Background: We have previously shown that the alternatively spliced fibronectin (fn) variant containing extra domain A (fn-EDA) plays a crucial role in heart failure development in mice. In the present study, we investigated the therapeutic potential and mechanisms of action of anti-EDA treatment using a monoclonal anti-EDA antibody in mice and pigs after myocardial infarction (MI). Show Methods: Balb/C mice and Landrace farm pigs underwent MI. At day 3 post-infarction animals were randomized to receive bolus i.v. injections of either monoclonal anti-EDA antibody, saline or isotype control. Mice survived for 28 days, while pigs were followed for 3 months. Cardiac MRI was used to assess cardiac function and geometry after 1 and 3 months follow-up. Results: Post-mortem analyses showed that fn-EDA is temporarily expressed in human heart specimens after MI. In mice, anti-EDA treatment resulted in less expansive remodeling and significantly improved systolic function as well as improved survival after MI. Anti-EDA treatment reduced tissue levels of pro-inflammatory cytokines (e.g. RANTES, IL-1β), without affecting leukocyte influx. Myofibroblast expression did not differ, however, myofibroblast activity (periostin levels) and function (adhesion, MMP activity) was modified in anti-EDA treated animals. Immunohistochemistry revealed altered provisional matrix turnover within the first week after MI partly due to reduced MMP-2 and -9 activity and increased TIMP-2 levels after anti-EDA treatment. Anti-EDA treated mice exhibited increased capillary density both in the infarcted area and border zone, while EDA activation significantly suppressed endothelial cell sprouting in vitro. Anti-EDA antibody treated swine displayed significantly less LV aneurysm formation (Figure 1).  Figure 1. Improved infarct healing in pigs. Conclusion: Our study demonstrates that anti-EDA treatment both in mice and pigs, even initiated 3 days after the initial ischemic injury, prevents maladaptive remodelling and heart failure development after acute MI. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: . Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: .
Review Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiencyTomoki Kawai et al. Allergol Int. 2012 Jun. Free article AbstractAnhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized according to its various manifestations, which include ectodermal dysplasia, vascular anomalies, osteopetrosis, and diverse immunological abnormalities such as susceptibility to pathogens, impaired antibody responses to polysaccharides, hypogammaglobulinemia, hyper-IgM syndrome, impaired natural killer cell cytotoxicity, and autoimmune diseases. Two genes responsible for EDA-ID have been identified: nuclear factor-κB (NF-κB) essential modulator (NEMO) for X-linked EDA-ID (XL-EDA-ID) and IκBα for autosomal-dominant EDA-ID (AD-EDA-ID). Both genes are involved in NF-κB activation, such that mutations or related defects cause impaired NF-κB signaling. In particular, NEMO mutations are scattered across the entire NEMO gene in XL-EDA-ID patients, which explains the broad spectrum of clinical manifestations and the difficulties associated with making a diagnosis. In this review, we focus on the pathophysiology of EDA-ID and different diagnostic strategies, which will be beneficial for early diagnosis and appropriate treatment. Similar articles
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