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Perri A, Patti ML, Velardi M, Sbordone A, Prontera G, Fattore S, D’Andrea V, Tana M, Vento G. Bile Acids Pneumonia: A Respiratory Distress Syndrome in Early-Term Neonates. J Clin Med 2023; 12:6565. [PMID: 37892703 PMCID: PMC10607698 DOI: 10.3390/jcm12206565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/09/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
Intrahepatic cholestasis of pregnancy (ICP) complicates among 0.2-2% of pregnancies and has been associated with adverse perinatal outcomes, including sudden stillbirth, meconium strained fluid, preterm birth, perinatal asphyxia, and transient tachypnea of the newborn. The diagnosis of "bile acids pneumonia" was previously proposed and a causative role of bile acids (BA) was supposed with a possible mechanism of action including surfactant dysfunction, inflammation, and chemical pneumonia. In the last few years, the role of lung ultrasound (LUS) in the diagnosis and management of neonatal respiratory distress syndrome has grown, and LUS scores have been introduced in the literature, as an effective predictor of the need for surfactant treatment among neonates with respiratory distress syndrome. We present four cases of infants born from pregnancies complicated by ICP, who developed respiratory distress syndrome early after birth. Lung ultrasound showed the same pattern for all infants, corresponding to a homogeneous alveolar-interstitial syndrome characterized by a diffuse coalescing B-line pattern (white lung). All infants evaluated require non-invasive respiratory support and in three cases surfactant administration, despite the near-term gestational age, with rapid improvement of respiratory disease and a good clinical outcome.
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Affiliation(s)
- Alessandro Perri
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
- Department of Woman and Child Health and Public Health, Child Health Area, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Maria Letizia Patti
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
| | - Margherita Velardi
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
| | - Annamaria Sbordone
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
| | - Giorgia Prontera
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
| | - Simona Fattore
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
| | - Vito D’Andrea
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
- Department of Woman and Child Health and Public Health, Child Health Area, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Milena Tana
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
- Department of Woman and Child Health and Public Health, Child Health Area, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giovanni Vento
- Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy; (M.V.); (A.S.); (G.P.); (S.F.); (V.D.); (M.T.); (G.V.)
- Department of Woman and Child Health and Public Health, Child Health Area, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Liu L, Zhang Y, Wang Y, He Y, Ding X, Chen L, Shi Y. The perinatal period should be considered in neonatal acute respiratory distress syndrome: comparison of the Montreux definition vs. the second pediatric acute lung injury consensus conference definition. Front Pediatr 2023; 11:1216073. [PMID: 37842021 PMCID: PMC10568643 DOI: 10.3389/fped.2023.1216073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 09/19/2023] [Indexed: 10/17/2023] Open
Abstract
Background The recently developed Montreux definition for neonatal acute respiratory distress syndrome (ARDS) partially differs from the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) definition. Here, we compare the Montreux and PALICC-2 definitions regarding morbidity, mortality, and prognosis of neonatal cases of ARDS in order to evaluate which definition is more appropriate for newborns. Methods Neonates admitted to our neonatal intensive care unit between 1 January 2018 and 30 September 2019 who met the Montreux or PALICC-2 definition of neonatal ARDS were retrospectively analyzed (n = 472). One comparison was made between application of the Montreux and PALICC-2 definitions to neonates outside the perinatal period (> 7 d after birth). A second comparison was made between a diagnosis of neonatal ARDS within (≤ 7 d of birth) and outside (> 7 d after birth) the perinatal period using the Montreux definition. Results No significant differences in morbidity, mortality, severity, therapies, or prognosis were observed between neonates in the extra perinatal group according to the Montreux and PALICC-2 definitions. However, epidemiology, clinical course, and prognosis of neonatal ARDS within the perinatal period did differ from those outside the perinatal period according to the Montreux definition. Conclusion Neonates with ARDS within the perinatal period have unique triggers, epidemiology, clinical course, and prognosis, yet a similar pathobiology pattern, to neonates at other ages. Therefore, it may be essential to consider the perinatal period when defining neonatal ARDS.
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Affiliation(s)
- Liting Liu
- Department of Neonatology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yihan Zhang
- Department of Neonatology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yiran Wang
- Department of Neonatology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yu He
- Department of Neonatology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Xionghui Ding
- Department of Burn and Plastic Surgery, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Long Chen
- Department of Neonatology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Yuan Shi
- Department of Neonatology, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing Key Laboratory of Child Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China
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Pulmonary inflammation, oxidative stress, and fibrosis in a mouse model of cholestasis: the potential protective properties of the dipeptide carnosine. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1129-1142. [PMID: 36651945 DOI: 10.1007/s00210-023-02391-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/09/2023] [Indexed: 01/19/2023]
Abstract
Cholestasis is a clinical complication that primarily influences the liver. However, it is well known that many other organs could be affected by cholestasis. Lung tissue is a major organ influenced during cholestasis. Cholestasis-induced lung injury could induce severe complications such as respiratory distress, serious pulmonary infections, and tissue fibrosis. Unfortunately, there is no specific pharmacological intervention against this complication. Several studies revealed that oxidative stress and inflammatory response play a role in cholestasis-induced lung injury. Carnosine (CARN) is a dipeptide found at high concentrations in different tissues of humans. CARN's antioxidant and antiinflammatory properties are repeatedly mentioned in various experimental models. This study aimed to assess the role of CARN on cholestasis-induced lung injury. Rats underwent bile duct ligation (BDL) to induce cholestasis. Broncho-alveolar lavage fluid (BALF) levels of inflammatory cells, pro-inflammatory cytokines, and immunoglobulin were monitored at scheduled intervals (7, 14, and 28 days after BDL). Moreover, lung tissue histopathological alterations and biomarkers of oxidative stress were evaluated. A significant increase in BALF inflammatory cells, TNF-α, IL-1β, IL-6, and immunoglobulin-G (IgG) was detected in the BALF of BDL rats. Moreover, lung tissue histopathological changes, collagen deposition, increased TGF-β, and elevated levels of oxidative stress biomarkers were evident in cholestatic animals. It was found that CARN (100 and 500 mg/kg, i.p.) significantly alleviated lung oxidative stress biomarkers, inflammatory response, tissue fibrosis, and histopathological alterations. These data indicate the potential protective properties of CARN in the management of cholestasis-induced pulmonary damage. The effects of CARN on inflammatory response and oxidative stress biomarkers seems to play a crucial role in its protective properties in the lung of cholestatic animals.
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Ommati MM, Mobasheri A, Ma Y, Xu D, Tang Z, Manthari RK, Abdoli N, Azarpira N, Lu Y, Sadeghian I, Mousavifaraz A, Nadgaran A, Nikoozadeh A, Mazloomi S, Mehrabani PS, Rezaei M, Xin H, Mingyu Y, Niknahad H, Heidari R. Taurine mitigates the development of pulmonary inflammation, oxidative stress, and histopathological alterations in a rat model of bile duct ligation. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2022; 395:1557-1572. [PMID: 36097067 DOI: 10.1007/s00210-022-02291-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022]
Abstract
Lung injury is a significant complication associated with cholestasis/cirrhosis. This problem significantly increases the risk of cirrhosis-related morbidity and mortality. Hence, finding effective therapeutic options in this field has significant clinical value. Severe inflammation and oxidative stress are involved in the mechanism of cirrhosis-induced lung injury. Taurine (TAU) is an abundant amino acid with substantial anti-inflammatory and antioxidative properties. The current study was designed to evaluate the role of TAU in cholestasis-related lung injury. For this purpose, bile duct ligated (BDL) rats were treated with TAU (0.5 and 1% w: v in drinking water). Significant increases in the broncho-alveolar lavage fluid (BALF) level of inflammatory cells (lymphocytes, neutrophils, basophils, monocytes, and eosinophils), increased IgG, and TNF-α were detected in the BDL animals (14 and 28 days after the BDL surgery). Alveolar congestion, hemorrhage, and fibrosis were the dominant pulmonary histopathological changes in the BDL group. Significant increases in the pulmonary tissue biomarkers of oxidative stress, including reactive oxygen species formation, lipid peroxidation, increased oxidized glutathione levels, and decreased reduced glutathione, were also detected in the BDL rats. Moreover, significant myeloperoxidase activity and nitric oxide levels were seen in the lung of BDL rats. It was found that TAU significantly blunted inflammation, alleviated oxidative stress, and mitigated lung histopathological changes in BDL animals. These data suggest TAU as a potential protective agent against cholestasis/cirrhosis-related lung injury.
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Affiliation(s)
- Mohammad Mehdi Ommati
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mobasheri
- Physics, and Technology, Faculty of Medicine, Research Unit of Medical Imaging, University of Oulu, 90014, Oulu, Finland
- Departments of Orthopedics, Rheumatology and Clinical Immunology, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands
- Department of Regenerative Medicine, State Research Institute Center for Innovative Medicine, 08406, Vilnius, Lithuania
| | - Yanqin Ma
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Dongmei Xu
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Zhongwei Tang
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Ram Kumar Manthari
- Department of Biotechnology, GITAM Institute of Science, Gandhi Institute of Technology and Management, Visakhapatnam-530045, Andhra Pradesh, India
| | - Narges Abdoli
- Food and Drug Administration, Iran Ministry of Health and Medical Education, Tehran, Iran
| | - Negar Azarpira
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yu Lu
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Issa Sadeghian
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abolghasem Mousavifaraz
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Nadgaran
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ahmad Nikoozadeh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sahra Mazloomi
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooria Sayar Mehrabani
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Rezaei
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hu Xin
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Yang Mingyu
- College of Life Sciences, Shanxi Agricultural University, Taigu, 030801, Shanxi, China
| | - Hossein Niknahad
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Reza Heidari
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Recognizing, Diagnosing, and Managing Pregnancy Dermatoses. Obstet Gynecol 2022; 140:679-695. [PMID: 36075066 DOI: 10.1097/aog.0000000000004938] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/26/2022] [Indexed: 01/05/2023]
Abstract
Pregnancy dermatoses are inflammatory skin disorders that occur during pregnancy or immediately postpartum. This heterogenous group of disorders includes pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, atopic eruption of pregnancy, and pustular psoriasis of pregnancy. In this article, we provide a comprehensive literature review of each condition focusing on nomenclature, epidemiology, pathogenesis, clinical presentation, diagnosis, differential diagnosis, maternal risk, fetal risk, and treatment. We aim to increase awareness and help clinicians recognize, diagnose, and manage these unique conditions.
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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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Salimi U, Dummula K, Tucker MH, Dela Cruz CS, Sampath V. Postnatal Sepsis and Bronchopulmonary Dysplasia in Premature Infants: Mechanistic Insights into "New BPD". Am J Respir Cell Mol Biol 2021; 66:137-145. [PMID: 34644520 DOI: 10.1165/rcmb.2021-0353ps] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Bronchopulmonary dysplasia (BPD) is a debilitating disease in premature infants resulting from lung injury that disrupts alveolar and pulmonary vascular development. Despite the use of lung-protective ventilation and targeted oxygen therapy, BPD rates have not significantly changed over the last decade. Recent evidence suggests that sepsis and conditions initiating the systemic inflammatory response syndrome in preterm infants are key risk factors for BPD. However, the mechanisms by which sepsis-associated systemic inflammation and microbial dissemination program aberrant lung development are not fully understood. Progress has been made within the last 5 years with the inception of animal models allowing mechanistic investigations into neonatal acute lung injury and alveolar remodeling due to endotoxemia and NEC. These recent studies begin to unravel the pathophysiology of early endothelial immune activation via pattern recognition receptors such as Toll Like Receptor 4 and disruption of critical lung developmental processes such as angiogenesis, extracellular matrix deposition, and ultimately alveologenesis. Here we review scientific evidence from preclinical models of neonatal sepsis-induced lung injury to new data emerging from clinical literature.
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Affiliation(s)
- Umar Salimi
- Yale University, 5755, Pediatrics, New Haven, Connecticut, United States
| | - Krishna Dummula
- Children's Mercy, 4204, Pediatrics, Kansas City, Missouri, United States
| | - Megan H Tucker
- Children's Mercy, 4204, Pediatrics, Kansas City, Missouri, United States
| | - Charles S Dela Cruz
- Yale University, Pulmonary and Critical Care Medicine, New Haven, Connecticut, United States
| | - Venkatesh Sampath
- Children\'s Mercy Hospitals and Clinics, 4204, Pediatrics, Kansas City, Missouri, United States;
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De Luca D, Autilio C. Strategies to protect surfactant and enhance its activity. Biomed J 2021; 44:654-662. [PMID: 34365021 PMCID: PMC8847817 DOI: 10.1016/j.bj.2021.07.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 06/21/2021] [Accepted: 07/29/2021] [Indexed: 11/22/2022] Open
Abstract
The knowledge about surfactant biology is now deeper and recent research has allowed to clarify its role in several human lung disorders. The balance between surfactant production and consumption is better known and the same applies to their regulatory mechanisms. This has allowed to hypothesize and investigate several new and original strategies to protect surfactant and enhance its activity. These interventions are potentially useful for several disorders and particularly for acute respiratory distress syndrome. We here highlight the mechanisms regulating surfactant consumption, encompassing surfactant catabolism but also surfactant injury due to other mechanisms, in a physiopathology-driven fashion. We then analyze each corresponding strategy to protect surfactant and enhance its activity. Some of these strategies are more advanced in terms of research & development pathway, some others are still investigational, but all are promising and deserve a joint effort from clinical-academic researchers and the industry.
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Affiliation(s)
- Daniele De Luca
- Division of Paediatrics and Neonatal Critical Care, "A.Béclère" Medical Centre, Paris Saclay University Hospitals, APHP, Paris, France; Physiopathology and Therapeutic Innovation Unit-INSERM U999, Paris Saclay University, Paris, France.
| | - Chiara Autilio
- Dpt. of Biochemistry and Molecular Biology and Research Institute "Hospital 12 de Octubre", Complutense University, Madrid, Spain
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Systems Biology and Bile Acid Signalling in Microbiome-Host Interactions in the Cystic Fibrosis Lung. Antibiotics (Basel) 2021; 10:antibiotics10070766. [PMID: 34202495 PMCID: PMC8300688 DOI: 10.3390/antibiotics10070766] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/14/2021] [Accepted: 06/21/2021] [Indexed: 12/16/2022] Open
Abstract
The study of the respiratory microbiota has revealed that the lungs of healthy and diseased individuals harbour distinct microbial communities. Imbalances in these communities can contribute to the pathogenesis of lung disease. How these imbalances occur and establish is largely unknown. This review is focused on the genetically inherited condition of Cystic Fibrosis (CF). Understanding the microbial and host-related factors that govern the establishment of chronic CF lung inflammation and pathogen colonisation is essential. Specifically, dissecting the interplay in the inflammation–pathogen–host axis. Bile acids are important host derived and microbially modified signal molecules that have been detected in CF lungs. These bile acids are associated with inflammation and restructuring of the lung microbiota linked to chronicity. This community remodelling involves a switch in the lung microbiota from a high biodiversity/low pathogen state to a low biodiversity/pathogen-dominated state. Bile acids are particularly associated with the dominance of Proteobacterial pathogens. The ability of bile acids to impact directly on both the lung microbiota and the host response offers a unifying principle underpinning the pathogenesis of CF. The modulating role of bile acids in lung microbiota dysbiosis and inflammation could offer new potential targets for designing innovative therapeutic approaches for respiratory disease.
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Steinhauser CB, Askelson K, Lambo CA, Hobbs KC, Bazer FW, Satterfield MC. Lipid metabolism is altered in maternal, placental, and fetal tissues of ewes with small for gestational age fetuses†. Biol Reprod 2020; 104:170-180. [PMID: 33001151 DOI: 10.1093/biolre/ioaa180] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/23/2020] [Accepted: 09/25/2020] [Indexed: 12/13/2022] Open
Abstract
Nutrient restriction (NR) has the potential to negatively impact birthweight, an indicator of neonatal survival and lifelong health. Those fetuses are termed as small for gestational age (SGA). Interestingly, there is a spectral phenotype of fetal growth rates in response to NR associated with changes in placental development, nutrient and waste transport, and lipid metabolism. A sheep model with a maternal diet, starting at Day 35, of 100% National Research Council (NRC) nutrient requirements (n = 8) or 50% NRC (n = 28) was used to assess alterations in fetuses designated NR SGA (n = 7) or NR NonSGA (n = 7) based on fetal weight at Day 135 of pregnancy. Allantoic fluid concentrations of triglycerides were greater in NR SGA fetuses than 100% NRC and NR NonSGA fetuses at Day 70 (P < 0.05). There was a negative correlation between allantoic fluid concentrations of triglycerides (R2 = 0.207) and bile acids (R2 = 0.179) on Day 70 and fetal weight at Day 135 for NR ewes (P < 0.05). Bile acids were more abundant in maternal and fetal blood for NR SGA compared to 100% NRC and NR NonSGA ewes (P < 0.05). Maternal blood concentrations of NEFAs increased in late pregnancy in NR NonSGA compared to NR SGA ewes (P < 0.05). Protein expression of fatty acid transporter SLC27A6 localized to placentomal maternal and fetal epithelia and decreased in Day 70 NR SGA compared to 100% NRC and NR NonSGA placentomes (P < 0.05). These results identify novel factors associated with an ability of placentae and fetuses in NR NonSGA ewes to adapt to, and overcome, nutritional hardship during pregnancy.
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Affiliation(s)
| | - Katharine Askelson
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
| | - Colleen A Lambo
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
| | - Kenneth C Hobbs
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
| | - Fuller W Bazer
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
| | - M Carey Satterfield
- Department of Animal Science, Texas A&M University, College Station, Texas, USA
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Walker KF, Chappell LC, Hague WM, Middleton P, Thornton JG. Pharmacological interventions for treating intrahepatic cholestasis of pregnancy. Cochrane Database Syst Rev 2020; 7:CD000493. [PMID: 32716060 PMCID: PMC7389072 DOI: 10.1002/14651858.cd000493.pub3] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013. OBJECTIVES To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes. SEARCH METHODS For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies. SELECTION CRITERIA Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy. DATA COLLECTION AND ANALYSIS The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy. AUTHORS' CONCLUSIONS When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).
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Affiliation(s)
- Kate F Walker
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
| | - Lucy C Chappell
- Department of Women and Children's Health, King's College London, London, UK
| | - William M Hague
- Women's and Children's Hospital, North Adelaide, Australia
- Robinson Research Institute, The University of Adelaide, North Adelaide, Australia
| | - Philippa Middleton
- Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia
| | - Jim G Thornton
- Division of Child Health, Obstetrics and Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK
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12
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Arthuis C, Diguisto C, Lorphelin H, Dochez V, Simon E, Perrotin F, Winer N. Perinatal outcomes of intrahepatic cholestasis during pregnancy: An 8-year case-control study. PLoS One 2020; 15:e0228213. [PMID: 32074108 PMCID: PMC7029845 DOI: 10.1371/journal.pone.0228213] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 01/10/2020] [Indexed: 12/27/2022] Open
Abstract
INTRODUCTION Previous studies of fetal effects have suggested that intrahepatic cholestasis of pregnancy is associated with a higher rate of adverse neonatal outcomes including preterm birth, neonatal respiratory distress syndrome, meconium-stained amniotic fluid, neonatal intensive care unit admission, and stillbirth. The objective was to compare the neonatal and maternal consequences in pregnancies affected by intrahepatic cholestasis and normal pregnancies. MATERIAL AND METHODS This case-control study compares pregnancies affected by intrahepatic cholestasis (pruritus and bile acid ≥ 10 μmol/L) with low-risk pregnancies managed between December 2006 and December 2014 at a French university hospital center. RESULTS There were 83 (59.3%) cases of mild cholestasis (10≤ BA ≤39 μmol/L), 46 (32.8%) of moderate cholestasis (40≤ BA ≤99 μmol/L), and 11 (7.9%) of severe cholestasis (BA ≥100 μmol/L). No in utero fetal deaths occurred in the 140 women with cholestasis or the 560 controls analyzed. The rate of respiratory distress syndrome was higher in neonates of women with intrahepatic cholestasis (17.1% vs. 4.6%, P<0.001; crude OR 4.46 (CI95% 2.49-8.03)). This risk was also significant after adjustment for gestational age at birth and mode of delivery, adjusted OR 2.56 (CI95%1.26-5.18). The postpartum hemorrhage rate was twice as high among the case mothers (25% versus 14.1% for controls, P = 0.002). CONCLUSION After adjustment on the confounding factors we found a higher rate of respiratory distress syndrome and neonatal morbidity among neonates of the cholestasis group.
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Affiliation(s)
- Chloé Arthuis
- Department of Gynecology and Obstetrics, University Hospital Regional Center Tours, Tours, France
- Department of Gynecology and Obstetrics, University Hospital Center Nantes, Nantes, France
- * E-mail:
| | - Caroline Diguisto
- Department of Gynecology and Obstetrics, University Hospital Regional Center Tours, Tours, France
| | - Henri Lorphelin
- Department of Gynecology and Obstetrics, University Hospital Regional Center Tours, Tours, France
| | - Vincent Dochez
- Department of Gynecology and Obstetrics, University Hospital Center Nantes, Nantes, France
| | - Emmanuel Simon
- Department of Gynecology and Obstetrics, University Hospital Regional Center Tours, Tours, France
| | - Franck Perrotin
- Department of Gynecology and Obstetrics, University Hospital Regional Center Tours, Tours, France
| | - Norbert Winer
- Department of Gynecology and Obstetrics, University Hospital Center Nantes, Nantes, France
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13
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Flynn S, Reen FJ, O'Gara F. Exposure to Bile Leads to the Emergence of Adaptive Signaling Variants in the Opportunistic Pathogen Pseudomonas aeruginosa. Front Microbiol 2019; 10:2013. [PMID: 31555243 PMCID: PMC6727882 DOI: 10.3389/fmicb.2019.02013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 08/16/2019] [Indexed: 12/18/2022] Open
Abstract
The chronic colonization of the respiratory tract by the opportunistic pathogen Pseudomonas aeruginosa is the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa has been shown to undergo extensive genomic adaptation facilitating its persistence within the CF lung allowing it to evade the host immune response and outcompete co-colonizing residents of the lung microbiota. However, whilst several studies have described the various mutations that frequently arise in clinical isolates of P. aeruginosa, the environmental factors governing the emergence of these genetic variants is less well characterized. Gastro-oesophageal reflux has recently emerged as a major co-morbidity in CF and is often associated with the presence of bile acids in the lungs most likely by (micro) aspiration. In order to investigate whether bile may select for genetic variants, P. aeruginosa was experimentally evolved in artificial sputum medium, a synthetic media resembling environmental conditions found within the CF lung. Pigmented derivatives of P. aeruginosa emerged exclusively in the presence of bile. Genome sequencing analysis identified single nucleotide polymorphisms (SNPs) in quorum sensing (lasR) and both the pyocyanin (phzS) and pyomelanin (hmgA) biosynthetic pathways. Phenotypic analysis revealed an altered bile response when compared to the ancestral P. aeruginosa progenitor strain. While the recovered pigmented derivatives retained the bile mediated suppression of swarming motility and enhanced antibiotic tolerance, the biofilm, and redox responses to bile were abolished in the adapted mutants. Though loss of pseudomonas quinolone signal (PQS) production in the pigmented isolates was not linked to the altered biofilm response, the loss of redox repression could be explained by defective alkyl-quinolone (AQ) production in the presence of bile. Collectively, these findings suggest that the adaptive variants of P. aeruginosa that arise following long term bile exposure enables the emergence of ecologically competitive sub-populations. Altered pigmentation and AQ signaling may contribute to an enhancement in fitness facilitating population survival within a bile positive environment.
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Affiliation(s)
- Stephanie Flynn
- BIOMERIT Research Centre, School of Microbiology, University College Cork - National University of Ireland, Cork, Ireland
| | - F Jerry Reen
- School of Microbiology, University College Cork - National University of Ireland, Cork, Ireland
| | - Fergal O'Gara
- BIOMERIT Research Centre, School of Microbiology, University College Cork - National University of Ireland, Cork, Ireland.,Telethon Kids Institute, Perth, WA, Australia.,School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
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14
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Batsry L, Zloto K, Kalter A, Baum M, Mazaki-Tovi S, Yinon Y. Perinatal outcomes of intrahepatic cholestasis of pregnancy in twin versus singleton pregnancies: is plurality associated with adverse outcomes? Arch Gynecol Obstet 2019; 300:881-887. [PMID: 31346701 DOI: 10.1007/s00404-019-05247-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 07/10/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE To determine the rate of obstetric and neonatal complications associated with intrahepatic cholestasis of pregnancy in twin versus singleton gestations. METHODS A retrospective cohort study including patients diagnosed with intrahepatic cholestasis of pregnancy at a single tertiary center between 2011 and 2016. Women were allocated into two groups: twin pregnancies (n = 56) and singleton pregnancies (n = 186). Obstetric and neonatal outcomes were compared between the two groups. RESULTS Intrahepatic cholestasis of pregnancy was diagnosed earlier in gestation in twin compared to singleton pregnancies (33.1 ± 2.8 vs. 35.1 ± 3.0 weeks, respectively; adjusted P < 0.001). Maternal serum levels of fasting total bile acids were significantly higher in twin pregnancies compared to singletons [27 (IQR 16-44) vs. 16 (IQR 10-26) µmol/L, respectively; P = 0.01]. None of the pregnancies in our cohort was complicated by fetal death. Apgar score at 5 min and umbilical artery and vein PH at delivery were comparable between the two groups. CONCLUSIONS Intrahepatic cholestasis of pregnancy in twin pregnancies appears to be more severe compared to singletons, as reflected by an earlier presentation and higher levels of maternal serum total bile acids. Large prospective studies are required to customize a management strategy specific for women with twin pregnancies and intrahepatic cholestasis of pregnancy.
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Affiliation(s)
- Linoy Batsry
- Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel. .,Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
| | - Keren Zloto
- Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.,Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Anat Kalter
- Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.,Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Micha Baum
- Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.,Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shali Mazaki-Tovi
- Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.,Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Yoav Yinon
- Department of Obstetrics and Gynecology, Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel.,Affiliated to the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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15
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Wang P, Zhong H, Song Y, Yuan P, Li Y, Lin S, Zhang X, Li J, Che L, Feng B, Lin Y, Xu S, Zhuo Y, Tian G, Chen D, Wu D, Burrin DG, Fang Z. Targeted metabolomics analysis of maternal-placental-fetal metabolism in pregnant swine reveals links in fetal bile acid homeostasis and sulfation capacity. Am J Physiol Gastrointest Liver Physiol 2019; 317:G8-G16. [PMID: 31021171 DOI: 10.1152/ajpgi.00056.2019] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Cholestasis of pregnancy endangers fetal and neonatal survival, yet systematic knowledge of the cause and effect of disrupted bile acid (BA) homeostasis in pregnancy is limited. Here we show that gestation stage-associated BA dysregulation in swine correlated with fetal death resulting from compromised capacity for BA secretion and increased alternative systemic efflux. The balance of BA input and output in the developing uterus suggested little uptake and metabolism of maternal BA by the placenta-fetus unit, implying a protection role of placenta in preventing maternal BA transported into the fetus. We showed that the maternal origin of BA accounted for the increase in placental total BA, leading to dysregulated expression of genes involved in BA transport and potentially impaired transplacental export of fetus-derived BA. Correspondingly, the secondary BA, mainly derived from the mother, gradually decreased in the fetus. Finally, we identified that sulfation rather than glucuronidation played pivotal roles in maintaining BA homeostasis of the developing fetus. These novel and systemic findings contribute to a whole picture of BA metabolism in pregnancy and provide new insights into mechanisms responsible for maternal and fetal BA homeostasis. NEW & NOTEWORTHY We used a swine model to demonstrate the potentially impaired transplacental bile acid (BA) export, immaturity of fetal hepatic excretory function, and elevated BA synthesis in the developing fetus. Under these conditions, we have further identified that BA sulfation plays a pivotal role in regulation of fetal BA homeostasis, which appears to depend on the balance of BA synthesis and sulfation capacity. These novel findings have uncovered a previously unknown mechanism of BA homeostasis regulation in the developing fetus.
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Affiliation(s)
- Peng Wang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Heju Zhong
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Yumo Song
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Peiqiang Yuan
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Yunxia Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Sen Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Xiaoling Zhang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Jian Li
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Lianqiang Che
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Bin Feng
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Yan Lin
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Shengyu Xu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Yong Zhuo
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Gang Tian
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Daiwen Chen
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - De Wu
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
| | - Douglas G Burrin
- United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine , Houston, Texas
| | - Zhengfeng Fang
- Key Laboratory for Animal Disease Resistance Nutrition of the Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University , Chengdu , China
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16
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Ao Z, Li Z, Wang X, Zhao C, Gan Y, Wu X, Zeng F, Shi J, Gu T, Hong L, Zheng E, Liu D, Xu Z, Wu Z, Cai G. Identification of amniotic fluid metabolomic and placental transcriptomic changes associated with abnormal development of cloned pig fetuses. Mol Reprod Dev 2019; 86:278-291. [PMID: 30618166 DOI: 10.1002/mrd.23102] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 12/19/2018] [Accepted: 12/31/2018] [Indexed: 12/27/2022]
Abstract
Piglets cloned by somatic cell nuclear transfer (SCNT) show a high incidence of malformations and a high death rate during the perinatal period. To investigate the underlying mechanisms for abnormal development of cloned pig fetuses, we compared body weight, amniotic fluid (AF) metabolome, and placental transcriptome between SCNT- and artificial insemination (AI)-derived pig fetuses. Results showed that the body weight of SCNT pig fetuses was significantly lower than that of AI pig fetuses. The identified differential metabolites between the two groups of AF were mainly involved in bile acids and steroid hormones. The levels of all detected bile acids in SCNT AF were significantly higher than those in AI AF. The increase in the AF bile acid levels in SCNT fetuses was linked with the downregulation of placental bile acid transporter expression and the abnormal development of placental folds (PFs), both of which negatively affected the transfer of bile acids from AF across the placenta into the mother's circulation. Alteration in the AF steroid hormone levels in cloned fetuses was associated with decreased expression of enzymes responsible for steroid hormone biosynthesis in the placenta. In conclusion, cloned pig fetuses undergo abnormal intrauterine development associated with alteration of bile acid and steroid hormone levels in AF, which may be due to the poor development of PFs and the erroneous expression of bile acid transporters and enzymes responsible for steroid hormone biosynthesis in the placentas.
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Affiliation(s)
- Zheng Ao
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Zicong Li
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Xingwang Wang
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Chengfa Zhao
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Yanmin Gan
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Xiao Wu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Fang Zeng
- College of Marine Sciences, South China Agricultural University, Guangzhou, Guangdong, China
| | - Junsong Shi
- Wen's Research Institute, Guangdong Wen's Foodstuff Group Ltd., Yunfu, Guangdong, China
| | - Ting Gu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Linjun Hong
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Enqin Zheng
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Dewu Liu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Zheng Xu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Zhenfang Wu
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
| | - Gengyuan Cai
- National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China.,Guangdong Provincial Key Laboratory of Agro-animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou, Guangdong, China
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17
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Calkovska A, Mokra D, Calkovsky V, Matasova K, Zibolen M. Clinical considerations when treating neonatal aspiration syndromes. Expert Rev Respir Med 2019; 13:193-203. [DOI: 10.1080/17476348.2019.1562340] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Affiliation(s)
- Andrea Calkovska
- Department of Physiology and Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia
| | - Daniela Mokra
- Department of Physiology and Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University, Martin, Slovakia
| | - Vladimir Calkovsky
- Clinic of Otorhinolaryngology and Head and Neck Surgery, Jessenius Faculty of Medicine, Comenius University and University Hospital Martin, Martin, Slovakia
| | - Katarina Matasova
- Clinic of Neonatology, Jessenius Faculty of Medicine, Comenius University and University Hospital Martin, Martin, Slovakia
| | - Mirko Zibolen
- Clinic of Neonatology, Jessenius Faculty of Medicine, Comenius University and University Hospital Martin, Martin, Slovakia
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18
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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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19
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The Montreux definition of neonatal ARDS: biological and clinical background behind the description of a new entity. THE LANCET RESPIRATORY MEDICINE 2017; 5:657-666. [PMID: 28687343 DOI: 10.1016/s2213-2600(17)30214-x] [Citation(s) in RCA: 189] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 04/22/2017] [Accepted: 04/24/2017] [Indexed: 11/21/2022]
Abstract
Acute respiratory distress syndrome (ARDS) is undefined in neonates, despite the long-standing existing formal recognition of ARDS syndrome in later life. We describe the Neonatal ARDS Project: an international, collaborative, multicentre, and multidisciplinary project which aimed to produce an ARDS consensus definition for neonates that is applicable from the perinatal period. The definition was created through discussions between five expert members of the European Society for Paediatric and Neonatal Intensive Care; four experts of the European Society for Paediatric Research; two independent experts from the USA and two from Australia. This Position Paper provides the first consensus definition for neonatal ARDS (called the Montreux definition). We also provide expert consensus that mechanisms causing ARDS in adults and older children-namely complex surfactant dysfunction, lung tissue inflammation, loss of lung volume, increased shunt, and diffuse alveolar damage-are also present in several critical neonatal respiratory disorders.
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20
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Mutlu MF, Aslan K, Guler I, Mutlu I, Erdem M, Bozkurt N, Erdem A. Two cases of first onset intrahepatic cholestasis of pregnancy associated with moderate ovarian hyperstimulation syndrome after IVF treatment and review of the literature. J OBSTET GYNAECOL 2017; 37:547-549. [PMID: 28319428 DOI: 10.1080/01443615.2017.1286302] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Intrahepatic cholestasis of pregnancy (ICP) is an uncommon disorder, which generally occurs in the second and third trimester of pregnancy with symptoms of pruritus. The cause of ICP is unknown but genetic, hormonal and environmental factors contribute to its pathogenesis. The aetiology of ICP is unclear but elevation in oestrogen levels thought to cause ICP is typically seen in the third trimester of pregnancy, and for this reason it is not usually considered in the differential diagnosis of pruritus and liver function disorders in the first trimester of the pregnancy. We present two cases of pregnancy after IVF treatment diagnosed with ICP following the development of OHSS, deteriorating liver function tests and severe pruritus.
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Affiliation(s)
- Mehmet Firat Mutlu
- a Department of Obstetrics & Gynecology , Yuksek Ihtisas University Faculty of Medicine , Ankara , Turkey
| | - Koray Aslan
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | - Ismail Guler
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | | | - Mehmet Erdem
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | - Nuray Bozkurt
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
| | - Ahmet Erdem
- b Department of Obstetrics & Gynecology , Gazi University Faculty of Medicine , Ankara , Turkey
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21
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Ulluwishewa D, Wang L, Pereira C, Flynn S, Cain E, Stick S, Reen FJ, Ramsay JP, O’Gara F. Dissecting the regulation of bile-induced biofilm formation in Staphylococcus aureus. Microbiology (Reading) 2016; 162:1398-1406. [DOI: 10.1099/mic.0.000317] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Affiliation(s)
- Dulantha Ulluwishewa
- School of Biomedical Sciences, CHIRI Research Institute, Curtin University, Perth, Australia
| | - Liang Wang
- School of Biomedical Sciences, CHIRI Research Institute, Curtin University, Perth, Australia
| | - Callen Pereira
- School of Biomedical Sciences, CHIRI Research Institute, Curtin University, Perth, Australia
| | - Stephanie Flynn
- BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland
| | - Elizabeth Cain
- School of Biomedical Sciences, CHIRI Research Institute, Curtin University, Perth, Australia
| | - Stephen Stick
- Telethon Kids Institute, School of Paediatric and Child Health, University of Western Australia, Perth, Australia
- Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, Western Australia, Australia
| | - F. Jerry Reen
- BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland
| | - Joshua P. Ramsay
- School of Biomedical Sciences, CHIRI Research Institute, Curtin University, Perth, Australia
| | - Fergal O’Gara
- School of Biomedical Sciences, CHIRI Research Institute, Curtin University, Perth, Australia
- BIOMERIT Research Centre, School of Microbiology, University College Cork, Cork, Ireland
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22
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Morphologic Damage of Rat Alveolar Epithelial Type II Cells Induced by Bile Acids Could Be Ameliorated by Farnesoid X Receptor Inhibitor Z-Guggulsterone In Vitro. BIOMED RESEARCH INTERNATIONAL 2016; 2016:9283204. [PMID: 27340672 PMCID: PMC4908247 DOI: 10.1155/2016/9283204] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Revised: 04/05/2016] [Accepted: 04/11/2016] [Indexed: 12/16/2022]
Abstract
Objective. To determine whether bile acids (BAs) affect respiratory functions through the farnesoid X receptor (FXR) expressed in the lungs and to explore the possible mechanisms of BAs-induced respiratory disorder. Methods. Primary cultured alveolar epithelial type II cells (AECIIs) of rat were treated with different concentrations of chenodeoxycholic acid (CDCA) in the presence or absence of FXR inhibitor Z-guggulsterone (GS). Then, expression of FXR in nuclei of AECIIs was assessed by immunofluorescence microscopy. And ultrastructural changes of the cells were observed under transmission electron microscope and analyzed by Image-Pro Plus software. Results. Morphologic damage of AECIIs was exhibited in high BAs group in vitro, with high-level expression of FXR, while FXR inhibitor GS could attenuate the cytotoxicity of BAs to AECIIs. Conclusions. FXR expression was related to the morphologic damage of AECIIs induced by BAs, thus influencing respiratory functions.
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23
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Chen B, Cai HR, Xue S, You WJ, Liu B, Jiang HD. Bile acids induce activation of alveolar epithelial cells and lung fibroblasts through farnesoid X receptor-dependent and independent pathways. Respirology 2016; 21:1075-80. [PMID: 27185272 DOI: 10.1111/resp.12815] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Revised: 12/28/2015] [Accepted: 01/19/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND OBJECTIVE The roles of bile acid microaspiration and bile acid-activated farnesoid X receptor (FXR) in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear. We hypothesized that bile acids activate alveolar epithelial cells (AECs) and lung fibroblasts, which may be regulated by FXR activation. METHODS Human AECs and normal or IPF-derived lung fibroblast cells were incubated with the three major bile acids: lithocholic acid (LCA), deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA). The AECs injury indices, epithelial-mesenchymal transition (EMT) and lung fibroblast activation were evaluated. FXR expression in IPF lungs and the roles of FXR and FXR-independent pathways in bile acid-induced profibrotic effects were also investigated. RESULTS LCA, DCA and CDCA reduced cell viability and increased intracellular reactive oxygen species (ROS) production in A549 cells. They all induced EMT, as shown by enhanced α-SMA and vimentin and decreased E-cadherin levels. LCA directly induced differentiation of lung fibroblasts to myofibroblasts. All three bile acids promoted cellular migration but not proliferation of lung fibroblasts. FXR expression was upregulated in IPF lungs, and inhibition of FXR restrained the bile acid-induced EMT and lung fibroblast activation. Differentiation and proliferation were enhanced in lung fibroblasts exposed to conditioned medium from bile acid-stimulated A549 cells, which contained increased levels of profibrotic factors. TGF-β/Smad3 signaling was also involved in the bile acid-induced EMT and lung fibroblast differentiation. CONCLUSION Bile acid microaspiration may promote the development of pulmonary fibrosis by inducing activation of AECs and lung fibroblasts via FXR-dependent and independent pathways.
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Affiliation(s)
- Bi Chen
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hou-Rong Cai
- Department of Respiratory Medicine, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Shan Xue
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wen-Jie You
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bin Liu
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Han-Dong Jiang
- Department of Respiratory Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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24
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Fabiano A, Gavilanes AWD, Zimmermann LJI, Kramer BW, Paolillo P, Livolti G, Picone S, Bressan K, Gazzolo D. The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia. Acta Paediatr 2016; 105:535-541. [PMID: 26439807 DOI: 10.1111/apa.13233] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Revised: 05/18/2015] [Accepted: 09/29/2015] [Indexed: 11/28/2022]
Abstract
AIM Despite advances in perinatal management, there is a flat trend in incidences of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants. The main feature of BPD development in preterm infants is an imbalance between increased exposure to free radicals and inadequate antioxidant defences. We investigated the associations between BPD and lipid hydro-peroxide (LOOH) and glutathione (GSH) concentrations in bronchoalveolar lavage fluid (BALF). METHODS In this prospective study, BALF samples were collected from 44 preterm infants with RDS and oxidative stress markers were measured in 11 with BPD and 33 controls without BPD. RESULTS LOOH levels were significantly higher (p < 0.01) in the BPD group (median 16.35; 25th-75th centile 13.75-17.05 nmol/mL) than in the no BPD group (median 13.18; 25th-75th centile 12.92-13.63 nmol/mL). Conversely, GSH levels were significantly lower in the BPD group (p < 0.01) (median 11.52; 25th-75th centile 6.95-13.85 μmol/mg) than the no BPD group (median: 18.69; 25th-75th centile: 13.89-23.64 μmol/mg). Multiple regression analysis showed significant correlations between BPD and mechanical ventilation time (p < 0.01) and LOOH levels (p < 0.05). CONCLUSION Early LOOH level increases in preterm infants developing BPD suggest that lung biochemical monitoring of sick infants might be possible and BPD could be predicted early by evaluating biomarkers.
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Affiliation(s)
- Adele Fabiano
- Department of Maternal, Fetal and Neonatal Medicine, NICU, Casilino Hospital, Rome, Italy
| | - Antonio W D Gavilanes
- Department of Pediatrics and Neonatology, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Luc J I Zimmermann
- Department of Pediatrics and Neonatology, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Boris W Kramer
- Department of Pediatrics and Neonatology, School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Piermichele Paolillo
- Department of Maternal, Fetal and Neonatal Medicine, NICU, Casilino Hospital, Rome, Italy
| | - Giovanni Livolti
- Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
| | - Simonetta Picone
- Department of Maternal, Fetal and Neonatal Medicine, NICU, Casilino Hospital, Rome, Italy
| | - Katia Bressan
- Department of Maternal, Fetal and Neonatal Medicine, NICU, Casilino Hospital, Rome, Italy
| | - Diego Gazzolo
- Department of Maternal, Fetal and Neonatal Medicine, C. Arrigo Children's Hospital, Alessandria, Italy
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25
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Abstract
Intrahepatic cholestasis of pregnancy, also known as obstetric cholestasis, is a pruritic condition of pregnancy characterized by an underlying elevation in circulating bile acids and liver derangement, and associated with adverse fetal outcomes, such as preterm labor and stillbirth. Limited understanding of the underlying pathophysiology and mechanisms involved in adverse outcomes has previously restricted treatment options and pregnancy management. Recent advances in these research fields provide tantalizing targets to improve the care of pregnant women affected by this condition.
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Affiliation(s)
- Caroline Ovadia
- Women's Health Academic Centre, King's College London, London, United Kingdom
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26
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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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27
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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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28
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Chen B, Ning JL, Gu JT, Cui J, Yang Y, Wang Z, Zeng J, Yi B, Lu KZ. Caspase-3 inhibition prevents the development of hepatopulmonary syndrome in common bile duct ligation rats by alleviating pulmonary injury. Liver Int 2015; 35:1373-82. [PMID: 25113058 DOI: 10.1111/liv.12655] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 08/05/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Common bile duct ligation (CBDL) rats is an accepted experimental model of hepatopulmonary syndrome (HPS), defined as liver disease and intrapulmonary vascular dilatation and hypoxaemia. Pulmonary Akt and ERK activation followed by angiogenesis in the later stages of CBDL, contribute to the pathogenesis of HPS. However, the mechanisms behind Akt and ERK activation remain undefined. Pulmonary injury induced by increased bilirubin, endotoxin and inflammatory mediators occurs in the early stages of CBDL. We assessed the effects of relieving pulmonary injury on Akt and ERK activation and on the development of HPS following CBDL. METHODS Pulmonary injury, angiogenesis, arterial oxygenation, cell proliferation and, phospho-Akt and ERK1 were evaluated in CBDL animals with or without caspase-3 inhibition (Z-DEVD-FMK). Pulmonary injury was assessed by histology and quantifying apoptosis and aquaporin-1 (AQP1) levels. Lung angiogenesis was assessed by quantifying AQP1 level, vWF-positive cells and microvessel count. RESULTS Pulmonary apoptosis and caspase-3 activation were markedly increased in the early stages of CBDL. Caspase-3 inhibition alleviated apoptosis, the reduction in AQP1, phospho-Akt and ERK1 levels and pulmonary injury 1 week after CBDL. Caspase-3 inhibition also reduced AQP1, phospho-Akt and ERK1 levels, vWF-positive cells, cell proliferation, microvessel count, and microvascular dilatation and improved arterial oxygenation 3 weeks following CBDL. CONCLUSIONS Caspase-3 inhibition alleviates pulmonary injury, thereby preventing angiogenesis as well as the development of HPS in CBDL rats. These effects are related to the regulation of the Akt and ERK1 pathways.
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Affiliation(s)
- Bing Chen
- Department of Anesthesia, Southwest Hospital, Third Military Medical University, Chongqing, China
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29
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Abstract
Itching is commonly reported by pregnant women and may be due to physiologic changes of pregnancy or could indicate a more serious health concern. Intrahepatic cholestasis of pregnancy, while classified as a pregnancy dermatosis, is actually a liver disease of pregnancy associated with significant fetal mortality and morbidity, as well as lifelong health risks for the offspring. In these challenging cases, nurses must understand the differential diagnoses and be prepared to provide comprehensive care, education and support to women with this condition. A case example is included.
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30
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Zhao C, Wang X, Cong Y, Deng Y, Xu Y, Chen A, Yin Y. Effects of bile acids and the bile acid receptor FXR agonist on the respiratory rhythm in the in vitro brainstem medulla slice of neonatal Sprague-Dawley rats. PLoS One 2014; 9:e112212. [PMID: 25405617 PMCID: PMC4236123 DOI: 10.1371/journal.pone.0112212] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 10/09/2014] [Indexed: 12/27/2022] Open
Abstract
Intrahepatic cholestasis of pregnancy is always accompanied by adverse fetal outcomes such as malfunctions of respiration. Farnesoid X receptor (FXR) plays a critical role in the homeostasis of bile acids. Thus, we are determined to explore the effects of farnesoid X receptor (FXR) and five bile acids on respiratory rhythm generation and modulation of neonatal rats. Spontaneous periodic respiratory-related rhythmical discharge activity (RRDA) was recorded from hypoglossal nerves during the perfusion of modified Krebs solution. Group 1–6 was each given GW4064 and five bile acids of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), cholic acid (CA) as well as ursodeoxycholic acid (UDCA) at different concentrations to identify their specific functions on respiratory rhythm modulations. Group 7 was applied to receive FXR blocker Z-guggulsterone and Z-guggulsterone with the above bile acids separately to explore the role of FXR in the respiratory rhythm modulation. Group 8 was given dimethyl sulfoxide (DMSO) as controls. Apart from UDCA, CDCA, DCA LCA and CA all exerted effects on RRDA recorded from hypoglossal nerves in a concentration-dependent manner. Respiratory cycle (RC), Inspiratory time (TI), Expiratory Time (TE) and Integral Amplitude (IA) were influenced and such effects could be reversed by Z-guggulsterone. FXR may contribute to the effects on the modulation of respiratory rhythm exerted by bile acids.
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Affiliation(s)
- Cong Zhao
- Department of Cardiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Xianbao Wang
- Department of Cardiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Yuling Cong
- Joint Surgery, Central Hospital of Shengli Oil Field, Dongying, China
| | - Yi Deng
- Department of Cardiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Yijun Xu
- Department of Physiology, Southern Medical University, Guangzhou, China
| | - Aihua Chen
- Department of Cardiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
- * E-mail: (AC); (YY)
| | - Yanru Yin
- Department of Physiology, Southern Medical University, Guangzhou, China
- * E-mail: (AC); (YY)
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31
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Madazli R, Yuksel MA, Oncul M, Tuten A, Guralp O, Aydin B. Pregnancy outcomes and prognostic factors in patients with intrahepatic cholestasis of pregnancy. J OBSTET GYNAECOL 2014; 35:358-61. [PMID: 25384180 DOI: 10.3109/01443615.2014.968102] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The aim of this study was to describe maternal and fetal characteristics associated with intrahepatic cholestasis of pregnancy (ICP) and to determine clinical and biochemical predictors of fetal complications. A total of 89 singleton pregnancies with ICP were analysed, retrospectively. All data concerning laboratory results, symptom onset time, treatment response, delivery time and infant information were recorded in the study protocol. The mean gestational age at diagnosis was 32.6 ± 3.4 weeks; mean time of delivery was 36.8 ± 1.9 weeks. Binary logistic regression revealed that gestational age at diagnosis was predictive of preterm delivery (OR = 2.3, 95% CI: 1.5-3.3, p = 0.001). The incidence of respiratory distress syndrome (RDS), fetal growth restriction, fetal distress and preterm delivery were significantly higher in patients who were diagnosed before 30 weeks than after 34 weeks' gestation (p < 0.01). Gestational age at diagnosis is an important independent factor predicting adverse perinatal outcomes in patients with ICP.
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Affiliation(s)
- R Madazli
- Department of Obstetrics and Gynecology, Cerrahpaşa Medical Faculty, Istanbul University , Istanbul , Turkey
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32
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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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Yu L, Ding Y, Huang T, Huang X. Effect of bile Acid on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Int J Endocrinol 2014; 2014:308274. [PMID: 24778648 PMCID: PMC3980923 DOI: 10.1155/2014/308274] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 02/12/2014] [Accepted: 02/13/2014] [Indexed: 12/27/2022] Open
Abstract
Objective. To determine the correlation between maternal bile acid (BA) level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A) 5.5 mg/kg BA, (B) 1.4 mg/kg BA, and (C) 1 ml physiological saline. Levels of total bile acid (TBA), ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats.
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Affiliation(s)
- Ling Yu
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, 139 Renmin Zhong Lu, Changsha, Hunan 410011, China
| | - Yiling Ding
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, 139 Renmin Zhong Lu, Changsha, Hunan 410011, China
- *Yiling Ding:
| | - Ting Huang
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, 139 Renmin Zhong Lu, Changsha, Hunan 410011, China
| | - Xiaoxia Huang
- Department of Obstetrics and Gynecology, The Second Xiangya Hospital of Central South University, 139 Renmin Zhong Lu, Changsha, Hunan 410011, China
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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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Role of macrophages in bile acid-induced inflammatory response of fetal lung during maternal cholestasis. J Mol Med (Berl) 2013; 92:359-72. [DOI: 10.1007/s00109-013-1106-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 09/17/2013] [Accepted: 11/14/2013] [Indexed: 01/14/2023]
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Gurung V, Stokes M, Middleton P, Milan SJ, Hague W, Thornton JG. Interventions for treating cholestasis in pregnancy. Cochrane Database Syst Rev 2013; 2013:CD000493. [PMID: 23794285 PMCID: PMC7043272 DOI: 10.1002/14651858.cd000493.pub2] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Obstetric cholestasis has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been empiric. The first version of this review, published in 2001, and including nine randomised controlled trials involving 227 women, concluded that there was insufficient evidence to recommend any of the interventions alone or in combination. This is the first update. OBJECTIVES To evaluate the effectiveness and safety of therapeutic and delivery interventions in women with cholestasis of pregnancy. SEARCH METHODS We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (20 February 2013) and reference lists of identified studies. SELECTION CRITERIA Randomised controlled trials that compared two intervention strategies for women with a clinical diagnosis of obstetric cholestasis. DATA COLLECTION AND ANALYSIS The review authors independently assessed trials for eligibility and risk of bias. We independently extracted data and checked these for accuracy. MAIN RESULTS We included 21 trials with a total of 1197 women. They were mostly at moderate to high risk of bias. They assessed 11 different interventions resulting in 15 different comparisons.Compared with placebo, ursodeoxycholic acid (UDCA) showed improvement in pruritus in five (228 women) out of seven trials. There were no significant differences in instances of fetal distress in the UDCA groups compared with placebo (average risk ratio (RR) 0.67; 95% confidence interval (CI) 0.22 to 2.02; five trials, 304 women; random-effects analysis: T² = 0.74; I² = 48%). There were significantly fewer total preterm births with UDCA (RR 0.46; 95% CI 0.28 to 0.73; two trials, 179 women). The difference for spontaneous preterm births was not significant (RR 0.99; 95% CI 0.41 to 2.36, two trials, 109 women).Two trials (48 women) reported lower (better) pruritus scores for S-adenosylmethionine (SAMe) compared with placebo, while two other trials of 34 women reported no significant differences between groups.UDCA was more effective in improving pruritus than either SAMe (four trials; 133 women) or cholestyramine (one trial; 84 women), as was combined UDCA+SAMe when compared with placebo (one trial; 16 women) and SAMe alone (two trials; 68 women). However, combined UDCA+SAMe was no more effective than UDCA alone in regard to pruritus improvement (one trial; 53 women) and two trials (80 women) reported data were insufficient to draw any conclusions from. In one trial comparing UDCA and dexamethasone (83 women), a significant improvement with UDCA was seen only in a subgroup of women with severe obstetric cholestasis (23 women).Danxiaoling significantly improved pruritus in comparison to Yiganling. No significant differences were seen in pruritus improvement with other interventions.Eight trials reported fetal or neonatal deaths, with two deaths reported overall (both in the placebo groups).Women receiving UDCA and cholestyramine experienced nausea, vomiting and diarrhoea. Guar gum caused mild abdominal distress, diarrhoea and flatulence during the first days of treatment. Women found charcoal suspension unpleasant to swallow. Dexamethasone caused nausea, dizziness and stomach pain in one woman.One trial (62 women) looked at the timing of delivery intervention. There were no stillbirths or neonatal deaths in 'early delivery' or the 'await spontaneous labour' group. There were no significant differences in the rates of caesarean section, meconium passage or admission to neonatal intensive care unit between the two groups. AUTHORS' CONCLUSIONS Different approaches to assessing and reporting pruritus precluded pooling of trials comparing the effects of UDCA versus placebo on pruritus, but examination of individual trials suggests that UDCA significantly improves pruritus, albeit by a small amount. Fewer instances of fetal distress/asphyxial events were seen in the UDCA groups when compared with placebo but the difference was not statistically significant. Large trials of UDCA to determine fetal benefits or risks are needed.A single trial was too small to rule in or out a clinically important effect of early term delivery on caesarean section.There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction (YCHD), Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy.
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Affiliation(s)
- Vinita Gurung
- University of NottinghamDepartment of Obstetrics and GynaecologyNottingham City Hospital NHS TrustHucknall RoadNottinghamNottinghamshireUKNG5 1PB
| | - Michael Stokes
- The University of AdelaideDiscipline of Obstetrics and Gynaecology1st Floor, Queen Victoria Building, Women's and Children's Hospital72 King William RoadNorth AdelaideSAAustralia5006
| | - Philippa Middleton
- Healthy Mothers, Babies and Children, South Australian Health and Medical Research InstituteWomen's and Children's Hospital72 King William RoadAdelaideSouth AustraliaAustralia5006
| | | | - William Hague
- Women's and Children's HospitalKing William RoadAdelaideSouth AustraliaAustraliaSA 5006
| | - Jim G Thornton
- University of NottinghamDivision of Child Health, Obstetrics and Gynaecology, School of MedicineNottingham City Hospital NHS TrustHucknall RoadNottinghamNottinghamshireUKNG5 1PB
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Intrahepatic cholestasis of pregnancy: Biochemical predictors of adverse perinatal outcomes. ACTA ACUST UNITED AC 2013; 33:412-417. [DOI: 10.1007/s11596-013-1133-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Indexed: 12/12/2022]
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Zhangxue H, Min G, Jinning Z, Yuan S, li W, Huapei S, Rui L, Chunyu Z. Glycochenodeoxycholate induces rat alveolar epithelial type II cell death and inhibits surfactant secretion in vitro. Free Radic Biol Med 2012; 53:122-8. [PMID: 22569305 DOI: 10.1016/j.freeradbiomed.2012.04.027] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Revised: 04/01/2012] [Accepted: 04/09/2012] [Indexed: 12/14/2022]
Abstract
Bile acid-induced lung injury has become an important topic for neonatologists after the discovery of a high incidence of infant respiratory distress syndrome complicated from maternal intrahepatic cholestasis. To explore the molecular pathway of bile acid-induced lung injury, we investigated the cytotoxicity of the glycochenodeoxycholate (GCDC) to alveolar epithelial type II cells (AECII), as the main component of bile acid. The results demonstrated that glycochenodeoxycholate induced oxidative stress, mitochondrial damage, and increased caspase activity in the primary cultured AECII. Moreover, ROS scavengers and caspase inhibitors could rescue cell death induced by GCDC in rat AECII. Our results also indicated that GCDC inhibited AECII surfactant secretion. In conclusion, this study suggested that cell death prevention and cell therapy should be considered as therapeutic strategies for infant respiratory distress syndrome complicated from maternal intrahepatic cholestasis.
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Affiliation(s)
- Hu Zhangxue
- Department of Pediatrics, Daping Hospital, Research Institute of Surgery, Third Military Medical University, Chongqing 400042, China.
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De Luca D, Minucci A, Trias J, Tripodi D, Conti G, Zuppi C, Capoluongo E. Varespladib Inhibits Secretory Phospholipase A2 in Bronchoalveolar Lavage of Different Types of Neonatal Lung Injury. J Clin Pharmacol 2012; 52:729-737. [DOI: 10.1177/0091270011405498] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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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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Zhang L, Li T, Yu D, Forman BM, Huang W. FXR protects lung from lipopolysaccharide-induced acute injury. Mol Endocrinol 2012; 26:27-36. [PMID: 22135065 PMCID: PMC3248324 DOI: 10.1210/me.2011-0042] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2011] [Accepted: 10/19/2011] [Indexed: 12/11/2022] Open
Abstract
Acute lung injury and its more severe form, acute respiratory distress syndrome, are characterized by an acute inflammatory response in the airspaces and lung parenchyma. The nuclear receptor farnesoid X receptor (FXR) is expressed in pulmonary artery endothelial cells. Here, we report a protective role of FXR in a lipopolysaccharide-induced mouse model of acute lung injury. Upon intratracheal injection of lipopolysaccharide, FXR-/- mice showed higher lung endothelial permeability, released more bronchoalveolar lavage cells to the alveoli, and developed acute pneumonia. Cell adhesion molecules were expressed at higher levels in FXR-/- mice as compared with control mice. Furthermore, lung regeneration was much slower in FXR-/- mice. In vitro experiments showed that FXR activation blocked TNFα-induced expression of P-selectin but stimulated proliferation of lung microvascular endothelial cells through up-regulation of Foxm1b. In addition, expression of a constitutively active FXR repressed the expression of proinflammatory genes and improved lung permeability and lung regeneration in FXR-/- mice. This study demonstrates a critical role of FXR in suppressing the inflammatory response in lung and promoting lung repair after injury.
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Affiliation(s)
- Lisheng Zhang
- Division of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA
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De Luca D, Capoluongo E, Rigo V. Secretory phospholipase A2 pathway in various types of lung injury in neonates and infants: a multicentre translational study. BMC Pediatr 2011; 11:101. [PMID: 22067747 PMCID: PMC3247178 DOI: 10.1186/1471-2431-11-101] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2010] [Accepted: 11/08/2011] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Secretory phospholipase A2 (sPLA2) is a group of enzymes involved in lung tissue inflammation and surfactant catabolism. sPLA2 plays a role in adults affected by acute lung injury and seems a promising therapeutic target. Preliminary data allow foreseeing the importance of such enzyme in some critical respiratory diseases in neonates and infants, as well. Our study aim is to clarify the role of sPLA2 and its modulators in the pathogenesis and clinical severity of hyaline membrane disease, infection related respiratory failure, meconium aspiration syndrome and acute respiratory distress syndrome. sPLA2 genes will also be sequenced and possible genetic involvement will be analysed. METHODS/DESIGN Multicentre, international, translational study, including several paediatric and neonatal intensive care units and one coordinating laboratory. Babies affected by the above mentioned conditions will be enrolled: broncho-alveolar lavage fluid, serum and whole blood will be obtained at definite time-points during the disease course. Several clinical, respiratory and outcome data will be recorded. Laboratory researchers who perform the bench part of the study will be blinded to the clinical data. DISCUSSION This study, thanks to its multicenter design, will clarify the role(s) of sPLA2 and its pathway in these diseases: sPLA2 might be the crossroad between inflammation and surfactant dysfunction. This may represent a crucial target for new anti-inflammatory therapies but also a novel approach to protect surfactant or spare it, improving alveolar stability, lung mechanics and gas exchange.
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Affiliation(s)
- Daniele De Luca
- Pediatric Intensive Care Unit, Dept of Emergency and Intensive Care, University Hospital "A.Gemelli", Catholic University of the Sacred Heart - Rome, Italy
- Laboratory of Clinical Molecular Biology, Dept of Molecular Medicine, University Hospital "A.Gemelli", Catholic University of the Sacred Heart - Rome, Italy
| | - Ettore Capoluongo
- Pediatric Intensive Care Unit, Dept of Emergency and Intensive Care, University Hospital "A.Gemelli", Catholic University of the Sacred Heart - Rome, Italy
| | - Vincent Rigo
- Neonatal Intensive Care Unit, University of Liège, CHU de Liège (CHR Citadelle), Belgium
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Abstract
The properties of the voltage-dependent H(+) channel have been studied in lung epithelial cells for many years, and recently HVCN1 mRNA expression has been linked directly to H(+) channel function in lung epithelium. The H(+) channel is activated by strong membrane depolarization, intracellular acidity, or extracellular alkalinity. Early on it was noted that these are surprising physiological channel characteristics when considering that lung epithelial cells have rather stable membrane potentials and a well pH-buffered intracellular milieu. This raised the question under which conditions the H(+) channel is active in lung epithelium and what is its physiological function there. Current understanding of the HVCN1 H(+) channel in lung epithelial acid secretion, its activation by an alkaline mucosal extracellular pH, and its role in the regulation of the mucosal pH of the lung has resulted in a model of mucosal pH regulation based on the parallel function of the HVCN1 H(+) channel and the CFTR HCO(3) (-) channel, which suggests that HVCN1 is a critical factor that maintains a neutral surface pH in the lung.
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Affiliation(s)
- Horst Fischer
- Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland CA 94609-1673, USA, phone 510 450 7696,
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Fabiano A, Gazzolo D, Zimmermann LJI, Gavilanes AWD, Paolillo P, Fanos V, Caboni P, Barberini L, Noto A, Atzori L. Metabolomic analysis of bronchoalveolar lavage fluid in preterm infants complicated by respiratory distress syndrome: preliminary results. J Matern Fetal Neonatal Med 2011; 24 Suppl 2:55-58. [PMID: 21781003 DOI: 10.3109/14767058.2011.606977] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
OBJECTIVE Metabolomics is a technique used to non-invasively determine a snapshot of the current metabolic status of an organism by analyzing intact tissue or bio-fluids. The aim of the present preliminary study was to analyze metabolic profiles in preterm infants complicated by respiratory distress syndrome (RDS) trough bronchoalveolar lavage fluid (BALF) measurement. METHODS Twelve BALF samples collected at birth prior surfactant, post-surfactant during mechanical ventilation and at extubation time-points, were analyzed by proton nuclear magnetic resonance spectroscopy and Gas chromatography-Mass Spectrometry (GC-MS). RESULTS GC-MS analysis identified 25 metabolites of whom 10 had a known molecular structure. They were: undecane, decanoic acid, dodecanoic acid, hexadecanoic acid, octadecanoic acid, hexadecanoic acid methyl ester, 9-octadecanoic acid, tetracosanoic acid, myristic acid, phosphate. These metabolites were over-expressed in BALF collected during mechanical ventilation after surfactant administration. CONCLUSIONS The present preliminary data suggest that metabolic profile in BALF of RDS infants is becoming possible opening a new cue of metabolomics as promising tool in management of sick premature infants.
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Affiliation(s)
- Adele Fabiano
- Department of Maternal, Fetal and Neonatal Medicine, CasilinoHospital, Rome, Italy
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Fabisiak JP, Medvedovic M, Alexander DC, McDunn JE, Concel VJ, Bein K, Jang AS, Berndt A, Vuga LJ, Brant KA, Pope-Varsalona H, Dopico RA, Ganguly K, Upadhyay S, Li Q, Hu Z, Kaminski N, Leikauf GD. Integrative metabolome and transcriptome profiling reveals discordant energetic stress between mouse strains with differential sensitivity to acrolein-induced acute lung injury. Mol Nutr Food Res 2011; 55:1423-34. [PMID: 21823223 DOI: 10.1002/mnfr.201100291] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 07/11/2011] [Accepted: 07/13/2011] [Indexed: 12/20/2022]
Abstract
SCOPE This investigation sought to better understand the metabolic role of the lung and to generate insights into the pathogenesis of acrolein-induced acute lung injury. A respiratory irritant, acrolein is generated by overheating cooking oils or by domestic cooking using biomass fuels, and is in environmental tobacco smoke, a health hazard in the restaurant workplace. METHODS AND RESULTS Using SM/J (sensitive) and 129X1/SvJ (resistant) inbred mouse strains, the lung metabolome was integrated with the transcriptome profile before and after acrolein exposure. A total of 280 small molecules were identified and mean values (log 2 >0.58 or <-0.58, p<0.05) were considered different for between-strain comparisons or within-strain responses to acrolein treatment. At baseline, 24 small molecules increased and 33 small molecules decreased in the SM/J mouse lung as compared to 129X1/SvJ mouse lung. Notable among the increased compounds was malonylcarnitine. Following acrolein exposure, several molecules indicative of glycolysis and branched chain amino acid metabolism increased similarly in both strains, whereas SM/J mice were less effective in generating metabolites related to fatty acid β-oxidation. CONCLUSION These findings suggest management of energetic stress varies between these strains, and that the ability to evoke auxiliary energy generating pathways rapidly and effectively may be critical in enhancing survival during acute lung injury in mice.
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Affiliation(s)
- James P Fabisiak
- Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219-3130, USA.
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Abstract
PURPOSE OF REVIEW To review the literature regarding the active management of intrahepatic cholestasis of pregnancy. RECENT FINDINGS There has been an increasing trend toward the active management of cholestasis of pregnancy. This trend exists because clinicians have yet to discover adequate solutions to avert the morbidities and mortalities associated with the disorder. It is believed that early intervention by induction of labor before the 38th week of gestation will decrease the incidence of intrauterine fetal demise associated with cholestasis of pregnancy. It is also believed that treating the clinical symptoms of cholestasis with 2-5 ursodeoxycholic acid will improve maternal symptoms, facilitate the prolongation of pregnancy, and possibly improve fetal outcomes. SUMMARY The current literature encourages the induction of labor between 37-38 weeks' gestation in order to reduce the incidence of stillbirth in women with intrahepatic cholestasis of pregnancy. The most widely used medication for both the treatment of maternal pruritus and the elevations in maternal liver enzymes associated with cholestasis of pregnancy is 2-5 ursodeoxycholic acid. Neither mode of practice has been subjected to randomized clinical trials.
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Current world literature. Curr Opin Obstet Gynecol 2010; 22:166-75. [PMID: 20216348 DOI: 10.1097/gco.0b013e328338c956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Abstract
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus in the third trimester, raised serum bile acids and increased rates of adverse fetal outcomes. The etiology of ICP is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites in genetically susceptible women. Equally unclear are the mechanisms by which the fetal complications occur. This article reviews the epidemiology, clinical features, diagnosis, etiology and management of ICP.
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Abstract
Several studies have characterized the cellular and molecular mechanisms of hepatocyte injury caused by the retention of hydrophobic bile acids (BAs) in cholestatic diseases. BAs may disrupt cell membranes through their detergent action on lipid components and can promote the generation of reactive oxygen species that, in turn, oxidatively modify lipids, proteins, and nucleic acids, and eventually cause hepatocyte necrosis and apoptosis. Several pathways are involved in triggering hepatocyte apoptosis. Toxic BAs can activate hepatocyte death receptors directly and induce oxidative damage, thereby causing mitochondrial dysfunction, and induce endoplasmic reticulum stress. When these compounds are taken up and accumulate inside biliary cells, they can also cause apoptosis. Regarding extrahepatic tissues, the accumulation of BAs in the systemic circulation may contribute to endothelial injury in the kidney and lungs. In gastrointestinal cells, BAs may behave as cancer promoters through an indirect mechanism involving oxidative stress and DNA damage, as well as acting as selection agents for apoptosis-resistant cells. The accumulation of BAs may have also deleterious effects on placental and fetal cells. However, other BAs, such as ursodeoxycholic acid, have been shown to modulate BA-induced injury in hepatocytes. The major beneficial effects of treatment with ursodeoxycholic acid are protection against cytotoxicity due to more toxic BAs; the stimulation of hepatobiliary secretion; antioxidant activity, due in part to an enhancement in glutathione levels; and the inhibition of liver cell apoptosis. Other natural BAs or their derivatives, such as cholyl-N-methylglycine or cholylsarcosine, have also aroused pharmacological interest owing to their protective properties.
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Current world literature. Curr Opin Pediatr 2009; 21:272-80. [PMID: 19307901 DOI: 10.1097/mop.0b013e32832ad5c0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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