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  • In conclusion we for the

    2020-03-26

    In conclusion, we for the first time demonstrated the enzyme activity and immunoprotective traits of bioactive recombinant SjCE-2b, which was successfully recovered by protein refolding from inclusion bodies. The results address two essential questions that were undocumented in previous investigations: “Does the S. japonicum cercarial elastase possess proteolytic activity which implies invasive function?” and “Does it generate immune response against cercariae infection in immunized animal?” We found that SjCE-2b displays proteolytic activity with a substrate preference and reaction pH similar to S. mansoni cercarial secretions, substantiating the assumption that SjCE-2b is orthologous to SmCE-2b. A significant immunoprotective response was induced by rSjCE-2b, demonstrating a difference in immunogenic response between SjCE and SmCE. The presentation of bioactive recombinant protein of SjCE with high yield and good quality allows further exploration on serine proteinase function and the molecular mechanisms in host skin invasion of different schistosome spp.
    Funding This study was supported by the National Natural Science Foundation of China [grant number 31572513]; the Foundation of National Science and Technology Major Program [grant number 2009ZX10004-302]; and the National Natural Science Foundation of China [grant number 81201315].
    Conflict of interest
    Introduction Non-cystic fibrosis bronchiectasis (non-CF BE) is an increasingly prevalent chronic lung disease and a cause of significant morbidity in adults [[1], [2], [3]]. While non-CF BE has diverse aetiologies, its pathology is mainly characterized by inflammation-mediated structural damage to the airways, leading to abnormal, permanently damaged and dilated BRD4770 synthesis that are susceptible to chronic bacterial infection [1]. Symptoms include chronic cough, purulent sputum production and frequent respiratory infections [1]. There is usually mild to moderate airflow obstruction and a progressive decline in lung function over time, with loss of forced expiratory volume in 1 s (FEV1) [[4], [5], [6]]. Recommendations for pharmacological treatments, which include antibiotics and bronchodilators (BD), are based on a low level of evidence owing to the lack of randomized controlled trials [1,[7], [8], [9]]. Much of the recent investigative focus in these patients has been on inhaled antibiotic therapy and chronic treatment with low-dose macrolides for their anti-inflammatory and immunoregulatory properties [[10], [11], [12], [13]]. However, these treatments do not target the underlying molecular mechanisms of tissue destruction that lead to permanent dilatation of the airways; this is mediated BRD4770 synthesis largely by neutrophils, the dominant cell type in the inflammation associated with non-CF BE [4]. Much of the tissue destruction appears to be caused by the proteolytic enzymes and oxygen free radicals that neutrophils release [4,14]. In particular, human neutrophil elastase (HNE), a serine protease, is a key mediator of lung tissue degradation and inflammation [15]. Excess HNE activity has been implicated in the pathology of inflammatory pulmonary diseases, including bronchiectasis (BE), so identifying this protein as a target for drug development [16,17]. Indeed, in a recent 4-week, placebo-controlled, phase 2, signal-searching study in patients with BE, the reversible HNE inhibitor AZD9668 improved lung function, and this was associated with significant reductions in some of the sputum inflammatory markers that were measured [18]. BAY 85-8501 is a selective and reversible HNE inhibitor that exhibits activity in the picomolar range [19]. In an animal model of acute lung injury, BAY 85-8501 prevented the development of lung injury and subsequent neutrophilic inflammation [19]. In a phase 1, multiple-dose escalation study in healthy volunteers, 2 weeks’ treatment with 1 mg BAY 85-8501 was well tolerated, with no evidence of adverse effects related to the drug or its mechanism of action [20]. The present phase 2a study aimed to assess the safety and efficacy of treatment with oral BAY 85-8501 for 28 days in patients with non-CF BE.