/kg of whole gastric fluid, 0.5 ml/kg pepsin (2.5 µg/ml), 0.5 ml/kg hydrochloric acid (pH=1.5) or 0.5 ml/kg bile salts (2.5 µg/ml) by injection into their trachea and lungs. In sham group nothing was injected. Results: Parenchymal and airways inflammation and fibrosis of bronchi, bronchioles and parenchyma were significantly more in the test groups compared to saline and sham groups (P<0.001); also inflammation in pepsin and bile salts groups (histopathology scores: 2.87±0.35 and 3.0±0.0 for bronchial, 2.87±0.35 and 2.87±0.35 for bronchioles, 2.87±0.35 and 2.87±0.35 for parenchymal inflammation) were more than hydrochloric acid and gastric fluid groups (1.75±0.46 and 2.5±0.53 for bronchial, 2.0±0.0 and 2.0±0.0 for bronchioles, 2.0±0.0 and 2.0±0.0 for parenchymal inflammation) (P<0.05). The same results were found for fibrosis, so that the fibrosis in pepsin and bile salts groups were more than hydrochloric acid and gastric fluid groups (P<0.05). Conclusion : The present results suggested that pulmonary complications causing from bile salts and pepsin might be more than gastric juice and hydrochloric acid.
    Iranian Journal of Basic Medical Science 06/2013; 16(6):790-6. · 1.23 Impact Factor
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    • "Pepsin has been reported to be present in the saliva and sputum of patients investigated for reflux.[2425] The micro-aspiration of gastro esophageal content and their pathogenic potential to induce severe lung damage was suggested in animal studies and some clinical studies of rare diseases.[262728] "
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    ABSTRACT: Background/Aim: Gastro-esophageal reflux has been suggested to be associated with several pulmonary complications such as asthma, and post-transplant bronchiolitis obliterans (BO). Pepsin or bile salts in the sputum is shown to be an optimal molecular marker of gastric contents macro/micro aspiration. In this study, we investigated sputum pepsin as a marker of micro-aspiration in sulfur mustard (SM) exposed cases compared to healthy controls. Materials and Methods: In a case controlled study, 26 cases with BO and 12 matched healthy controls were recruited and all cases were symptomatic and their exposure to SM was previously documented during Iran-Iraq conflict. Pepsin levels in sputum and total bile acids were measured using enzymatic assay. The severity of respiratory disorder was categorized based upon the spirometric values. Result: The average concentration of pepsin in sputum was higher in the case group (0.29 ± 0.23) compared with healthy subjects (0.13 ± 0.07; P ± 0.003). Moreover, the average concentration of bile acids in the sputum cases was not significantly different in comparison to the controls (P = 0.5). Conclusion: Higher pepsin concentrations in sputum of SM exposed patients compared with healthy control subjects indicate the occurrence of significantly more gastric micro-aspiration in SM exposed patients.
    Saudi Journal of Gastroenterology 05/2013; 19(3):121-5. DOI:10.4103/1319-3767.111954 · 1.12 Impact Factor
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    • "GER has also been shown to be associated with obstructive sleep apnea [3]. The respiratory diseases that have most frequently been studied with GER are asthma [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] and chronic cough [5, 13, 14, 16– 23], but recently many studies have been published on GER and lung transplant (LTx) rejection [24] [25] [26] [27] [28] [29] [30] [31] [32]. "
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    ABSTRACT: Gastroesophageal reflux (GER) is commonly associated with respiratory symptoms, either through a vagal bronchoconstrictive reflex or through microaspiration of gastric contents. No diagnostic test is available, however, to diagnose when respiratory illnesses are caused by GER and when not, but research in this field has been moving forward. Various biomarkers in different types of biosamples have been studied in this context. The aim of this review is to summarize the present knowledge in this field. GER patients with respiratory diseases seem to have a different biochemical profile from similar patients without GER. Inflammatory biomarkers differ in asthmatics based on GER status, tachykinins are elevated in patients with GER-related cough, and bile acids are elevated in lung transplant patients with GER. However, studies on these biomarkers are often limited by their small size, methods of analysis, and case selections. The two pathogenesis mechanisms are associated with different respiratory illnesses and biochemical profiles. A reliable test to identify GER-induced respiratory disorders needs to be developed. Bronchoalveolar lavage is too invasive to be of use in most patients. Exhaled breath condensate samples need further evaluation and standardization. The newly developed particles in exhaled air measurements remain to be studied further.
    Gastroenterology Research and Practice 04/2013; 2013:148086. DOI:10.1155/2013/148086 · 1.75 Impact Factor
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