Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis

Berry, Michael A.; Parker, Debbie; Neale, Natalie; Woodman, Lucy; Morgan, Angela; Monk, Phillip; Bradding, Peter; Wardlaw, Andrew J.; Pavord, Ian D.; Brightling, Christopher E.

doi:10.1016/j.jaci.2004.08.032

Cited by 147 publications

(115 citation statements)

References 20 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…Our previous studies revealed that interleukin-13 (IL-13), one of the major cytokines upregulated in the airways of asthmatics (35,36), is capable of induction of RhoA protein upregulation in hBSMCs (37,38) and of induction of airway hyperresponsiveness in naive mice (37). IL-13 also caused an upregulation of RhoA mRNA and a downregulation of miR-133a in hBSMCs (32).…”

Section: Negative Regulation Of Rhoa Expression By Mir133a In Bsmmentioning

confidence: 99%

MicroRNAs and Their Therapeutic Potential for Human Diseases: MiR-133a and Bronchial Smooth Muscle Hyperresponsiveness in Asthma

Chiba

Misawa

2010

J Pharmacol Sci

View full text Add to dashboard Cite

Abstract. MicroRNAs (miRNAs) play important roles in normal and diseased cell functions. The small-GTPase RhoA is one of the key proteins of bronchial smooth muscle (BSM) contraction, and an upregulation of RhoA has been demonstrated in BSMs of experimental asthma. Although the mechanism of RhoA upregulation in the diseased BSMs is not fully understood, recent observations suggest that RhoA translation is controlled by a miRNA, miR-133a, in cardiomyocytes. Similarly, in human BSM cells (hBSMCs), our recent studies revealed that an upregulation of RhoA was induced when the function of endogenous miR-133a was inhibited by its antagomir. Treatment of hBSMCs with interleukin-13 (IL-13) caused an upregulation of RhoA and a downregulation of miR-133a. In a mouse model of allergic bronchial asthma, increased expression of IL-13 and RhoA and the BSM hyperresponsiveness were observed. The level of miR-133a was significantly decreased in BSMs of the diseased animals. These findings suggest that RhoA expression is negatively regulated by miR-133a in BSMs and that the miR-133a downregulation causes an upregulation of RhoA, resulting in an augmentation of the contraction. MiR-133a might be a key regulator of BSM hyperresponsiveness and provide us with new insight into the treatment of airway hyperresponsiveness in asthmatics.

show abstract

Section: Negative Regulation Of Rhoa Expression By Mir133a In Bsmmentioning

confidence: 99%

MicroRNAs and Their Therapeutic Potential for Human Diseases: MiR-133a and Bronchial Smooth Muscle Hyperresponsiveness in Asthma

Chiba

Misawa

2010

J Pharmacol Sci

View full text Add to dashboard Cite

show abstract

“…Asthma is an eosinophilic inflammatory disease of the airways characterized by increased airway responsiveness to various stimuli, causing chronic inflammation and as a consequence airway remodeling (Juniper et al 2002). Unlike asthma, EB characteristically manifests as chronic cough and sputum eosinophilia without airflow limitation or airway hyperresponsiveness (Gibson et al 1989;Brightling et al 2003;Berry et al 2004). Likewise, the main pathophysiology of AR is nasal mucosal eosinophilic inflammation (Greiff et al 1999;Nielsen et al 2009).…”

Section: Introductionmentioning

confidence: 99%

Expression Levels of Eosinophil Granule Protein mRNAs in Induced Sputum Reflect Airway Hyperresponsiveness and Airflow Limitation

Jung

Kang

Lee

et al. 2014

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Eosinophils are regarded as the major effector cells that produce symptoms in allergic diseases. Activation of eosinophils induces extracellular release of a number of eosinophil granule proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and eosinophilderived neurotoxin. The objective of this study was to evaluate the differences and significance of the sputum eosinophil% and expression levels of eosinophilic granule protein mRNAs in allergic airway disease. Induced sputum samples were obtained from non-smokers with 25 asthma, 54 eosinophilic bronchitis, 16 allergic rhinitis, and 19 healthy control subjects. The eosinophil granule protein mRNAs were measured with real time RT-PCR. There was no correlation between the sputum eosinophil% and the mRNA level of any of eosinophil granule proteins. However, the expression levels of MBP and ECP mRNAs were higher in subjects with each of the specified allergic diseases than those in control subjects (P < 0.05). Moreover, in the subjects with allergic sensitization, the expression levels of MBP and EPO mRNAs were significantly higher in those with airway hyperresponsiveness (13 subjects) than in those without airway hyperresponsiveness (32 subjects) (P = 0.004 and 0.010, respectively). In asthma patients, the FEV1% was negatively correlated with ECP mRNA levels (r = −0.510, P = 0.022), but showed no correlation with sputum eosinophil%. In conclusion, mRNA levels of eosinophil granule proteins, rather than sputum eosinophil%, may reflect airway hyperresponsiveness and airflow limitation. In practice, consideration for the eosinophil% as well as the eosinophil granule proteins levels in induced sputum is needed.

show abstract

“…Elevated IL-13 production has been detected in the airways and sputum of patients with asthma [7,8], and mast cell-derived IL-13 (as well as IL-4) has been demonstrated in airway smooth muscle of patients with asthma [5,9]. Animal model data show that IL-13 causes AHR, eosinophilic inflammation and mucus hypersecretion [6,[10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

An open‐label, single‐dose bioavailability study of the pharmacokinetics of CAT‐354 after subcutaneous and intravenous administration in healthy males

Oh¹,

Faggioni²,

Jin³

et al. 2010

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The safety profile and effective dose of CAT-354 have been determined with intravenous (i.v.) administration, but no information is available on subcutaneous (s.c.) administration. WHAT THIS STUDY ADDS• This study characterized the pharmacokinetics of CAT-354 following s.c. administration of 150 mg and 300 mg doses, and indicated a bioavailability of approximately 60%. AIMTo assess the bioavailability and pharmacokinetics of CAT-354, an anti-IL-13 human monoclonal IgG4 antibody, following subcutaneous (s.c.) and intravenous (i.v.) administration. METHODSThis was a single-dose, randomized, open-label, parallel-group bioavailability study. Healthy male subjects aged 20-54 years were randomly assigned to one of three dose groups (n = 10/group) to receive CAT-354: 150 mg i.v.; 150 mg s.c. or 300 mg s.c. (two 150 mg injections). Serum pharmacokinetics, adverse events (AEs), vital signs, electrocardiograms and laboratory parameters were assessed. RESULTSCAT-354 showed bioavailability of 62% and 60% after 150 mg and 300 mg s.c. doses, respectively, and linear pharmacokinetics over the dose range tested. Peak serum concentrations in the s.c. groups occurred after 3-9 (median 5) days, with a mean elimination half-life of 19.2 Ϯ 3.1 days (150 mg) and 19.4 Ϯ 3.59 days (300 mg) after s.c. and 21.4 Ϯ 2.46 days after i.v. administration. Volume of distribution at steady state (Vss) was 4960 Ϯ 1440 ml kg -1 after i.v. (slightly greater than plasma volume). Average apparent clearances (CL/F) were 292 Ϯ 82.3 and 307 Ϯ 109 ml day -1 after 150 and 300 mg s.c., respectively; systemic CL of 188 Ϯ 84.0 ml day -1 after i.v. dosing was consistent with endogenous IgG and reticuloendothelial elimination. No severe or serious AEs occurred. Among 40 reported AEs, 25 were headache, sinus disorders/respiratory symptoms and changes in body temperature perception. CONCLUSIONSCAT-354 exhibited bioavailability of approximately 60% when given s.c. to healthy male subjects.

show abstract

Sputum and bronchial submucosal IL-13 expression in asthma and eosinophilic bronchitis

Cited by 147 publications

References 20 publications

MicroRNAs and Their Therapeutic Potential for Human Diseases: MiR-133a and Bronchial Smooth Muscle Hyperresponsiveness in Asthma

MicroRNAs and Their Therapeutic Potential for Human Diseases: MiR-133a and Bronchial Smooth Muscle Hyperresponsiveness in Asthma

Expression Levels of Eosinophil Granule Protein mRNAs in Induced Sputum Reflect Airway Hyperresponsiveness and Airflow Limitation

An open‐label, single‐dose bioavailability study of the pharmacokinetics of CAT‐354 after subcutaneous and intravenous administration in healthy males

Contact Info

Product

Resources

About