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      Contribution of STAT3 to Inflammatory and Fibrotic Diseases and Prospects for its Targeting for Treatment

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          Abstract

          Signal transducer and activator of transcription (STAT) 3 plays a central role in the host response to injury. It is activated rapidly within cells by many cytokines, most notably those in the IL-6 family, leading to pro-proliferative and pro-survival programs that assist the host in regaining homeostasis. With persistent activation, however, chronic inflammation and fibrosis ensue, leading to a number of debilitating diseases. This review summarizes advances in our understanding of the role of STAT3 and its targeting in diseases marked by chronic inflammation and/or fibrosis with a focus on those with the largest unmet medical need.

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          Inflammatory bowel disease.

          Clara Abraham, Judy H Cho, Peter Moses (2010)
          Article 0 comments Cited 866 times – based on 0 reviews     Review now
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            Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial.

            Ian D Pavord, Stephanie Korn, Peter Howarth … (2012)
            Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab. We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506. 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment. Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Inflammatory bowel disease: clinical aspects and established and evolving therapies.

              Daniel Baumgart, William J Sandborn (2007)
              Crohn's disease and ulcerative colitis are two idiopathic inflammatory bowel disorders. In this paper we discuss the current diagnostic approach, their pathology, natural course, and common complications, the assessment of disease activity, extraintestinal manifestations, and medical and surgical management, and provide diagnostic and therapeutic algorithms. We critically review the evidence for established (5-aminosalicylic acid compounds, corticosteroids, immunomodulators, calcineurin inhibitors) and emerging novel therapies--including biological therapies--directed at cytokines (eg, infliximab, adalimumab, certolizumab pegol) and receptors (eg, visilizumab, abatacept) involved in T-cell activation, selective adhesion molecule blockers (eg, natalizumab, MLN-02, alicaforsen), anti-inflammatory cytokines (eg, interleukin 10), modulation of the intestinal flora (eg, antibiotics, prebiotics, probiotics), leucocyte apheresis and many more monoclonal antibodies, small molecules, recombinant growth factors, and MAP kinase inhibitors targeting various inflammatory cells and pathways. Finally, we summarise the practical aspects of standard therapies including dosing, precautions, and side-effects.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: MDPI
                ISSN (Electronic): 1422-0067
                Publication date (Electronic): 05 August 2018
                Publication date Collection: August 2018
                Volume: 19
                Issue: 8
                Electronic Location Identifier: 2299
                Affiliations
                [1 ]Department of Infectious Disease, Infection Control and Employee Health, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; MMKasembeli@ 123456mdanderson.org (M.M.K.); UBharadwaj@ 123456mdanderson.org (U.B.); PRobinson1@ 123456mdanderson.org (P.R.)
                [2 ]Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
                Author notes
                Article
                Publisher ID: ijms-19-02299
                DOI: 10.3390/ijms19082299
                PMC ID: 6121470
                PubMed ID: 30081609
                SO-VID: e2838676-cef5-4724-af2f-494952038031
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 13 June 2018
                Date accepted : 02 August 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: stat3,asthma,inflammatory bowel disease (ibd),ulcerative colitis (uc),crohn’s disease (cd),fibrosis,cachexia
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: stat3, asthma, inflammatory bowel disease (ibd), ulcerative colitis (uc), crohn’s disease (cd), fibrosis, cachexia

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