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Yu H, Zhang C, Pan H, Gao X, Wang X, Xiao W, Yan S, Gao Y, Fu J, Zhou Y. Indeno[1,2,3-cd]pyrene enhances the sensitivity of airway epithelial cells to ferroptosis and aggravates asthma. CHEMOSPHERE 2024; 363:142885. [PMID: 39025314 DOI: 10.1016/j.chemosphere.2024.142885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/02/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
Particulate matter of aerodynamic diameter ≤2.5 μm (PM2.5) exposure induces oxidative stress in lung tissues. Ferroptosis is a form of regulated cell death based on oxidative damage and lipid peroxidation. Whether PM2.5 exposure-induced oxidative stress can promote ferroptosis to aggravate asthma is not known. To investigate if PM2.5 exposure induces oxidative stress to promote ferroptosis and influence asthma development, a cockroach extract-induced asthma model in mice was used for in vivo studies. Airway epithelial cell (AEC) ferroptosis was detected by assays (CCK8, malonaldehyde, and 4-hydroxynonenal). Molecular mechanisms were investigated by real-time reverse transcription-quantitative polymerase chain reaction, western blotting, flow cytometry, liquid chromatography-tandem mass spectrometry, and chromatin immunoprecipitation. We found that exposure to PM2.5 and Indeno[1,2,3-cd] pyrene (IP; one of the prominent absorbed polycyclic aromatic hydrocarbons in PM2.5) enhanced the sensitivity of AECs to ferroptosis to aggravate asthma, whereas ferroptosis inhibitors and cytosolic phospholipase A2 (cPLA2) inhibitors reversed this augmented inflammatory response in mice suffering from asthma. IP treatment enhanced cPLA2 expression/activation through aryl hydrocarbon receptor (AhR) genomic and non-genomic pathways, resulting in arachidonic-acid release to promote the sensitivity of AECs to ferroptosis. IP exposure enhanced the release of leukotriene-B4 from lung macrophages, resulting in enhanced expression of acyl-coA synthetase long chain family member4 (ACSL4) and the sensitivity of AECs to ferroptosis. This finding suggests that exposure to PM2.5 and IP promote ferroptosis sensitivity in AECs to aggravate asthma, which may provide new targets for the prevention and treatment of asthma.
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Affiliation(s)
- Hongmiao Yu
- Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Caiyan Zhang
- Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China
| | - Hongguang Pan
- Department of Otorhinolaryngology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China
| | - Xia Gao
- Department of Experimental Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiang Wang
- Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Wenfeng Xiao
- Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Shang Yan
- Department of Otorhinolaryngology, Shenzhen Children's Hospital, Shenzhen, Guangdong, China
| | - Yajing Gao
- Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China
| | - Jinrong Fu
- Department of General Medicine, Children's Hospital of Fudan University, Shanghai, China.
| | - Yufeng Zhou
- Department of Critical Care Medicine, Children's Hospital of Fudan University, National Children's Medical Center, and the Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China; National Health Commission (NHC) Key Laboratory of Neonatal Diseases, Fudan University, Shanghai, China.
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Kotoulas SC, Domvri K, Tsantos A, Papagiouvanni I, Michailidou A, Spyratos DG, Porpodis K, Grigoriou I, Papakosta D, Pataka A. Is there a correlation between the changes in airway inflammation and the changes in respiratory mechanics after vaping in patients with asthma? World J Methodol 2024; 14:89284. [PMID: 38983659 PMCID: PMC11229872 DOI: 10.5662/wjm.v14.i2.89284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/08/2024] [Accepted: 02/26/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Electronic cigarettes (ECs) have been promoted as alternatives to traditional cigarettes. AIM To investigate ECs' effects on respiratory system, especially in patients with respiratory diseases. METHODS We randomly selected 25 smokers with stable moderate asthma and matched them with 25 healthy smokers. All were subjucted to pulmonary function tests (PFTs), impulse oscillometry (IOS), fraction exhaled Nitric Oxide (FeNO), exhaled breathe condensate (EBC) and biomarker measurements before and after vaping one nicotine-containing EC. RESULTS The increase in FeNO 30 minutes after EC, reflecting airway inflammation, significantly correlated with increase of residual volume (RV), total lung capacity, respiratory impedance at 5 Hz (Z5Hz) and respiratory resistance at 5 and 20 Hz (R5Hz and R20Hz). No significant correlations were found between EBC biomarkers' changes and respiratory mechanics. CONCLUSION This is the first study demonstrating that the changes in airway inflammation caused by EC have direct effects in respiratory mechanics of asthmatic patients.
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Affiliation(s)
| | - Kalliopi Domvri
- Pulmonary Department-Oncology Unit, Aristotle University of Thessaloniki, Thessaloniki 57010, Greece
| | - Alexandros Tsantos
- 2nd Department of Internal Medicine, General Hospital of Thessaloniki ‘’Ippokration’’, Thessaloniki 54642, Greece
| | - Ioanna Papagiouvanni
- Fourth Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki 54642, Thessaloniki, Greece
| | - Anastasia Michailidou
- 2nd Propaedeutic Department of Internal Medicine, General Hospital of Thessaloniki “Ippokration”, Thessaloniki 54642, Greece
| | - Dionisios G Spyratos
- Department of Pulmonary, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
| | - Konstantinos Porpodis
- Department of Pulmonary, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
| | - Ioanna Grigoriou
- Respiratory Failure Clinic, Papanikolaou General Hospital, Thessloniki 57001, Greece
| | - Despina Papakosta
- Department of Pulmonary, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
| | - Athanasia Pataka
- Department of Respiratory Medicine, Aristotle Univ Thessaloniki, Sch Med, G Papanikolaou Hosp, Resp Failure Unit, Aristotle University of Thessaloniki, Thessaloniki 57001, Greece
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Kotoulas SC, Katsaounou P, Riha R, Grigoriou I, Papakosta D, Spyratos D, Porpodis K, Domvri K, Pataka A. Electronic Cigarettes and Asthma: What Do We Know So Far? J Pers Med 2021; 11:jpm11080723. [PMID: 34442368 PMCID: PMC8399607 DOI: 10.3390/jpm11080723] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 07/19/2021] [Accepted: 07/23/2021] [Indexed: 12/20/2022] Open
Abstract
Electronic cigarettes (EC) are a novel product, marketed as an alternative to tobacco cigarette. Its effects on human health have not been investigated widely yet, especially in specific populations such as patients with asthma. With this review, we use the existing literature in order to answer four crucial questions concerning: (1) ECs' role in the pathogenesis of asthma; (2) ECs' effects on lung function and airway inflammation in patients with asthma; (3) ECs' effects on asthma clinical characteristics in asthmatics who use it regularly; and (4) ECs' effectiveness as a smoking cessation tool in these patients. Evidence suggests that many EC compounds might contribute to the pathogenesis of asthma. Lung function seems to deteriorate by the use of EC in this population, while airway inflammation alters, with the aggravation of T-helper-type-2 (Th2) inflammation being the most prominent but not the exclusive effect. EC also seems to worsen asthma symptoms and the rate and severity of exacerbations in asthmatics who are current vapers, whilst evidence suggests that its effectiveness as a smoking cessation tool might be limited. Asthmatic patients should avoid using EC.
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Affiliation(s)
- Serafeim-Chrysovalantis Kotoulas
- Clinic of Respiratory Failure, General Hospital of Thessaloniki Georgios Papanikolaou, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (I.G.); (A.P.)
- Correspondence: ; Tel.: +30-6977-705450
| | - Paraskevi Katsaounou
- 1st ICU “Evangelismos Hospital”, School of Medicine, National and Kapodistrian University of Athens, Ypsilantou 45-47, 10676 Athens, Greece;
| | - Renata Riha
- Sleep Research Unit, Department of Sleep Medicine, The University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK;
| | - Ioanna Grigoriou
- Clinic of Respiratory Failure, General Hospital of Thessaloniki Georgios Papanikolaou, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (I.G.); (A.P.)
| | - Despoina Papakosta
- Department of Pulmonary Medicine, General Hospital of Thessaloniki “Georgios Papanikolaou”, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (D.P.); (D.S.); (K.P.); (K.D.)
| | - Dionysios Spyratos
- Department of Pulmonary Medicine, General Hospital of Thessaloniki “Georgios Papanikolaou”, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (D.P.); (D.S.); (K.P.); (K.D.)
| | - Konstantinos Porpodis
- Department of Pulmonary Medicine, General Hospital of Thessaloniki “Georgios Papanikolaou”, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (D.P.); (D.S.); (K.P.); (K.D.)
| | - Kalliopi Domvri
- Department of Pulmonary Medicine, General Hospital of Thessaloniki “Georgios Papanikolaou”, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (D.P.); (D.S.); (K.P.); (K.D.)
| | - Athanasia Pataka
- Clinic of Respiratory Failure, General Hospital of Thessaloniki Georgios Papanikolaou, Aristotle University of Thessaloniki, Leoforos Papanikolaou, 57010 Thessaloniki, Greece; (I.G.); (A.P.)
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Kotoulas SC, Pataka A, Domvri K, Spyratos D, Katsaounou P, Porpodis K, Fouka E, Markopoulou A, Passa-Fekete K, Grigoriou I, Kontakiotis T, Argyropoulou P, Papakosta D. Acute effects of e-cigarette vaping on pulmonary function and airway inflammation in healthy individuals and in patients with asthma. Respirology 2020; 25:1037-1045. [PMID: 32239706 DOI: 10.1111/resp.13806] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 01/21/2020] [Accepted: 02/27/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND OBJECTIVE The acute effects of e-cigarettes have not been scientifically demonstrated yet. The aim of this study was to assess the acute changes in pulmonary function and airway inflammation in patients with asthma after vaping one e-cigarette. METHODS Twenty-five smokers suffering from stable moderate asthma according to GINA guidelines with no other comorbidities and 25 healthy smokers matched with the baseline characteristics of the asthmatic patients were recruited. PFT, IOS, FeNO and EBC were performed before and after vaping one e-cigarette with nicotine. pH and concentrations of IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17A, TNF-α, ISO8 and LTB4 were measured in EBC. RESULTS FFEV1/FVC ratio and PEF were reduced in asthmatic patients after e-cigarette. Z5Hz and R5Hz, R10Hz and R20Hz increased in both groups. FeNO and EBC pH increased by 3.60 ppb (P = 0.001) and 0.15 (P = 0.014) in asthmatic patients after e-cigarette, whereas they decreased in control group by 3.28 ppb (P < 0.001) and 0.12 (P = 0.064), respectively. The concentrations of IL-10, TNF-α and ISO8 in EBC increased in asthmatic patients after e-cigarette and the changes in concentrations of IL-1β and IL-4 differed significantly between the two groups. CONCLUSION E-cigarette vaping resulted in acute alteration of both pulmonary function and airway inflammation in stable moderate asthmatic patients.
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Affiliation(s)
- Serafeim-Chrysovalantis Kotoulas
- Clinic of Respiratory Failure, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Athanasia Pataka
- Clinic of Respiratory Failure, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kalliopi Domvri
- Department of Pulmonary Medicine, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dionisios Spyratos
- Department of Pulmonary Medicine, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paraskevi Katsaounou
- 1st ICU 'Evangelismos Hospital' School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Konstantinos Porpodis
- Department of Pulmonary Medicine, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelia Fouka
- Department of Pulmonary Medicine, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aikaterini Markopoulou
- Clinic of Pulmonary Medicine of National Healthcare System, General Hospital of Thessaloniki 'Georgios Papanikolaou', Thessaloniki, Greece
| | - Katalin Passa-Fekete
- Clinic of Respiratory Failure, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Ioanna Grigoriou
- Clinic of Respiratory Failure, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theodoros Kontakiotis
- Department of Pulmonary Medicine, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Paraskevi Argyropoulou
- Clinic of Respiratory Failure, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Despoina Papakosta
- Department of Pulmonary Medicine, General Hospital of Thessaloniki 'Georgios Papanikolaou', Aristotle University of Thessaloniki, Thessaloniki, Greece
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Evolution of Airway Inflammation in Preschoolers with Asthma-Results of a Two-Year Longitudinal Study. J Clin Med 2020; 9:jcm9010187. [PMID: 31936693 PMCID: PMC7020050 DOI: 10.3390/jcm9010187] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 01/04/2020] [Accepted: 01/06/2020] [Indexed: 12/12/2022] Open
Abstract
Fractional exhaled nitric oxide (FeNO) is a non-invasive marker for eosinophilic airway inflammation and has been used for monitoring asthma. Here, we assess the characteristics of FeNO from preschool to school age, in parallel with asthma activity. A total of 167 asthmatic children and 66 healthy, age-matched controls were included in the 2-year prospective PreDicta study evaluating wheeze/asthma persistence in preschool-aged children. Information on asthma/rhinitis activity, infections and atopy was recorded at baseline. Follow-up visits were performed at 6-month intervals, as well as upon exacerbation/cold and 4–6 weeks later in the asthmatic group. We obtained 539 FeNO measurements from asthmatics and 42 from controls. At baseline, FeNO values did not differ between the two groups (median: 3.0 ppb vs. 2.0 ppb, respectively). FeNO values at 6, 12, 18 and 24 months (4.0, CI: 0.0–8.6; 6.0, CI: 2.8–12.0; 8.0, CI: 4.0–14.0; 8.5, CI: 4.4–14.5 ppb, respectively) increased with age (correlation p ≤ 0.001) and atopy (p = 0.03). FeNO was non-significantly increased from baseline to the symptomatic visit, while it decreased after convalescence (p = 0.007). Markers of disease activity, such as wheezing episodes and days with asthma were associated with increased FeNO values during the study (p < 0.05 for all). Age, atopy and disease activity were found to be important FeNO determinants in preschool children. Longitudinal and individualized FeNO assessment may be valuable in monitoring asthmatic children with recurrent wheezing or mild asthma.
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Kang N, Chang KJ, Park SY, Um JH, Han EJ, Lee W, Kim EA, Oh JY, Kim SH, Jeon YJ, Ahn CB, Cheong SH, Ahn G. Anti-inflammatory Effects of Galactose-Taurine Sodium Salt in LPS-Activated RAW 264.7 Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 975 Pt 2:943-953. [PMID: 28849513 DOI: 10.1007/978-94-024-1079-2_75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
In this study, we synthesized Galactose-Taurine sodium salt (G-T) as a functional food ingredient to enhance biological activities of taurine. Also, anti-inflammatory effects of G-T were investigated in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. G-T found to reduce the generations of the LPS-stimulated nitric oxide (NO) and prostaglandin E2 (PGE2) via down-regulating the expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Also, G-T reduced the secretion of inflammatory cytokines including interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF-α) in LPS-treated RAW 264.7 cells. Finally, we identified that G-T inhibits the activation of nuclear factor-κB (NF-κB) and the phosphorylation of inhibitor κB (IκB)-α. From these results, this study first suggests that G-T could be considered as an effective anti-inflammatory agent.
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Affiliation(s)
- Nalae Kang
- Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu, Republic of Korea
| | - Kyung Ja Chang
- Department of Food and Nutrition, Inha University, Incheon, Republic of Korea
| | - Soo Yeon Park
- Department of Food Technology and Nutrition, Chonnam National University, Yeosu, Republic of Korea
| | - Ju Hyung Um
- Department of Food Technology and Nutrition, Chonnam National University, Yeosu, Republic of Korea
| | - Eui Jeong Han
- Department of Food Technology and Nutrition, Chonnam National University, Yeosu, Republic of Korea
| | - WonWoo Lee
- Department of Marine Life Science, Jeju National University, Jeju, Republic of Korea
| | - Eun A Kim
- Jeju International Marine Science Center for Research and Education, Korea Institute of Ocean Science and Technology (KIOST), Jeju, Republic of Korea
| | - Jae Young Oh
- Department of Marine Life Science, Jeju National University, Jeju, Republic of Korea
| | - Sung Hoon Kim
- Department of Chemistry, Konkuk University, Seoul, Republic of Korea
| | - You-Jin Jeon
- Department of Marine Life Science, Jeju National University, Jeju, Republic of Korea
| | - Chang-Bum Ahn
- Department of Food Technology and Nutrition, Chonnam National University, Yeosu, Republic of Korea
- Division of Food and Nutrition, Chonnam National University, Gwang ju, Republic of Korea
| | - Sun Hee Cheong
- Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu, Republic of Korea.
- Department of Food Technology and Nutrition, Chonnam National University, Yeosu, Republic of Korea.
| | - Ginnae Ahn
- Department of Marine Bio-Food Sciences, Chonnam National University, Yeosu, Republic of Korea.
- Department of Food Technology and Nutrition, Chonnam National University, Yeosu, Republic of Korea.
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Kuribayashi R, Yamaguchi T, Sako H, Takishita T, Takagi K. Bioequivalence Evaluations of Generic Dry Powder Inhaler Drug Products: Similarities and Differences Between Japan, USA, and the European Union. Clin Pharmacokinet 2017; 56:225-233. [PMID: 27461251 DOI: 10.1007/s40262-016-0438-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
In Japan, the development of generic oral dry powder inhaler (DPI) drug products for marketing approval has recently increased. The Pharmaceuticals and Medical Devices Agency (PMDA) considers the required data for each drug product in the consultation meeting. However, guidelines for DPI drug products have been published by the US Food and Drug Administration and the European Medicines Agency. Recently, the basic principles of bioequivalence evaluations of generic DPI drug products were published in March 2016 by the Ministry of Health, Labour and Welfare. The document mainly outlines the current understanding regarding the bioequivalence evaluations of generic DPI drug products based on knowledge from PMDA consultation meetings. In this review, we compared the bioequivalence evaluations of DPI drug products among Japan, USA, and the European Union and discuss future development of generic DPI drug products in Japan.
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Affiliation(s)
- Ryosuke Kuribayashi
- Office of Generic Drugs, Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan.
| | - Toru Yamaguchi
- Office of Generic Drugs, Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan
| | - Hanaka Sako
- Office of Generic Drugs, Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan
| | - Tomoko Takishita
- Office of Generic Drugs, Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan
| | - Kazunori Takagi
- Office of Generic Drugs, Pharmaceuticals and Medical Devices Agency, 3-3-2 Kasumigaseki, Chiyoda-ku, Tokyo, 100-0013, Japan
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Ma J, Huang H, Xie Y, Liu Z, Zhao J, Zhang C, Jia Y, Zhang Y, Zhang H, Zhang T, Ju J. Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents. Nat Commun 2017; 8:391. [PMID: 28855504 PMCID: PMC5577134 DOI: 10.1038/s41467-017-00419-5] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Accepted: 06/28/2017] [Indexed: 11/13/2022] Open
Abstract
Tuberculosis remains one of the world’s deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1–6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6–8) from the respective mutants. Most impressively, ilamycins E1/E2, which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads. Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.
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Affiliation(s)
- Junying Ma
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China.
| | - Hongbo Huang
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Yunchang Xie
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Zhiyong Liu
- Tuberculosis Research Laboratory, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jin Zhao
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, 523808, China
| | - Chunyan Zhang
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yanxi Jia
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yun Zhang
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Hua Zhang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Institute of Laboratory Medicine, Guangdong Medical University, Dongguan, 523808, China
| | - Tianyu Zhang
- Tuberculosis Research Laboratory, State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China
| | - Jianhua Ju
- CAS Key Laboratory of Tropical Marine Bio-Resources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
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Lee SL, Saluja B, García-Arieta A, Santos GML, Li Y, Lu S, Hou S, Rebello J, Vaidya A, Gogtay J, Purandare S, Lyapustina S. Regulatory Considerations for Approval of Generic Inhalation Drug Products in the US, EU, Brazil, China, and India. AAPS JOURNAL 2015; 17:1285-304. [PMID: 26002510 DOI: 10.1208/s12248-015-9787-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 05/09/2015] [Indexed: 11/30/2022]
Abstract
This article describes regulatory approaches for approval of "generic" orally inhaled drug products (OIDPs) in the United States, European Union, Brazil, China and India. While registration of a generic OIDP in any given market may require some documentation of the formulation and device similarity to the "original" product as well as comparative testing of in vitro characteristics and in vivo performance, the specific documentation approaches, tests and acceptance criteria vary by the country. This divergence is due to several factors, including unique cultural, historical, legal and economic circumstances of each region; the diverse healthcare and regulatory systems; the different definitions of key terms such as "generic" and "reference" drug; the acknowledged absence of in vitro in vivo correlations for OIDPs; and the scientific and statistical issues related to OIDP testing (such as how best to account for the batch-to-batch variability of the Reference product, whether to use average bioequivalence or population bioequivalence in the statistical analysis of results, whether to use healthy volunteers or patients for pharmacokinetic studies, and which pharmacodynamic or clinical end-points should be used). As a result of this discrepancy, there are ample opportunities for the regulatory and scientific communities around the world to collaborate in developing more consistent, better aligned, science-based approaches. Moving in that direction will require both further research and further open discussion of the pros and cons of various approaches.
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Affiliation(s)
- Sau L Lee
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA,
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10
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Ghanim H, Green K, Abuaysheh S, Batra M, Kuhadiya ND, Patel R, Makdissi A, Dhindsa S, Chaudhuri A, Dandona P. Suppressive effect of insulin on the gene expression and plasma concentrations of mediators of asthmatic inflammation. J Diabetes Res 2015; 2015:202406. [PMID: 25642424 PMCID: PMC4302348 DOI: 10.1155/2015/202406] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/20/2014] [Accepted: 12/18/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND AND HYPOTHESIS Following our recent demonstration that the chronic inflammatory and insulin resistant state of obesity is associated with an increase in the expression of mediators known to contribute to the pathogenesis of asthma and that weight loss after gastric bypass surgery results in the reduction of these genes, we have now hypothesized that insulin suppresses the cellular expression and plasma concentrations of these mediators. METHODS The expression of IL-4, LIGHT, LTBR, ADAM-33, and TSLP in MNC and plasma concentrations of LIGHT, TGF-β1, MMP-9, MCP-1, TSLP, and NOM in obese patients with T2DM were measured before, during, and after the infusion of a low dose (2 U/h) infusion of insulin for 4 hours. The patients were also infused with dextrose or saline for 4 hours on two separate visits and served as controls. Results. Following insulin infusion, the mRNA expression of IL-4, ADAM-33, LIGHT, and LTBR mRNA expression fell significantly (P < 0.05 for all). There was also a concomitant reduction in plasma NOM, LIGHT, TGF-β1, MCP-1, and MMP-9 concentrations. CONCLUSIONS Insulin suppresses the expression of these genes and mediators related to asthma and may, therefore, have a potential role in the treatment of asthma.
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Affiliation(s)
- Husam Ghanim
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Kelly Green
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Sanaa Abuaysheh
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Manav Batra
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Nitesh D. Kuhadiya
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Reema Patel
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Antoine Makdissi
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Sandeep Dhindsa
- Division of Endocrinology and Metabolism, Texas Tech University Health Sciences Center, 701 W 5th Street, Odessa, TX 79763, USA
| | - Ajay Chaudhuri
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
| | - Paresh Dandona
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, NY 14221, USA
- *Paresh Dandona:
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Muccilli V, Saletti R, Cunsolo V, Ho J, Gili E, Conte E, Sichili S, Vancheri C, Foti S. Protein profile of exhaled breath condensate determined by high resolution mass spectrometry. J Pharm Biomed Anal 2014; 105:134-149. [PMID: 25555262 DOI: 10.1016/j.jpba.2014.11.050] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 11/27/2014] [Accepted: 11/29/2014] [Indexed: 11/30/2022]
Abstract
A method based on liquid chromatography/high resolution tandem mass spectrometry coupled with electrophoretic separation, for determination and relative quantification of the protein composition of exhaled breath condensate (EBC), was developed. Application of the procedure to a sample of EBC, pooled from nine healthy subjects, resulted in the identification of 167 unique gene products, 113 of which not previously reported in EBC samples. The abundance of the protein identified was estimated by means of the exponentially modified protein abundance index protocol (emPAI). Cytokeratins were by far the most abundant proteins in EBC samples. Many of the identified proteins were associated with multiple cellular location with cytoplasm constituting the largest group. Cytosol, nucleus, membrane, cytoskeleton and extracellular were other abundantly represented locations. No amylase was detected, suggesting the absence of saliva protein contamination. The profile obtained represents the most comprehensive protein characterization of EBC so far reported and demonstrates that this approach provides a powerful tool for investigating the protein profile of EBC samples. Compared with analogous investigations, this study also shows that the protein profile of EBC is strongly affected by the sampling method adopted.
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Affiliation(s)
- Vera Muccilli
- Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Rosaria Saletti
- Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.
| | - Vincenzo Cunsolo
- Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
| | - Jenny Ho
- ThermoFisher Scientific, Stafford House, Boundary Way, Hemel Hempstead HP2 7GE, United Kingdom
| | - Elisa Gili
- Department of Clinical and Molecular Biomedicine, University Hospital Policlinico-Vittorio Emanuele, Via Santa Sofia 78, 95123 Catania, Italy
| | - Enrico Conte
- Department of Clinical and Molecular Biomedicine, University Hospital Policlinico-Vittorio Emanuele, Via Santa Sofia 78, 95123 Catania, Italy
| | - Stefania Sichili
- Department of Clinical and Molecular Biomedicine, University Hospital Policlinico-Vittorio Emanuele, Via Santa Sofia 78, 95123 Catania, Italy
| | - Carlo Vancheri
- Department of Clinical and Molecular Biomedicine, University Hospital Policlinico-Vittorio Emanuele, Via Santa Sofia 78, 95123 Catania, Italy
| | - Salvatore Foti
- Department of Chemical Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
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12
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Dandona P, Ghanim H, Monte SV, Caruana JA, Green K, Abuaysheh S, Lohano T, Schentag J, Dhindsa S, Chaudhuri A. Increase in the mediators of asthma in obesity and obesity with type 2 diabetes: reduction with weight loss. Obesity (Silver Spring) 2014; 22:356-62. [PMID: 23804543 DOI: 10.1002/oby.20524] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 05/26/2013] [Indexed: 01/06/2023]
Abstract
OBJECTIVE To determine whether the expression of key asthma related genes, IL-4, LIGHT, LTBR, MMP-9, CCR-2, and ADAM-33 in mononuclear cells and the plasma concentration of nitric oxide metabolites (NOM) and MMP-9 are increased in the obese, obese type 2 diabetics (T2DM) and in morbidly obese patients prior to and after gastric bypass surgery (RYGB). DESIGN AND METHODS The expression of these genes in MNC and plasma concentrations of these indices was measured in healthy lean and in obese with and without T2DM and following RYGB in obese T2DM. RESULTS The expression of IL-4, MMP-9, LIGHT and CCR-2 and plasma NOM concentrations was significantly higher in the obese subjects and in obese T2DM patients than in normal subjects. The expression of IL-4, LIGHT, MMP-9, and CCR-2 expression was related to BMI and HOMA-IR. The expression of IL-4, LIGHT, LTBR, ADAM-33, MMP-9, and CCR-2 fell after RYGB surgery as did plasma concentrations of MMP-9 and NOM. CONCLUSIONS Obesity with and without T2DM is associated with an increase in the expression of IL-4, LIGHT, MMP-9 and CCR-2; plasma NOM and MMP-9 concentrations are also increased. Following RYGB surgery and weight loss, the expression of these factors in MNC and plasma concentrations falls significantly.
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MESH Headings
- Adult
- Asthma/complications
- Asthma/prevention & control
- Body Mass Index
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/immunology
- Diabetes Mellitus, Type 2/metabolism
- Female
- Follow-Up Studies
- Gastric Bypass
- Gene Expression Regulation
- Humans
- Inflammation Mediators/blood
- Inflammation Mediators/metabolism
- Insulin Resistance
- Interleukin-4/genetics
- Interleukin-4/metabolism
- Leukocytes, Mononuclear/immunology
- Leukocytes, Mononuclear/metabolism
- Male
- Matrix Metalloproteinase 9/blood
- Matrix Metalloproteinase 9/genetics
- Matrix Metalloproteinase 9/metabolism
- Middle Aged
- Nitric Oxide/blood
- Obesity/blood
- Obesity/complications
- Obesity/immunology
- Obesity/metabolism
- Obesity, Morbid/complications
- Obesity, Morbid/immunology
- Obesity, Morbid/metabolism
- Obesity, Morbid/surgery
- Receptors, CCR2/genetics
- Receptors, CCR2/metabolism
- Tumor Necrosis Factor Ligand Superfamily Member 14/genetics
- Tumor Necrosis Factor Ligand Superfamily Member 14/metabolism
- Weight Loss
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Affiliation(s)
- Paresh Dandona
- Division of Endocrinology, Diabetes and Metabolism, State University of New York at Buffalo and Kaleida Health, 115 Flint Road, Williamsville, New York, USA
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13
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Taylor-Clark TE, Undem BJ. Sensing pulmonary oxidative stress by lung vagal afferents. Respir Physiol Neurobiol 2011; 178:406-13. [PMID: 21600314 DOI: 10.1016/j.resp.2011.05.003] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Revised: 04/06/2011] [Accepted: 05/04/2011] [Indexed: 12/30/2022]
Abstract
Oxidative stress in the bronchopulmonary airways can occur through a variety of inflammatory mechanisms and also following the inhalation of environmental pollutants. Oxidative stress causes cellular dysfunction and thus mammals (including humans) have developed mechanisms for detecting oxidative stress, such that defensive behavior and defensive biological mechanisms can be induced to lessen its potential damage. Vagal sensory nerves innervating the airways play a critical role in the detection of the microenvironment in the airways. Oxidative stress and associated compounds activate unmyelinated bronchopulmonary C-fibers, initiating action potentials in these nerves that conduct centrally to evoke unpleasant sensations (e.g. urge to cough, dyspnea, chest-tightness) and to stimulate/modulate reflexes (e.g. cough, bronchoconstriction, respiratory rate, inspiratory drive). This review will summarize the published evidence regarding the mechanisms by which oxidative stress, reactive oxygen species, environmental pollutants and lipid products of peroxidation activate bronchopulmonary C-fibers. Evidence suggests a key role for transient receptor potential ankyrin 1 (TRPA1), although transient receptor potential vanilloid 1 (TRPV1) and purinergic P2X channels may also play a role. Knowledge of these pathways greatly aids our understanding of the role of oxidative stress in health and disease and represents novel therapeutic targets for diseases of the airways.
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Affiliation(s)
- Thomas E Taylor-Clark
- Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, United States.
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14
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Stern G, de Jongste J, van der Valk R, Baraldi E, Carraro S, Thamrin C, Frey U. Fluctuation phenotyping based on daily fraction of exhaled nitric oxide values in asthmatic children. J Allergy Clin Immunol 2011; 128:293-300. [PMID: 21489612 DOI: 10.1016/j.jaci.2011.03.010] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Revised: 03/01/2011] [Accepted: 03/08/2011] [Indexed: 12/26/2022]
Abstract
BACKGROUND Fraction of exhaled nitric oxide (Feno), a marker of airway inflammation, has been proposed to be useful for asthma management, but conclusions are inconsistent. This might be due to the failure of mean statistics to characterize individual variability in Feno values, which is possibly a better indicator of asthma control than single measurements. OBJECTIVE We characterized fractal fluctuations in daily Feno values over time and the relationship between Feno values and symptom scores. We investigated whether these are associated with asthma severity, control, and exacerbation risk. METHODS Daily Feno values and symptom scores over 192 days in 41 atopic asthmatic children from the Childhood Asthma Respiratory Inflammatory Status Monitoring study were analyzed. Two methods of time-series analysis were used: detrended fluctuation analysis to quantify fractal patterns in fluctuations in daily Feno values (α value) and cross-correlation to quantify the strength of the relationship between daily Feno values and symptom scores. The associations of α values and cross-correlation with markers of asthma severity and control were assessed by means of regression analysis. RESULTS Daily fluctuations in Feno values exhibited fractal-type long-range correlations. Those subjects receiving higher doses of inhaled corticosteroids at study entry had a significantly lower α value, corresponding to more random fluctuations in Feno values in those with greater inhaled corticosteroid need. The cross-correlation between Feno values and symptom scores was significantly higher in those subjects who had exacerbations. CONCLUSIONS Fluctuation in Feno values and their cross-correlation to symptom scores contains information on asthma severity and control. Methods that quantify the complexity of asthma over time might assist in identifying asthmatic subjects with concordance between eosinophilic inflammation and symptoms and thus increased exacerbation risk.
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Affiliation(s)
- Georgette Stern
- Department of Pediatrics, University Hospital of Bern, Bern, Switzerland
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15
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Yasuda S, Yasuda T, Liu MY, Shetty S, Idell S, Boggaram V, Suiko M, Sakakibara Y, Fu J, Liu MC. Sulfation of chlorotyrosine and nitrotyrosine by human lung endothelial and epithelial cells: Role of the human SULT1A3. Toxicol Appl Pharmacol 2011; 251:104-9. [DOI: 10.1016/j.taap.2010.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Revised: 12/07/2010] [Accepted: 12/09/2010] [Indexed: 10/18/2022]
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16
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Tashkin DP, Varghese ST. Combined treatment with formoterol and tiotropium is more efficacious than treatment with tiotropium alone in patients with chronic obstructive pulmonary disease, regardless of smoking status, inhaled corticosteroid use, baseline severity, or gender. Pulm Pharmacol Ther 2010; 24:147-52. [PMID: 20659577 DOI: 10.1016/j.pupt.2010.07.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2010] [Revised: 06/24/2010] [Accepted: 07/16/2010] [Indexed: 11/24/2022]
Abstract
A recent randomized, double-blind, parallel-group, active-controlled, multicenter study of 255 patients ≥ 40 years of age with chronic obstructive pulmonary disease (COPD) showed that combined formoterol (FOR) and tiotropium (TIO) treatment in patients with COPD significantly improved lung function as well as symptoms and other patient-reported outcomes compared with TIO alone. FOR and TIO are long-acting bronchodilators that represent the β₂-adrenergic agonist and anticholinergic classes, respectively. However, the possible influence of smoking status, inhaled corticosteroid (ICS) use, baseline disease severity, and gender differences on bronchodilator efficacy requires further investigation. Using data from the previously published study mentioned above, a post hoc analysis was performed to examine the efficacy of combined FOR + TIO treatment compared with TIO monotherapy in subgroup analyses of men and women, current and ex-smokers, ICS users and non-ICS users, and patients with moderate and severe/very severe COPD. Efficacy comparisons were based on the changes in forced expiratory volume in 1 s measured 0-4 h after the morning dose (FEV₁ AUC₀₋₄h). After a run-in period, patients were treated for 12 weeks with either FOR 12 μg twice daily (BID) plus TIO 18 μg once daily (QD) in the morning (AM, n = 124) or with FOR placebo BID plus TIO 18 μg QD AM (n = 131). The least squares mean change from baseline in the normalized FEV₁ AUC₀₋₄h was assessed using analysis of covariance. With the exception of treatment differences at week 4 in smokers and subjects with "very severe" COPD, and at weeks 4, 8, and 12 for ICS users and non-ICS users (p values not determined), FOR + TIO was significantly superior (P < 0.05) to TIO alone at all time points (weeks 4, 8, 12, and endpoint), regardless of gender, smoking status, ICS use, or COPD severity. We conclude that coadministered FOR + TIO significantly improves lung function compared with TIO treatment alone in COPD patients regardless of differences in patient subgroups.
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Affiliation(s)
- Donald P Tashkin
- David Geffen School of Medicine at UCLA, 37-131 Center for Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
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17
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Ghosh S, Gal J, Marczin N. Carbon monoxide: endogenous mediator, potential diagnostic and therapeutic target. Ann Med 2010; 42:1-12. [PMID: 20092397 DOI: 10.3109/07853890903482877] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The primary objectives of this article are to review the potential role of carbon monoxide (CO) as an endogenous mediator, diagnostic marker for pulmonary disorders, and therapeutic target in critical illness. The review will start by focusing on the importance of the heme oxygenase (HO)-CO axis as an endogenous system as it relates to the cardiovascular and pulmonary systems. It will elucidate the influence of HO gene expression on critical events like shock, sepsis, ischemia-reperfusion and others. Our focus will then shift and look at the potential diagnostic role of exhaled CO in major inflammatory states of the lung, and finally we will highlight the activities on inhaled CO being considered as a possible therapeutic tool and the controversies surrounding it.
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Affiliation(s)
- Subhamay Ghosh
- Department of Anaesthesiology and Intensive Therapy, University of Pecs, 7624 Pecs, Hungary.
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18
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Sandrini A, Taylor DR, Thomas PS, Yates DH. Fractional exhaled nitric oxide in asthma: an update. Respirology 2009; 15:57-70. [PMID: 19761537 DOI: 10.1111/j.1440-1843.2009.01616.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
In asthma, clinical symptoms and lung function are insensitive in reflecting the underlying airway inflammation, and monitoring of this process has only recently become available. Fractional exhaled nitric oxide (Fe(NO)) is now recognized as a reliable surrogate marker of eosinophilic airway inflammation and offers the advantage of being completely non-invasive and very easy to obtain. This review summarizes the clinical use of Fe(NO) in asthma. It covers the relationship between Fe(NO) and the underlying eosinophilic inflammation, the pathophysiology and production of Fe(NO), technical aspects of Fe(NO) measurement and potential confounding factors in interpreting levels. Fe(NO) reference values and the role of Fe(NO) in asthma assessment, diagnosis and management are also discussed.
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Affiliation(s)
- Alessandra Sandrini
- Department of Thoracic Medicine, St Vincent's Hospital, Sydney, NSW 2010, Australia
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19
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Chow S, Campbell C, Sandrini A, Thomas PS, Johnson AR, Yates DH. Exhaled breath condensate biomarkers in asbestos-related lung disorders. Respir Med 2009; 103:1091-7. [PMID: 19520561 DOI: 10.1016/j.rmed.2009.04.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2008] [Revised: 04/02/2009] [Accepted: 04/02/2009] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Asbestos induces generation of reactive oxygen and nitrogen species in laboratory studies. Several such species can be measured non-invasively in humans in exhaled breath condensate (EBC) but few have been evaluated. This study aimed to assess oxidative stress and lung inflammation in vivo. METHODS Eighty six men were studied: sixty subjects with asbestos-related disorders (asbestosis: 18, diffuse pleural thickening (DPT): 16, pleural plaques (PPs): 26) and twenty six age- and gender-matched normal individuals. RESULTS Subjects with asbestosis had raised EBC markers of oxidative stress compared with normal controls [8-isoprostane (geometric mean (95% CI) 0.51 (0.17-1.51) vs 0.07 (0.04-0.13) ng/ml, p<0.01); hydrogen peroxide (13.68 (8.63-21.68) vs 5.89 (3.99-8.69) microM, p<0.05), as well as increased EBC total protein (17.27 (10.57-28.23) vs 7.62 (5.13-11.34) microg/ml, p<0.05), and fractional exhaled nitric oxide (mean+/-SD) (9.67+/-3.26 vs 7.57+/-1.89ppb; p<0.05). EBC pH was lower in subjects with asbestosis compared with subjects with DPT (7.26+/-0.31 vs 7.53+/-0.24; p<0.05). There were no significant differences in exhaled carbon monoxide, EBC total nitrogen oxides and 3-nitrotyrosine between any of the asbestos-related disorders, or between these and controls. CONCLUSION In asbestos-related disorders, markers of inflammation and oxidative stress are significantly elevated in subjects with asbestosis compared with healthy individuals but not in pleural diseases.
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Affiliation(s)
- Sharron Chow
- Research and Education Unit, Workers' Compensation (Dust Diseases) Board of New South Wales, Sydney, Australia
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20
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de Amorim CG, Malbouisson LMS, Saraiva BM, Pedro FMDS, Martins MA, Carmona MJC. Evaluation of Exhaled Nitric Oxide in Patients Undergoing Myocardial Revascularization with Cardiopulmonary Bypass. Rev Bras Anestesiol 2009; 59:286-96. [DOI: 10.1590/s0034-70942009000300003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2007] [Accepted: 01/20/2009] [Indexed: 11/21/2022] Open
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Martínez-Lozano P, Fernández de la Mora J. Direct analysis of fatty acid vapors in breath by electrospray ionization and atmospheric pressure ionization-mass spectrometry. Anal Chem 2008; 80:8210-5. [PMID: 18821733 DOI: 10.1021/ac801185e] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Real time analysis of human breath is achieved in an atmospheric pressure ionization mass spectrometer (API-MS) by negatively charging exhaled vapors via contact with an electrospray cloud. The spectrum observed is dominated by a wide range of deprotonated fatty acids, including saturated chains up to C14. Above C14, the background from cutaneous sources becomes dominant. We also tentatively identify a series of unsaturated fatty acids (C7-C10), ketomonocarboxylic acids (C6-C10), and a family of aldehydes. The ionization probability of large fatty acids increases drastically when the humidity changes from 20% to 95%. Accordingly, distinguishing lung vapors (humid) from those in the background (dry) requires special precautions. Estimated fatty acid vapor concentrations in breath based on our measurements ( approximately 100 ppt) are in fair agreement with values expected from blood concentrations in the range for which data are available (C3-C6).
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Abstract
Asthma is a chronic inflammatory disease that affects about 300 million people worldwide, a total that is expected to rise to about 400 million over the next 15-20 years. Most asthmatic individuals respond well to the currently available treatments of inhaled corticosteroids and beta-adrenergic agonists; however, 5-10% have severe disease that responds poorly. Improved knowledge of asthma mechanisms has led to the recognition of different asthma phenotypes that might reflect distinct types of inflammation, explaining the effectiveness of anti-leucotrienes and the anti-IgE monoclonal antibody omalizumab in some patients. However, more knowledge of the inflammatory mechanisms within the airways is required. Improvements in available therapies-such as the development of fast-onset, once-a-day combination drugs with better safety profiles-will occur. Other drugs, such as inhaled p38 MAPK inhibitors and anti-oxidants, that target specific pathways or mediators could prove useful as monotherapies, but could also, in combination with corticosteroids, reduce the corticosteroid insensitivity often seen in severe asthma. Biological agents directed against the interleukin-13 pathway and new immunoregulatory agents that modulate functions of T-regulatory and T-helper-17 cells are likely to be successful. Patient-specific treatments will depend on the development of discriminatory handprints of distinct asthma subtypes and are probably over the horizon. Although a cure is unlikely to be developed in the near future, a greater understanding of disease mechanisms could bring such a situation nearer to reality.
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Affiliation(s)
- Ian M Adcock
- Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK
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Lara A, Khatri SB, Wang Z, Comhair SAA, Xu W, Dweik RA, Bodine M, Levison BS, Hammel J, Bleecker E, Busse W, Calhoun WJ, Castro M, Chung KF, Curran-Everett D, Gaston B, Israel E, Jarjour N, Moore W, Peters SP, Teague WG, Wenzel S, Hazen SL, Erzurum SC. Alterations of the arginine metabolome in asthma. Am J Respir Crit Care Med 2008; 178:673-81. [PMID: 18635886 DOI: 10.1164/rccm.200710-1542oc] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE As the sole nitrogen donor in nitric oxide (NO) synthesis and key intermediate in the urea cycle, arginine and its metabolic pathways are integrally linked to cellular respiration, metabolism, and inflammation. OBJECTIVES We hypothesized that arginine (Arg) bioavailability would be associated with airflow abnormalities and inflammation in subjects with asthma, and would be informative for asthma severity. METHODS Arg bioavailability was assessed in subjects with severe and nonsevere asthma and healthy control subjects by determination of plasma Arg relative to its metabolic products, ornithine and citrulline, and relative to methylarginine inhibitors of NO synthases, and by serum arginase activity. Inflammatory parameters, including fraction of exhaled NO (Fe(NO)), IgE, skin test positivity to allergens, bronchoalveolar lavage, and blood eosinophils, were also evaluated. MEASUREMENTS AND MAIN RESULTS Subjects with asthma had greater Arg bioavailability, but also increased Arg catabolism compared with healthy control subjects, as evidenced by higher levels of Fe(NO) and serum arginase activity. However, Arg bioavailability was positively associated with Fe(NO) only in healthy control subjects; Arg bioavailability was unrelated to Fe(NO) or other inflammatory parameters in severe or nonsevere asthma. Inflammatory parameters were related to airflow obstruction and reactivity in nonsevere asthma, but not in severe asthma. Conversely, Arg bioavailability was related to airflow obstruction in severe asthma, but not in nonsevere asthma. Modeling confirmed that measures of Arg bioavailabilty predict airflow obstruction only in severe asthma. CONCLUSIONS Unlike Fe(NO), Arg bioavailability is not a surrogate measure of inflammation; however, Arg bioavailability is strongly associated with airflow abnormalities in severe asthma.
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Affiliation(s)
- Abigail Lara
- Department of Pathobiology, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
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Fayon M, Chiron R, Abely M. Mesure de l’inflammation pulmonaire dans la mucoviscidose. Rev Mal Respir 2008; 25:705-24. [DOI: 10.1016/s0761-8425(08)73800-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF. Steroid resistance in asthma: mechanisms and treatment options. Curr Allergy Asthma Rep 2008; 8:171-8. [PMID: 18417060 DOI: 10.1007/s11882-008-0028-4] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Glucocorticoid insensitivity presents a profound management problem in patients with asthma because conventional therapies are not effective. Glucocorticoids, acting through the glucocorticoid receptor (GR), are able to selectively repress inflammatory gene expression by utilizing several distinct mechanisms targeting nuclear factor-varphiB and activator protein-1 activation complexes and by effects on mitogen-activated protein kinases. Different model systems often activate distinct sets of signaling molecules and different glucocorticoid responsiveness may result from differences in concentrations and timing of steroid treatment of cells, GR expression levels, and the precise inflammatory stimulus used. Thus, abnormal activation of many signaling pathways may affect corticosteroid responsiveness in patients with corticosteroid-resistant asthma. Understanding the molecular mechanisms of GR action and inaction may lead to the development of new anti-inflammatory drugs or enable clinicians to reverse the relative steroid-insensitivity that is characteristic of some patients with severe asthma.
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Affiliation(s)
- Ian M Adcock
- Cell and Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
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26
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Fumagalli M, Dolcini L, Sala A, Stolk J, Fregonese L, Ferrari F, Viglio S, Luisetti M, Iadarola P. Proteomic analysis of exhaled breath condensate from single patients with pulmonary emphysema associated to alpha1-antitrypsin deficiency. J Proteomics 2008; 71:211-21. [PMID: 18617147 DOI: 10.1016/j.jprot.2008.03.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2008] [Revised: 03/11/2008] [Accepted: 03/11/2008] [Indexed: 11/19/2022]
Abstract
The non-invasive character of exhaled breath (EBC) collection makes this fluid attractive for monitoring the respiratory tract by the measurement of various compounds. Because EBC is likely to reflect the composition of the airway-lining fluid, it can provide valuable information on possible disease states. Aim of our study was to apply proteomic technology to the study of EBC samples collected from single patients with pulmonary emphysema associated to alpha(1)-antitrypsin deficiency. The protein profiles from EBC of twenty patients and of twenty-five healthy individuals, used as controls, have been analyzed in parallel by a combination of 1-DE, 2-DE, micro-HPLC and MS. These sensitive techniques allowed to identify a number of cytokines and cytokeratins. Their level was found to be higher in patients than in controls.
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Affiliation(s)
- Marco Fumagalli
- Dipartimento di Biochimica A. Castellani, Università di Pavia, Italy
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27
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Lionberger RA. FDA critical path initiatives: opportunities for generic drug development. AAPS J 2008; 10:103-9. [PMID: 18446510 PMCID: PMC2751455 DOI: 10.1208/s12248-008-9010-2] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2007] [Accepted: 01/17/2008] [Indexed: 11/30/2022] Open
Abstract
FDA's critical path initiative documents have focused on the challenges involved in the development of new drugs. Some of the focus areas identified apply equally to the production of generic drugs. However, there are scientific challenges unique to the development of generic drugs as well. In May 2007, FDA released a document "Critical Path Opportunities for Generic Drugs" that identified some of the specific challenges in the development of generic drugs. The key steps in generic product development are usually characterization of the reference product, design of a pharmaceutically equivalent and bioequivalent product, design of a consistent manufacturing process and conduct of the pivotal bioequivalence study. There are several areas of opportunity where scientific progress could accelerate the development and approval of generic products and expand the range of products for which generic versions are available, while maintaining high standards for quality, safety, and efficacy. These areas include the use of quality by design to develop bioequivalent products, more efficient bioequivalence methods for systemically acting drugs (expansion of BCS waivers, highly variable drugs), and development of new bioequivalence methods for locally acting drugs.
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Affiliation(s)
- Robert A Lionberger
- Office of Generic Drugs, Food and Drug Administration, 7519 Standish Place, Rockville, Maryland 20850, USA.
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28
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Paro-Heitor MLZ, Bussamra MHCF, Saraiva-Romanholo BM, Martins MA, Okay TS, Rodrigues JC. Exhaled nitric oxide for monitoring childhood asthma inflammation compared to sputum analysis, serum interleukins and pulmonary function. Pediatr Pulmonol 2008; 43:134-41. [PMID: 18085692 DOI: 10.1002/ppul.20747] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The level of fractional exhaled nitric oxide (FENO) is significantly elevated in uncontrolled asthma and decreases after anti-inflammatory therapy. The aim of this prospective study was to analyze the behavior of FENO in the follow-up and management of the inflammation in asthmatic pediatric patients treated with inhaled corticosteroids (ICS), compared to sputum cellularity, serum interleukins (IL), and pulmonary function. Twenty-six clinically stable asthmatic children aged from 6 to 18 years, previously treated or not with ICS were included. Following an international consensus (GINA), the patients were submitted to standard treatment with inhaled fluticasone for 3 months according to the severity of the disease. During this period, each patient underwent three assessments at intervals of approximately 6 weeks. Each evaluation consisted of the measurement of FENO, determination of serum interleukins IL-5, IL-10, IL-13, and interferon gamma (INF-gamma), spirometry and cytological analysis of spontaneous or induced sputum. A significant reduction in mean FENO and IL-5, without concomitant changes in FEV1, was observed along the study. There was no significant correlation between FeNO and FEV1 in the three assessments. A significant correlation between FeNO and IL-5 levels was only observed in the third assessment (r = 0.499, P = 0.025). In most patients, serum IL-10, IL-13, and INF-gamma concentrations were undetectable throughout the study. Sputum samples were obtained spontaneously in 11 occasions and in 56 by induction with 3% hypertonic saline solution (success rate: 50.8%), with 39 (69.9%) of them adequate for analysis. Only two of the 26 patients produced adequate samples in the three consecutive evaluations, which impaired the determination of a potential association between sputum cellularity and FeNO levels throughout the study. In conclusion, among the parameters of this study, it was difficult to perform and to interpret the serial analysis of spontaneous or induced sputum. Serum interleukins, which remained at very low or undetectable levels in most patients, were not found to be useful for therapeutic monitoring, except for IL-5 that seems to present some correlation with levels of FeNO exhaled. Monitoring of the mean FEV1 indicated no significant variations during the treatment, demonstrating that functional stability or the absence of obstruction may not reflect the adequate management of asthma. Serial measurement of FeNO seemed to best reflect the progressive anti-inflammatory action of ICS in asthma.
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Affiliation(s)
- Maria Luisa Z Paro-Heitor
- Department of Pediatrics, Pediatric Pulmonology Unit, Instituto da Criança, Hospital das Clinicas, School of Medicine, University of São Paulo, São Paulo, Brazil
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Jones E, Adcock IM, Ahmed BY, Punchard NA. Modulation of LPS stimulated NF-kappaB mediated Nitric Oxide production by PKCepsilon and JAK2 in RAW macrophages. J Inflamm (Lond) 2007; 4:23. [PMID: 18036230 PMCID: PMC2211292 DOI: 10.1186/1476-9255-4-23] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2007] [Accepted: 11/24/2007] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Nuclear factor kappa B (NF-kappaB) has been shown to play an important role in regulating the expression of many genes involved in cell survival, immunity and in the inflammatory processes. NF-kappaB activation upregulates inducible nitric oxide synthase leading to enhanced nitric oxide production during an inflammatory response. NF-kappaB activation is regulated by distinct kinase pathways independent of inhibitor of kappaB kinase (IKK). Here, we examine the role of protein kinase C isoforms and janus activated kinase 2 (JAK2) activation in NF-kappaB activation and LPS-stimulated NO production. METHODS Murine RAW 264.7 macrophages were treated with lipopolysaccharide (LPS), Phorbol 12-myristate 13-acetate (PMA) and a combination of LPS and PMA in the presence or absence of various inhibitors of PKC isoforms and JAK2. Nuclear translocation of the NF-kappaB p65 subunit, was assessed by Western blot analysis whilst NO levels were assessed by Greiss assay. RESULTS LPS-stimulated NO production was attenuated by PMA whilst PMA alone did not affect NO release. These effects were associated with changes in p65 nuclear translocation. The PKCalpha, beta, gamma, delta and zeta inhibitor Gö 6983 (Go) had no effect on LPS-induced NO release. In contrast, Bisindolymalemide I (Bis), a PKC alpha, betaI, betaII, gamma, delta and epsilon isoform inhibitors completely inhibited LPS-stimulated NO production without affecting p65 nuclear translocation. Furthermore, a partial inhibitory effect on LPS-induced NO release was seen with the JAK2 inhibitor AG-490 and the p38 MAPK inhibitor SB 203850. CONCLUSION The results further define the role of NF-kappaB in LPS stimulated NO production in RAW macrophages. The data support a function for PKCepsilon, JAK2 and p38 MAPK in NF-kappaB activation following p65 nuclear import.
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Affiliation(s)
- Edward Jones
- Division of Science, University of Luton, Luton. UK
| | - Ian M Adcock
- Airway Diseases, NHLI, Imperial College London, London. UK
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Arab S, Liu PP, Emili A. Lost in translation: five grand challenges for proteomic biomarker discovery. EXPERT OPINION ON MEDICAL DIAGNOSTICS 2007; 1:325-336. [PMID: 23489353 DOI: 10.1517/17530059.1.3.325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
The biomedical community has the imperative to develop reliable, clinically relevant and generalizable bioassays that can be used to accurately recognize those individuals with early-stage disease or those patients who will respond to therapy, with the ultimate aim of achieving individualized medicine. In recent years, increasingly sophisticated proteomic screening technologies have been introduced, providing the biomedical community with a valuable new approach for the systematic discovery and validation of novel diagnostic, prognostic and therapeutic tools. Nevertheless, the complexity of the cellular milieu wherein a variety of macromolecules interact in dynamic fashion, combined with the complex clinical manifestation of chronic pathologies and widespread diversity of patient populations, mean that universal biomarkers will not be easily developed. In this review, the five key challenges that must be surmounted in order to advance the clinical impact of this nascent field are described, and plausible solutions based on the authors' own ongoing proteomic profiling of cardiovascular disease is outlined.
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Affiliation(s)
- Sara Arab
- University of Toronto, Toronto General Hospital, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada
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31
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Casado B, Iadarola P, Pannell LK, Luisetti M, Corsico A, Ansaldo E, Ferrarotti I, Boschetto P, Baraniuk JN. Protein Expression in Sputum of Smokers and Chronic Obstructive Pulmonary Disease Patients: A Pilot Study by CapLC-ESI-Q-TOF. J Proteome Res 2007; 6:4615-23. [DOI: 10.1021/pr070440q] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Begoña Casado
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Paolo Iadarola
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Lewis K. Pannell
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Maurizio Luisetti
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Angelo Corsico
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Elena Ansaldo
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Ilaria Ferrarotti
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - Piera Boschetto
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
| | - James N. Baraniuk
- Dipartimento di Biochimica “A. Castellani”, Universitaʼ di Pavia, Italy, Division of Rheumatology, Immunology and Allergy, Georgetown University Proteomics Laboratory, Washington, DC 20057, Cancer Research Institute, University of South Alabama, Mobile, AL 36688, Laboratorio di Biochimica e Genetica, Clinica di Malattie dellʼApparato Respiratorio, Fondazione IRCCS Policlinico San Matteo, Universitaʼdi Pavia, Italy, and Dipartimento di Medicina Clinica e Sperimentale, Sezione di Igiene e Medicina del
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Ichikawa T, Matsunaga K, Minakata Y, Yanagisawa S, Ueshima K, Akamatsu K, Hirano T, Nakanishi M, Sugiura H, Yamagata T, Ichinose M. Possible Impact of Salivary Influence on Cytokine Analysis in Exhaled Breath Condensate. ANALYTICAL CHEMISTRY INSIGHTS 2007. [DOI: 10.4137/117739010700200007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Background Exhaled breath condensate (EBC) is thought to contain substances of the lower airway epithelial lining fluid (ELF) aerosolized by turbulent flow. However, contamination by saliva may affect the EBC when collected orally. Objective The purpose of this study was to compare the cytokine expression levels in EBC with those in saliva, and to clarify the influence of saliva on cytokine measurements of EBC. Methods EBC and saliva samples were obtained from 10 adult subjects with stable asthma. To estimate differences in the contents of substances between EBC and saliva, the total protein concentration of each sample was measured. Further, we also measured the total protein concentration of ELF obtained from another patient group with suspected lung cancer using a micro sampling probe during bronchoscopic examination and roughly estimated the dilution of EBC by comparing the total protein concentration of EBC and ELF from those two patient groups. The cytokine expression levels of EBC and saliva from asthmatic group were assessed by a cytokine protein array. Results The mean total protein concentrations in EBC, saliva and ELF were 4.6 μg/ml, 2,398 μg/ml and 14,111 μg/ml, respectively. The dilution of EBC could be estimated as 1:3000. Forty cytokines were analyzed by a cytokine protein array and each cytokine expression level of EBC was found to be different from that of saliva. Corrected by the total protein concentration, all cytokine expression levels of EBC were significantly higher than those of saliva. Conclusion These results suggest that the salivary influence on the cytokine assessment in EBC may be negligible.
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Affiliation(s)
- T. Ichikawa
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - K. Matsunaga
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - Y. Minakata
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - S. Yanagisawa
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - K. Ueshima
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - K. Akamatsu
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - T. Hirano
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - M. Nakanishi
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - H. Sugiura
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - T. Yamagata
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
| | - M. Ichinose
- The Third Department of Internal Medicine, Wakayama Medical University, School of Medicine, Wakayama, Japan
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Menzies D, Nair A, Lipworth BJ. Non-invasive measurement of airway inflammation in asthma. J Asthma 2006; 43:407-15. [PMID: 16952856 DOI: 10.1080/02770900600758218] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Assessing the severity and control of a patient's asthma is of great importance to ensure that pharmacotherapy is optimized. Measures such as lung function, symptoms, and reliever use have traditionally been used as objective means of undertaking this assessment, but until now the level of airway inflammation has not been quantified. As asthma is primarily an inflammatory disorder, it would be desirable to include a measure of this process when evaluating disease control. The following article outlines methods of non-invasively measuring asthmatic airway inflammation and highlights their potential role in clinical practice.
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Affiliation(s)
- Daniel Menzies
- Department of Medicine and Therapeutics, Asthma & Allergy Research Group, Ninewells Hospital and Perth Royal Infirmary, University of Dundee, Scotland, UK.
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Abstract
Asthma is a chronic inflammatory disease involving many different cell types and cellular elements. Evidence suggests that, in the long term, this inflammation leads to remodeling of the airways, airflow obstruction, and the bronchial hyperreactivity symptoms of asthma, and is present even in patients with intermittent disease. Patients with allergic asthma and those with seasonal allergic rhinitis are believed to have minimal persistent inflammation, and the two diseases often occur together. Early intervention with inhaled corticosteroids (ICS) is believed to modify the disease process and may limit long-term remodeling. ICS remain the cornerstone and "gold standard" of treatment for asthma.
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Affiliation(s)
- G Walter Canonica
- Allergy and Respiratory Diseases, DIMI, Department of Internal Medicine, University of Genoa, Genoa, Italy.
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Currie GP, Lee DKC, Menzies D, Lipworth BJ. Evaluating the effects of "triple therapy" with inhaled corticosteroids, long-acting beta2-agonists, and leukotriene modifiers in asthma. Chest 2006; 130:301-2. [PMID: 16840420 DOI: 10.1378/chest.130.1.301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Cockcroft DW. Deep inhalation bronchodilation and oral corticosteroids in asthma. Chest 2006; 130:7-8. [PMID: 16840374 DOI: 10.1378/chest.130.1.7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
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Bhandari V, Choo-Wing R, Chapoval SP, Lee CG, Tang C, Kim YK, Ma B, Baluk P, Lin MI, McDonald DM, Homer RJ, Sessa WC, Elias JA. Essential role of nitric oxide in VEGF-induced, asthma-like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci U S A 2006; 103:11021-6. [PMID: 16832062 PMCID: PMC1544167 DOI: 10.1073/pnas.0601057103] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2006] [Indexed: 12/30/2022] Open
Abstract
VEGF, nitric oxide (NO), inflammation, and vascular- and extravascular remodeling coexist in asthma and other disorders. In these responses, VEGF regulates angiogenesis. VEGF also induces inflammation and remodeling. The mechanisms of the latter responses have not been defined, however. We hypothesized that VEGF-induces extravascular tissue responses via NO-dependent mechanisms. To evaluate this hypothesis, we compared the effects of transgenic VEGF165 in lungs from normal mice, mice treated with pan-NO synthase (NOS) or endothelial NOS (eNOS) inhibitors, and mice with null mutations of inducible NOS (iNOS) or eNOS. These studies demonstrate that VEGF selectively stimulates eNOS and iNOS. They also demonstrate that VEGF induces pulmonary alterations via NO-dependent and -independent mechanisms with angiogenesis, edema, mucus metaplasia, airway hyperresponsiveness, lymphocyte accumulation, dendritic cell hyperplasia and S-nitrosoglutathione reductase stimulation being NO-dependent and dendritic cell activation being NO-independent. Furthermore, they demonstrate that eNOS and iNOS both contribute to these responses. NO/NOS-based interventions may be therapeutic in VEGF-driven inflammation and remodeling.
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Affiliation(s)
- Vineet Bhandari
- *Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, LCI 401-B, New Haven, CT 06520-8057
| | - Rayman Choo-Wing
- *Division of Perinatal Medicine, Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, LCI 401-B, New Haven, CT 06520-8057
| | - Svetlana P. Chapoval
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057
| | - Chun G. Lee
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057
| | - C. Tang
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057
| | - Y. K. Kim
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057
| | - Bing Ma
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057
| | - Peter Baluk
- Cardiovascular Research Institute, Department of Anatomy and Comprehensive Cancer Center, University of California, 513 Paramus Avenue, San Francisco, CA 94143-0130
| | - Michelle I. Lin
- Department of Pharmacology, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, Room 436, New Haven, CT 06520-8057; and
| | - Donald M. McDonald
- Cardiovascular Research Institute, Department of Anatomy and Comprehensive Cancer Center, University of California, 513 Paramus Avenue, San Francisco, CA 94143-0130
| | - Robert J. Homer
- Department of Pathology, Yale University School of Medicine, 310 Cedar Street, New Haven, CT 06520-8057
| | - William C. Sessa
- Department of Pharmacology, Yale University School of Medicine, Boyer Center for Molecular Medicine, 295 Congress Avenue, Room 436, New Haven, CT 06520-8057; and
| | - Jack A. Elias
- Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, 441-C TAC, New Haven, CT 06520-8057
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Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006; 117:522-43. [PMID: 16522450 DOI: 10.1016/j.jaci.2006.01.032] [Citation(s) in RCA: 278] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2006] [Revised: 01/25/2006] [Accepted: 01/25/2006] [Indexed: 12/11/2022]
Abstract
Extensive development of inhaled and oral glucocorticoids has resulted in highly potent molecules that have been optimized to target activity to the lung and minimize systemic exposure. These have proved highly effective for most asthmatic subjects, but despite these developments, there are a number of subjects with asthma who fail to respond to even high doses of inhaled or even oral glucocorticoids. Advances in delineating the fundamental mechanisms of glucocorticoid pharmacology, especially the concepts of transactivation and transrepression and cofactor recruitment, have resulted in better understanding of the molecular mechanisms whereby glucocorticoids suppress inflammation. The existence of multiple mechanisms underlying glucocorticoid insensitivity raises the possibility that this might indeed reflect different diseases with a common phenotype, and studies examining the efficacy of potential new agents should be targeted toward subgroups of patients with severe corticosteroid-resistant asthma who clearly require effective new drugs and other approaches to improved asthma control.
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Affiliation(s)
- Kazuhiro Ito
- Cell and Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Imperial College London, UK
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Antoniu SA. Infliximab for chronic obstructive pulmonary disease: towards a more specific inflammation targeting? Expert Opin Investig Drugs 2006; 15:181-4. [PMID: 16433597 DOI: 10.1517/13543784.15.2.181] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is a predominantly smoking-related condition in which chronic progressive airways obstruction results because of inflammation that is triggered and maintained by the causative agent and enhanced during exacerbations. Inflammation is dominated by neutrophils, and macrophages and their mediators. TNF-alpha is a proinflammatory cytokine involved in COPD pathogenesis. Treatment of the stable disease is mainly inhalatory with anticholinergics, beta(2) agonsists and inhaled corticosteroids being involved in various stages of the disease. Novel therapeutic agents are currently under investigation for COPD treatment and some of them target various inflammation mediators. Infliximab is a monoclonal anti-TNF-alpha antibody with demonstrated efficacy in other autoimmune diseases, such as Crohn's disease and rheumatoid arthritis. The current study assesses the scientific rationale for the use of infliximab in COPD patients.
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Murphy TF. The role of bacteria in airway inflammation in exacerbations of chronic obstructive pulmonary disease. Curr Opin Infect Dis 2006; 19:225-30. [PMID: 16645482 DOI: 10.1097/01.qco.0000224815.89363.15] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Bacteria cause approximately half of all chronic obstructive pulmonary disease exacerbations. The purpose of this review is to evaluate the status of research on the role of bacteria in airway inflammation during exacerbations and the mechanisms by which bacterial antigens induce inflammation. RECENT FINDINGS Bacteria in the airways of adults with chronic obstructive pulmonary disease release antigens including endotoxin, peptidoglycan fragments, lipoproteins, and other molecules into the airways. These bacterial antigens induce potent inflammatory effects in the airways. Bacterial exacerbations are associated with systemic inflammation. Studies of Haemophilus influenzae, the most common bacterial cause of exacerbations, reveal that strains associated with exacerbations induce more inflammation compared to colonizing strains. H. influenzae antigens induce production of interleukin-8 and tumor necrosis factor-alpha, activate Toll-like 2 receptors, activate NFkappaB and p38 mitogen-activated protein signaling pathways, and have other inflammatory effects. SUMMARY Research on the role of bacteria in causing inflammation in chronic obstructive pulmonary disease has been neglected for decades. Research should be directed at further evaluating the role of bacterial antigens in airway inflammation. Reducing or modulating bacterial infection of the airways in chronic obstructive pulmonary disease has the potential to reduce airway inflammation by eliminating an important inciting cause.
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Affiliation(s)
- Timothy F Murphy
- Division of Infectious Diseases, University at Buffalo, State University of New York and Veterans Affairs Western New York Healthcare System, Buffalo, New York, USA.
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Fabbri LM, Luppi F, Beghé B, Rabe KF. Update in Chronic Obstructive Pulmonary Disease 2005. Am J Respir Crit Care Med 2006; 173:1056-65. [PMID: 16679444 DOI: 10.1164/rccm.2603005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
- Leonardo M Fabbri
- Department of Respiratory Diseases, University of Modena and Reggio Emilia, Via del Pozzo 71, 41100 Modena, Italy.
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Freiler JF, Arora R, Kelley TC, Hagan L, Allan PF. Randomized placebo controlled assessment of airway inflammation due to racemic albuterol and levalbuterol via exhaled nitric oxide testing. Int J Chron Obstruct Pulmon Dis 2006; 1:461-6. [PMID: 18044102 PMCID: PMC2707806 DOI: 10.2147/copd.2006.1.4.461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
STUDY OBJECTIVES The S-stereoisomer found in racemic albuterol may have associated proinflammatory properties. We tested the hypothesis that airway inflammation as assessed by exhaled nitric oxide is no different in patients with COPD when using racemic albuterol relative to levalbuterol or placebo. MEASUREMENTS Twelve mild to moderate COPD patients were assigned to five days each of nebulized racemic albuterol, levalbuterol, and saline placebo. Before and after each course of treatment, airway inflammation was assessed via exhaled nitric oxide breath testing. Secondary functional outcomes that were measured included spirometry, a functional assessment utilizing a six-minute walk, and symptoms score using the University of California, San Diego Shortness of Breath Questionnaire. RESULTS There was no statistically significant difference in pre and post FeNO levels within and between treatment groups (p = 0.121). There were also no significant differences within or between treatment groups for the secondary outcome measurements of FEV1 (p = 0.913), functional assessment utilizing a six-minute walk (p = 0.838) and the symptom scores using Shortness of Breath Questionnaire (p = 0.500). CONCLUSION We found no difference in mild to moderate COPD patients treated with racemic albuterol, levalbuterol or placebo for measurement of exhaled nitric oxide or the secondary outcomes that were measured.
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Affiliation(s)
- John F Freiler
- USAF, Department of Allergy/Immunology, Travis AFB, CA 94535, USA.
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