Neglected interstitial space in malaria recurrence and treatment
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S Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China University of Chinese Academy of Sciences, Beijing 100049, China 3 Department of Traditional Chinese Medicine, Chengde Medical University, Chengde 066000, China 4 Artemisinin Research Center and the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100049, China 2
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020 Received: 14 May 2020 / Revised: 15 June 2020 / Accepted: 19 June 2020
ABSTRACT The interstitial space, a widespread fluid-filled compartment throughout the body, is related to many pathophysiological alterations and diseases, attracting increasing attention. The vital role of interstitial space in malaria infection and treatment has been neglected current research efforts. We confirmed the reinfection capacity of parasites sequestrated in interstitial space, which replenish the mechanism of recurrence. Malaria parasite-infected mice were treated with artemisinin-loaded liposomes through the interstitial space and exhibited a better therapeutic response. Notably, compared with oral administration, interstitial administration showed an unexpectedly high activation and recruitment of immune cells, and resulted in better clearance of sequestered parasites from organs, and enhanced pathological recovery. The interstitial route of administration prolongs the blood circulation time of artemisinin and increases its plasma concentration, and may compensate for the inefficiency of oral administration and the nanotoxicity of intravenous administration, providing a potential strategy for infectious disease therapy.
KEYWORDS interstitial space, malaria, infection, recurrence, treatment
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Introduction
Complex living organisms have typical soft matter with structure-function units in hierarchical encapsulation of the interstitium. Among these, interstitial architectures are formed from large porous network of fibers (such as extracellular matrix, loose connective tissue matrix) into gradually dense fibrous network. The matrix gel is extruded between single fiber lamellae, and the multilayer assembly eventually forms the generalized fascia, and compresses into a tendon or surrounds the interstitial space, which can interpenetrate all organs and muscles. Blood vessels, lymphatic vessels, and nerve bundles pass through the interstitial space. The most real image of life activities is the interstitial structure that runs through the whole body, with an internal green pathway (interstitial stream)—the “hierarchical complex fluid-interstitial stream” life model—which makes the whole body become an organic whole of flattened connections [1]. The interstitial fluid can work as a shock absorber to protect organs and tissues [2, 3]. The interstitial structure and composition vary in different organs, but are similar to some extent, consisting of flowing interstitial fluid and a complex network of collagen bundles [4]. In addition to nutriti
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