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De Luca D, Alonso A, Autilio C. Bile acids-induced lung injury: update of reverse translational biology. Am J Physiol Lung Cell Mol Physiol 2022; 323:L93-L106. [DOI: 10.1152/ajplung.00523.2021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The presence of bile acids in lung tissue is associated with some clinical features observed in various medical specialties, but it took time to understand that these are due to a "bile acid-induced lung injury" since specific translational studies and cross-disciplinary awareness were lacking. We used a reverse translational approach to update and summarize the current knowledge about the mechanisms of bile acid-induced lung injury. This has been done in a cross-disciplinary fashion since these conditions may occur in patients of various age and in different medical fields. We here define these clinical conditions, then we review the physiopathology of these conditions and the animal models used to mimic them and, finally, their pathobiology. Mechanisms of bile acid-induced lung injury have been partially clarified overtime and are represented by: 1) the interaction with secretory phospholipase A2 pathway, 2) the effect on surfactant function and structure, 3) the biological effects on inflammation and local immunity, 4) the direct cellular toxicity. These mechanisms are schematically illustrated and histological comparisons between ARDS induced by bile acids and other triggers are also provided. Based on these mechanisms we propose possible direct therapeutic applications and, finally, we discuss further research steps to improve the understanding of processes that generate pathological clinical conditions.
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Affiliation(s)
- Daniele De Luca
- Division of Pediatrics and Neonatal Critical Care, Paris Saclay University Hospital, Clamart, Paris, France
- Physiopathology and Therapeutic Innovation Unit-INSERM U999, Paris Saclay University, Le Plessis Robinson, France
| | - Alejandro Alonso
- Department of Biochemistry and Molecular Biology, Faculty of Biology, and Research, Institut-Hospital, Complutense University, Madrid, Spain
| | - Chiara Autilio
- Department of Biochemistry and Molecular Biology, Faculty of Biology, and Research, Institut-Hospital, Complutense University, Madrid, Spain
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Hegyi P, Maléth J, Walters JR, Hofmann AF, Keely SJ. Guts and Gall: Bile Acids in Regulation of Intestinal Epithelial Function in Health and Disease. Physiol Rev 2018; 98:1983-2023. [PMID: 30067158 DOI: 10.1152/physrev.00054.2017] [Citation(s) in RCA: 190] [Impact Index Per Article: 27.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Epithelial cells line the entire surface of the gastrointestinal tract and its accessory organs where they primarily function in transporting digestive enzymes, nutrients, electrolytes, and fluid to and from the luminal contents. At the same time, epithelial cells are responsible for forming a physical and biochemical barrier that prevents the entry into the body of harmful agents, such as bacteria and their toxins. Dysregulation of epithelial transport and barrier function is associated with the pathogenesis of a number of conditions throughout the intestine, such as inflammatory bowel disease, chronic diarrhea, pancreatitis, reflux esophagitis, and cancer. Driven by discovery of specific receptors on intestinal epithelial cells, new insights into mechanisms that control their synthesis and enterohepatic circulation, and a growing appreciation of their roles as bioactive bacterial metabolites, bile acids are currently receiving a great deal of interest as critical regulators of epithelial function in health and disease. This review aims to summarize recent advances in this field and to highlight how bile acids are now emerging as exciting new targets for disease intervention.
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Affiliation(s)
- Peter Hegyi
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Joszef Maléth
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Julian R Walters
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Alan F Hofmann
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
| | - Stephen J Keely
- Momentum Translational Gastroenterology Research Group, Hungarian Academy of Sciences-University of Szeged , Szeged , Hungary ; Institute for Translational Medicine, Medical School, University of Pécs , Pécs , Hungary ; Momentum Epithelial Cell Signalling and Secretion Research Group and First Department of Medicine, University of Szeged , Szeged , Hungary ; Division of Digestive Diseases, Department of Gastroenterology, Hammersmith Hospital, Imperial College London , London , United Kingdom ; Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California ; and Department of Molecular Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital , Dublin , Ireland
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Ataalla WM, Ziada DH, Gaber R, Ossman A, Bayomy S, Elemary BR. The impact of total bile acid levels on fetal cardiac function in intrahepatic cholestasis of pregnancy using fetal echocardiography: a tissue Doppler imaging study. J Matern Fetal Neonatal Med 2015; 29:1445-50. [PMID: 26067266 DOI: 10.3109/14767058.2015.1051020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
AIM The aim of this study was to assess total bile acid (TBA) levels and its impact on systolic and diastolic functions in fetuses of mothers with intrahepatic cholestasis of pregnancy (ICP) using tissue Doppler imaging (TDI), and to explore the correlation between TBA levels and fetal cardiac function. SUBJECTS AND METHODS The study employed 98 pregnant women with ICP who were divided into two groups according to their bile acid levels. Fifty pregnant women without ICP represented the control group. RESULTS Significant differences in the myocardial tissue velocities of both mitral and tricuspid valves were found between the fetuses of mothers with ICP and TBA levels of <40 mmol/L and the control group, versus fetuses of mothers with ICP and TBA levels >40 mmol/L. There was a significant increase in neonatal respiratory distress, meconium staining and neonatal TBAs in group II compared to the control group and group I. There was a correlation between maternal TBA levels and preterm delivery, APGAR scores and neonatal TBA levels at birth. There was also a positive correlation between maternal TBA and fetal myocardial tissue velocities of both mitral and tricuspid, and fetal diastolic myocardial tissue Doppler velocities. CONCLUSION ICP is a very serious condition especially when maternal TBA levels are >40 mmol/L. Fetal echocardiography with tissue Doppler is a useful tool for fetal assessment in patients with ICP. It could be an indication of induction of labor in cases of ICP and bile acid levels ≥40 mol/L. Neonatal echocardiography is mandatory for follow-up and management of these neonates.
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Affiliation(s)
| | - Dina H Ziada
- b Department of Tropical and Infectious Diseases , and
| | - Rania Gaber
- c Department of Cardiology, Tanta University , Tanta , Egypt , and
| | | | - Suzan Bayomy
- c Department of Cardiology, Tanta University , Tanta , Egypt , and
| | - Berihan R Elemary
- d Department of Applied Statistics & Insurance , Damietta University , Damietta , Egypt
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Li Y, Cui Y, Wang C, Liu X, Han J. A risk factor analysis on disease severity in 47 premature infants with bronchopulmonary dysplasia. Intractable Rare Dis Res 2015; 4:82-6. [PMID: 25984426 PMCID: PMC4428191 DOI: 10.5582/irdr.2015.01000] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 03/10/2015] [Accepted: 03/16/2015] [Indexed: 11/05/2022] Open
Abstract
Bronchopulmonary Dysplasia (BPD) is a rare chronic lung disease and one of the most difficult complications to treat in premature infants. With the progress at the medical treatment level, an increasing number of BPD premature infants are born, meanwhile, they would be at an increasing risk for numerous complications and rehospitalization because BPD affects many vital organ systems. The pathogenesis of BPD is clearly multifactorial. As the prognosis is closely connected with the severity of BPD, early diagnosis and treatment are of great help to control the development of BPD. This article focuses on risk factors that could influence the severity of BPD in order to provide a reliable basis for early diagnosis, treatment, and better patient assessment.
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Affiliation(s)
- Yan Li
- Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease of Shandong Province, Shandong Medicinal Biotechnology Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong, China
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Science, Ji'nan, Shandong, China
| | - Yazhou Cui
- Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease of Shandong Province, Shandong Medicinal Biotechnology Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong, China
| | - Chao Wang
- Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease of Shandong Province, Shandong Medicinal Biotechnology Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong, China
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Science, Ji'nan, Shandong, China
| | - Xiao Liu
- Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease of Shandong Province, Shandong Medicinal Biotechnology Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong, China
- School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Science, Ji'nan, Shandong, China
| | - Jinxiang Han
- Key Laboratory for Biotech Drugs of the Ministry of Health, Key Laboratory for Rare Disease of Shandong Province, Shandong Medicinal Biotechnology Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong, China
- Address correspondence to: Dr. Jinxiang Han, Key Laboratory for Rare Disease Research of Shandong Province, Key Laboratory for Biotech Drugs of the Ministry of Health, Shandong Medical Biotechnological Center, Shandong Academy of Medical Sciences, Ji'nan, Shandong 250062, China. E-mail:
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Hendrick SM, Mroz MS, Greene CM, Keely SJ, Harvey BJ. Bile acids stimulate chloride secretion through CFTR and calcium-activated Cl- channels in Calu-3 airway epithelial cells. Am J Physiol Lung Cell Mol Physiol 2014; 307:L407-18. [PMID: 24993131 DOI: 10.1152/ajplung.00352.2013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Bile acids resulting from the aspiration of gastroesophageal refluxate are often present in the lower airways of people with cystic fibrosis and other respiratory distress diseases. Surprisingly, there is little or no information on the modulation of airway epithelial ion transport by bile acids. The secretory effect of a variety of conjugated and unconjugated secondary bile acids was investigated in Calu-3 airway epithelial cells grown under an air-liquid interface and mounted in Ussing chambers. Electrogenic transepithelial ion transport was measured as short-circuit current (Isc). The taurine-conjugated secondary bile acid, taurodeoxycholic acid (TDCA), was found to be the most potent modulator of basal ion transport. Acute treatment (5 min) of Calu-3 cells with TDCA (25 μM) on the basolateral side caused a stimulation of Isc, and removal of extracellular Cl(-) abolished this response. TDCA produced an increase in the cystic fibrosis transmembrane conductance regulator (CFTR)-dependent current that was abolished by pretreatment with the CFTR inhibitor CFTRinh172. TDCA treatment also increased Cl(-) secretion through calcium-activated chloride (CaCC) channels and increased the Na(+)/K(+) pump current. Acute treatment with TDCA resulted in a rapid cellular influx of Ca(2+) and increased cAMP levels in Calu-3 cells. Bile acid receptor-selective activation with INT-777 revealed TGR5 localized at the basolateral membrane as the receptor involved in TDCA-induced Cl(-) secretion. In summary, we demonstrate for the first time that low concentrations of bile acids can modulate Cl(-) secretion in airway epithelial cells, and this effect is dependent on both the duration and sidedness of exposure to the bile acid.
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Affiliation(s)
| | | | - Catherine M Greene
- Respiratory Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
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Su KC, Wu YC, Chen CS, Hung MH, Hsiao YH, Tseng CM, Chang SC, Lee YC, Perng DW. Bile acids increase alveolar epithelial permeability via mitogen-activated protein kinase, cytosolic phospholipase A2 , cyclooxygenase-2, prostaglandin E2 and junctional proteins. Respirology 2014; 18:848-56. [PMID: 23521748 DOI: 10.1111/resp.12086] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Revised: 10/13/2012] [Accepted: 01/03/2013] [Indexed: 12/01/2022]
Abstract
BACKGROUND AND OBJECTIVE Bile acid (BA) aspiration is associated with various lung diseases. It was hypothesized that BA may induce changes in alveolar epithelium permeability and contribute to the pathogenesis of lung injury. METHODS Human alveolar epithelial cells were grown in monolayer and stimulated with a major component of BA, chenodeoxycholic acid (CDCA). Transepithelial electrical resistance (TER) and paracellular fluxes were measured to assess permeability alteration. Prostaglandin E2 ( PGE2 ) production was measured, and its effect on TER and junctional proteins (JP) was also examined. Reverse transcription polymerase chain reaction and Western blots were used to investigate the expression of messenger RNA and JP. RESULTS CDCA induced significant p38 and c-Jun N-terminal kinase (JNK) phosphorylation, cytosolic phospholipase A2 (cPLA2 ) and cyclooxygenase-2 (COX-2) messenger RNA expression, PGE2 production, TER reduction and decay of JP (including occludin, zonula occludens-1 (ZO-1) and E-cadherin, in which ZO-1 had maximal change). CDCA also increased paracellular fluxes, which was abolished by dexamethasone. Both CDCA and PGE2 contributed to TER reduction in an identical trend and a dose-response manner. PGE2 also reduced ZO-1 expression, which was similar to that observed by CDCA stimulation. Pretreatment with inhibitors of p38 (SB203580), JNK (SP600125), cPLA2 (mepacrine) and COX-2 (NS398) as well as dexamethasone reversed the CDCA-induced PGE2 production, TER reduction and decay of ZO-1. CONCLUSIONS The increase in alveolar permeability was associated with decay of JP. BA may induce permeability alteration through the upregulation of mitogen-activated protein kinase, cPLA2 , COX-2, PGE2 and JP, which may contribute to the pathogenesis of BA-associated lung injury.
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Affiliation(s)
- Kang-Cheng Su
- Institute of Emergency and Critical Care Medicine, School of Medicine, Taipei, Taiwan
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Ding YL, Zhang LJ, Wang X, Zhou QC, Li N, Wang CX, Zhang XQ. Fetal lung surfactant and development alterations in intrahepatic cholestasis of pregnancy. World J Obstet Gynecol 2014; 3:78. [DOI: 10.5317/wjog.v3.i2.78] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 11/07/2013] [Accepted: 01/14/2014] [Indexed: 02/05/2023] Open
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Rook M, Vargas J, Caughey A, Bacchetti P, Rosenthal P, Bull L. Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One 2012; 7:e28343. [PMID: 22403605 PMCID: PMC3293870 DOI: 10.1371/journal.pone.0028343] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 11/06/2011] [Indexed: 12/27/2022] Open
Abstract
Background Intrahepatic cholestasis of pregnancy (ICP) has important fetal implications. There is increased risk for poor fetal outcomes, including preterm delivery, meconium staining of amniotic fluid, respiratory distress, fetal distress and demise. Methods One hundred and one women diagnosed with ICP between January 2005 and March 2009 at San Francisco General Hospital were included in this study. Single predictor logistic regression models were used to assess the associations of maternal clinical and biochemical predictors with fetal complications. Clinical predictors analyzed included age, race/ethnicity, gravidity, parity, history of liver or biliary disease, history of ICP in previous pregnancies, and induction. Biochemical predictors analyzed included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, and total bile acids (TBA). Results The prevalence of ICP was 1.9%. Most were Latina (90%). Labor was induced in the majority (87%) and most were delivered by normal spontaneous vaginal delivery (84%). Fetal complications occurred in 33% of the deliveries, with respiratory distress accounting for the majority of complications. There were no statistically significant clinical or biochemical predictors associated with an increased risk of fetal complications. Elevated TBA had little association with fetal complications until reaching greater than 100 µmoL/L, with 3 out of 5 having reported complications. ICP in previous pregnancies was associated with decreased risk of fetal complications (OR 0.21, p = 0.046). There were no cases of late term fetal demise. Conclusions Maternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.
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Affiliation(s)
- Michelle Rook
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America
| | - Juan Vargas
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America
- Department of Radiology, University of California San Francisco, San Francisco, California, United States of America
| | - Aaron Caughey
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of California San Francisco, San Francisco, California, United States of America
| | - Peter Bacchetti
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America
| | - Philip Rosenthal
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of California San Francisco, San Francisco, California, United States of America
- Department of Surgery, University of California San Francisco, San Francisco, California, United States of America
| | - Laura Bull
- Liver Center Laboratory and Institute for Human Genetics, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America
- * E-mail:
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Tsai HC, Lin FC, Chen YC, Chang SC. The role of total bile acid in oral secretions in ventilator-associated pneumonia. J Crit Care 2012; 27:526.e1-6. [PMID: 22300490 DOI: 10.1016/j.jcrc.2011.12.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Revised: 11/14/2011] [Accepted: 12/08/2011] [Indexed: 12/29/2022]
Abstract
PURPOSE The aim of this study was to investigate the role of inflammatory biomarkers and total bile acid (TBA) in oral secretions in the development of ventilator-associated pneumonia (VAP). MATERIALS This prospective study was conducted in an intensive care unit. Oral secretions were collected from mechanically ventilated patients who met the selection criteria for VAP prevention protocol. The levels of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor α, soluble intercellular adhesion molecule-1, monocyte chemoattractant protein-1, C-reactive protein, surfactant protein D, and TBA in oral secretions were measured and compared between the patients with and those without VAP. RESULTS Thirty-nine patients with and 39 patients without VAP were studied. The levels of inflammatory biomarkers in oral secretions showed no significant difference between the 2 groups. However, the patients with VAP had significantly higher values of TBA in oral secretions than did those without VAP (median and 25th-75th interquartile range, 9.59 and 1.37-24.66 μmol/L vs 2.74 and 0.00-8.22 μmol/L; P < .003). No significant correlations were found between TBA and inflammatory biomarkers in oral secretions. CONCLUSIONS Duodenogastroesophageal reflux as evidenced by the presence of TBA in oral secretions is common in mechanically ventilated patients and may play a role in the development of VAP.
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Affiliation(s)
- Han-Chen Tsai
- Respiratory Care Unit, Department of Nursing, Taipei Veterans General Hospital, Taipei, Taiwan
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Wu YC, Hsu PK, Su KC, Liu LY, Tsai CC, Tsai SH, Hsu WH, Lee YC, Perng DW. Bile acid aspiration in suspected ventilator-associated pneumonia. Chest 2009; 136:118-124. [PMID: 19318678 DOI: 10.1378/chest.08-2668] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
AIMS The aims of this study were to measure the levels of bile acids in patients with suspected ventilator-associated pneumonia (VAP) and provide a possible pathway for neutrophilic inflammation to explain its proinflammatory effect on the airway. METHODS Bile acid levels were measured by spectrophotometric enzymatic assay, and liquid chromatography mass spectrometry was used to quantify the major bile acids. Alveolar cells were grown on modified air-liquid interface culture inserts, and bile acids were then employed to stimulate the cells. Reverse transcriptase polymerase chain reaction and Western blots were used to determine the involved gene expression and protein levels. RESULTS The mean (+/- SE) concentration of total bile acids in tracheal aspirates was 6.2 +/- 2.1 and 1.1 +/- 0.4 mumol/L/g sputum, respectively, for patients with and without VAP (p < 0.05). The interleukin (IL)-8 level was significantly higher in the VAP group (p < 0.05). The major bile acid, chenodeoxycholic acid, stimulated alveolar epithelial cells to increase IL-8 production at both the messenger RNA and protein level through p38 and c-Jun N-terminal kinase (JNK) activation. The selective p38 and JNK inhibitors, as well as dexamethasone, successfully inhibited IL-8 production. CONCLUSION These data suggest that early intervention to prevent bile acid aspiration may reduce the intensity of neutrophilic inflammation in intubated and mechanically ventilated patients in the ICU.
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Affiliation(s)
- Yu-Chung Wu
- Division of Thoracic Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Po-Kuei Hsu
- Division of Thoracic Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Kang-Cheng Su
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Lung-Yu Liu
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Cheng-Chien Tsai
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; School of Nursing, National Yang-Ming University, Taipei, Taiwan
| | - Shu-Ho Tsai
- Department of Surgery, and the Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Wen-Hu Hsu
- Division of Thoracic Surgery, Taipei Veterans General Hospital, Taipei, Taiwan; Department of Surgery, and the Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yu-Chin Lee
- Department of Surgery, and the Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Diahn-Warng Perng
- Department of Surgery, and the Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan.
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De Luca D, Minucci A, Zecca E, Piastra M, Pietrini D, Carnielli VP, Zuppi C, Tridente A, Conti G, Capoluongo ED. Bile acids cause secretory phospholipase A2 activity enhancement, revertible by exogenous surfactant administration. Intensive Care Med 2009; 35:321-6. [PMID: 18853138 DOI: 10.1007/s00134-008-1321-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2008] [Accepted: 09/21/2008] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND PURPOSES Bile acids have been implicated in some forms of acute lung injury, including meconium aspiration and bile acid pneumonia in neonates, or aspiration related ARDS in adults. Secretory phospholipase A2 (sPLA2) is now known as a key enzyme in the lung injury pathways and is supposed to be responsible for surfactant dysfunction. Our aim was to investigate the interaction between bile acids and sPLA2 in an extracellular environment representing an in vitro model of aspiration. METHODS In vitro study using broncho-alveolar lavage (BAL) of 23 neonates/infants (<6 m) with healthy lungs. BAL supernatants were assayed for sPLA2 activity in basal condition and after addition of randomly assigned concentrations of bile acids (BA) or normal saline. Samples coming from neonates were then challenged with poractant-alfa up to a phospholipid concentration equal to that found in babies after the surfactant treatment for respiratory distress syndrome. sPLA2 activity was again measured, being corrected for serum/supernatant urea ratio and for confounding factors. RESULTS High concentrations of BA (5 micromol/l) significantly increased (P = 0.012) sPLA2 activity, leading to increased surfactant catabolism. This finding was not observed with lower BA concentration and this is consistent with available literature data and may indicate an anionic activation of the enzyme by bile acids. Increased activity was significantly reverted by the addition of exogenous surfactant (P = 0.004) which was able to reduce sPLA2 activity almost to the baseline level. CONCLUSIONS BA are likely to contribute to lung injury, causing surfactant inactivation through the increased sPLA2 activity. Other mechanisms cannot be excluded and require further studies to be clarified.
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Affiliation(s)
- Daniele De Luca
- Pediatric Intensive Care Unit, Department of Anaesthesiology and Intensive Care, University Hospital A.Gemelli, Catholic University of the Sacred Heart, L.go A. Gemelli 8, 00168, Rome, Italy.
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Zecca E, De Luca D, Barbato G, Marras M, Tiberi E, Romagnoli C. Predicting respiratory distress syndrome in neonates from mothers with intrahepatic cholestasis of pregnancy. Early Hum Dev 2008; 84:337-41. [PMID: 17928172 DOI: 10.1016/j.earlhumdev.2007.09.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2006] [Revised: 04/21/2007] [Accepted: 09/10/2007] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Intrahepatic cholestasis of pregnancy (ICP) has been associated with prematurity and fetal mortality. Recently, ICP has also been recognised as a risk factor for neonatal respiratory distress syndrome (RDS) in term or near-term neonates. Since fetal mortality is more frequent in pregnancies with an early ICP onset, we speculated that the time of exposure (ET) to maternal bile acids at the delivery (BAdeliv) could be involved in neonatal lung damage too. Study aim was to develop a scoring system to predict the RDS occurrence. DESIGN We conducted a retrospective analysis of 77 pregnancies complicated by ICP (years 2000-2004) looking for factors associated to the neonatal RDS. We developed a risk score as follows: RDS risk score=BAdeliv x ET/gestational age and we prospectively applied it to 30 neonates from ICP pregnancies (years 2005-2006). RESULTS ROC analysis indicated 9 as the score with the highest sensitivity (83.3%) and specificity (87.5%). Considering a RDS incidence of about 25% in babies coming from ICP pregnancies, the post-test probability showed a risk increased to 66.7% with a score>9 and reduced to 4.8% with a score<or=9. CONCLUSION Our score is easy to apply and is based on the three most important variables involved in the RDS genesis. Score reliability is high enough to use it in clinical practice and to verify it in wider populations.
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Affiliation(s)
- Enrico Zecca
- Division of Neonatology, Institute of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy
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Zecca E, De Luca D, Baroni S, Vento G, Tiberi E, Romagnoli C. Bile acid-induced lung injury in newborn infants: a bronchoalveolar lavage fluid study. Pediatrics 2008; 121:e146-9. [PMID: 18166532 DOI: 10.1542/peds.2007-1220] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES Neonatal respiratory distress syndrome is associated with intrahepatic cholestasis of pregnancy, and bile acids may play a major role in neonatal bile acid pneumonia. Our aim was to demonstrate the bile acid presence in the bronchoalveolar lavage fluid of neonates affected by respiratory distress syndrome who were born from intrahepatic cholestasis of pregnancy and to investigate bile acid mechanisms of action in acute lung injury. METHODS In this prospective study, we enrolled 10 neonates delivered from intrahepatic cholestasis of pregnancy, affected by respiratory distress syndrome requiring mechanical ventilation (intrahepatic cholestasis of pregnancy group) and 2 control groups. The first group consisted of 20 infants with respiratory distress syndrome delivered from pregnancies without any sign of intrahepatic cholestasis of pregnancy (respiratory-distress-syndrome group), and the second group included 20 neonates with no lung disease who were ventilated for extrapulmonary reasons (no-lung-disease group). We measured bile acid and pH in the bronchoalveolar lavage fluid and serum bile acid levels in the first 24 hours of life. RESULTS Bile acids were measurable in the bronchoalveolar lavage fluid of all of the infants in the intrahepatic cholestasis of pregnancy group but were absent in the 2 control groups. Bronchoalveolar lavage fluid pH was not different among the 3 groups. Infants in the intrahepatic-cholestasis-of-pregnancy group had significantly higher serum bile acid levels compared with those in both of the control groups. CONCLUSIONS Bile acids are detectable in the bronchoalveolar lavage fluid of newborns from intrahepatic cholestasis of pregnancy affected by respiratory distress syndrome. Elevated serum bile acid levels in these infants allow us to hypothesize that bile acid reaches the lung after an uptake from the circulation. These findings strongly support a role for bile acid in causing bile acid pneumonia.
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Affiliation(s)
- Enrico Zecca
- Division of Neonatology, Department of Pediatrics, University Hospital A. Gemelli, Catholic University of the Sacred Heart, Rome, Italy.
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Affiliation(s)
- F D'Ovidio
- Toronto Lung Transplant Program, University of Toronto, Toronto, Ontario, Canada
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Zecca E, De Luca D, Marras M, Caruso A, Bernardini T, Romagnoli C. Intrahepatic cholestasis of pregnancy and neonatal respiratory distress syndrome. Pediatrics 2006; 117:1669-72. [PMID: 16651322 DOI: 10.1542/peds.2005-1801] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES We sought to verify the association between maternal intrahepatic cholestasis of pregnancy (ICP) and neonatal respiratory distress syndrome (RDS) and to determine how bile acids levels alter the risk of developing neonatal RDS. METHODS We extracted data from our divisional database about all of the newborns born during the years 2000-2004. We compared 77 neonates born from pregnancies complicated by ICP with 427 neonates in the same range of gestational age born from noncomplicated pregnancies. We studied maternal bile acids levels immediately before delivery in mothers with ICP and measured bile acid levels during the first 24 hours of life in their newborns. RESULTS The incidence of RDS in newborns from cholestatic pregnancies was twice that the reference population (28.6% vs 14%). The multivariate analysis showed that the risk of RDS in these newborns was approximately 2.5 times higher than in control infants. Within the ICP group, maternal and neonatal bile acid levels of infants affected by RDS were not significantly higher than those of healthy infants. The multivariate analysis showed that a low gestational age was the most important risk factor, but the probability of respiratory distress syndrome also increased by 2 per thousand for every additional micromole of the interaction term "neonatal by maternal bile acids level." CONCLUSIONS Maternal ICP is significantly associated with the occurrence of RDS in the newborn. We hypothesize that bile acids can produce surfactant depletion in the alveoli reverting the reaction of phospholipase A2. This hypothesis could potentially be confirmed by bronchoalveolar lavage study.
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Affiliation(s)
- Enrico Zecca
- Division of Neonatology, Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy.
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D'Ovidio F, Mura M, Tsang M, Waddell TK, Hutcheon MA, Singer LG, Hadjiliadis D, Chaparro C, Gutierrez C, Pierre A, Darling G, Liu M, Keshavjee S. Bile acid aspiration and the development of bronchiolitis obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005; 129:1144-52. [PMID: 15867792 DOI: 10.1016/j.jtcvs.2004.10.035] [Citation(s) in RCA: 224] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
BACKGROUND 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. MATERIALS AND METHODS 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). RESULTS 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). CONCLUSIONS 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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Affiliation(s)
- Frank D'Ovidio
- Toronto Lung Transplant Program, University of Toronto, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, Canada M5G 2C4
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Abstract
Gastroesophageal reflux (GER) and apnea are both common occurrences in premature infants but their relationship is controversial. We present the evidence for and against an association between GER and apnea and discuss the merits and limitations of the various methodologies employed in characterizing such a relationship. Overall, GER and apnea do not appear temporally related in preterm infants, despite strong physiologic evidence that stimulation of laryngeal afferents elicits central apnea and laryngeal adduction. In a subpopulation of infants with neurodevelopmental compromise, there may be an increased incidence of both apnea and GER, although the direct association between GER and apnea in this population is unclear. Therefore, we believe there is no evidence to support widespread use of anti-reflux medications in the treatment of apnea in preterm infants. Further studies are needed to clarify the existence of a small subpopulation of infants who may have GER-induced apnea, to identify potential triggering mechanisms, and to document benefit from newer pharmacological approaches.
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Affiliation(s)
- Eleanor J Molloy
- Division of Neonatology, Department of Pediatrics, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA
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Zecca E, Costa S, Lauriola V, Vento G, Papacci P, Romagnoli C. Bile acid pneumonia: a "new" form of neonatal respiratory distress syndrome? Pediatrics 2004; 114:269-72. [PMID: 15231944 DOI: 10.1542/peds.114.1.269] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
We describe 3 cases of neonatal respiratory distress syndrome (RDS) in near-term infants, born from mothers with severe intrahepatic cholestasis of pregnancy. Common pictures of the cases were: good indices of lung maturity in the amniotic fluid; severe RDS requiring mechanical ventilation; high serum bile acid (BA) levels in the early days of life; no meconium aspiration; negative cultures; and absence of indirect laboratory signs of infection. After the first case, we hypothesized that abnormally high BA levels could have reversed the action of phospholipase A2 in the lungs, causing a degradation of phosphatidylcholines to lysophosphatidylcholines and the consequent lack of surfactant activity, leading to the severe respiratory distress. Consequently, in cases 2 and 3, we gave intratracheal surfactant to the infants, which, although administered around the first 24 hours of life, showed to be helpful. Our experience suggests that a high level of attention in the management of newborn infants (even near-term infants) born from women with intrahepatic cholestasis of pregnancy is necessary to detect as soon as possible signs and symptoms of this "unexpected" RDS, which can assume a very severe clinical picture. In such instances, we recommend that the diagnosis of BA pneumonia be kept in mind and that exogenous surfactant be given as soon as possible, even in the presence of indices of normal lung maturity in the amniotic fluid. Finding high levels of BA and lysophosphatidylcholines in the bronchoalveolar lavage of affected infants would aid in support of the diagnosis.
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Affiliation(s)
- Enrico Zecca
- Division of Neonatology, Catholic University of the Sacred Heart, Rome, Italy.
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Chang AB, Wilson SJ, Masters IB, Yuill M, Williams J, Williams G, Hubbard M. Altered arousal response in infants exposed to cigarette smoke. Arch Dis Child 2003; 88:30-3. [PMID: 12495956 PMCID: PMC1719296 DOI: 10.1136/adc.88.1.30] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
AIMS A failure of the arousal mechanism is a key feature in the apnoea theory for sudden infant death syndrome (SIDS). In infants studied at an age when the incidence of SIDS is highest, we evaluated whether in utero smoke exposed infants have altered arousal response to standardised auditory stimuli, and/or sleep pattern, as recorded on overnight complex sleep polysomnography. METHODS A standardised sequence of audiology stimuli was applied binaurally to 20 in utero smoke and non-smoke exposed infants aged 8-12 weeks during a rapid eye movement (REM) and NREM epoch, in a controlled (temperature, position, pacifier use, noise) sleep environment. Infants were monitored for 10-12 hours using complex sleep polysomnography. RESULTS Five infants exposed to in utero tobacco smoke did not have behavioural arousal response, whereas all non-smoke exposed infants aroused during NREM (p = 0.016). There was, however, no difference in REM sleep, and the groups did not differ in routine overnight complex sleep polysomnography parameters. CONCLUSION At the age when the incidence of SIDS is at its peak, infants of smoking mothers are less rousable than those of non-smoking mothers in NREM sleep; this may partly explain why such infants are more at risk of SIDS.
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Affiliation(s)
- A B Chang
- Department of Respiratory Medicine, Royal Children's Hospital Foundation, Brisbane.
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Chen Y, Plenderleith MB, Hills BA. Influence of surfactant on the activity of slowly adapting stretch receptors in the lung. RESPIRATION PHYSIOLOGY 1998; 112:135-43. [PMID: 9716297 DOI: 10.1016/s0034-5687(98)00030-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Since surfactant has a major role in lung mechanics, this study was designed to determine whether it influences afferent neural feedback to the brainstem. Rats were anaesthetised, paralysed, artificially ventilated and unilaterally vagotomised before recording neural action potentials responding to ventilation stroke (NAPvS) from single units of slowly adapting receptors. The mean (+/-SEM) NAPvs decreased by 7.4% (+/-2.3%) at post-instillation of Tween-20 (a commercial surfactant previously employed in pulmonary studies) from their pre-instillation levels, whereas, by contrast, NAPvs increased by 12.4% (+/-2.3%) at post-instillation of saline--a significant finding (P=0.029). These changes support the concept that surfactant influences afferent neural feedback to the brainstem from mechanoreceptors in the lung, with implications to surfactant deficiency in respiratory control disorders.
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Affiliation(s)
- Y Chen
- Paediatric Respiratory Research Centre, Mater Children's Hospital, South Brisbane, Queensland, Australia
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