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      Toll‐like receptor 4: A promising therapeutic target for pneumonia caused by Gram‐negative bacteria

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          Abstract

          Gram‐negative bacteria (GNB) emerge as important pathogens causing pulmonary infection, which can develop into sepsis due to bacterial resistance to antibiotics. GNB pneumonia poses a huge social and economic burden all over the world. During GNB infection in the lung, Toll‐like receptor 4 (TLR4) can form a complex with MD2 and CD14 after recognizing lipopolysaccharide of GNB, initiate the MyD88‐ and TRIF‐dependent signalling pathways and stimulate host non‐specific immune response. In this review, we summarize recent progress in our understanding of the role of TLR4 in GNB pneumonia. The latest experimental results, especially in TLR4 knockout animals, suggest a promising potential of targeting TLR4 signalling pathway for the treatment of GNB pneumonia. Furthermore, we highlight the benefits of Traditional Chinese Medicine as novel candidates for the therapy of GNB pneumonia due to the modulation of TLR4 signalling pathway. Finally, we discuss the promise and challenge in the development of TLR4‐based drugs for GNB pneumonia.

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          The epidemic of antibiotic-resistant infections: a call to action for the medical community from the Infectious Diseases Society of America.

          B Spellberg, R. Guidos, D. Gilbert … (2008)
          The ongoing explosion of antibiotic-resistant infections continues to plague global and US health care. Meanwhile, an equally alarming decline has occurred in the research and development of new antibiotics to deal with the threat. In response to this microbial "perfect storm," in 2001, the federal Interagency Task Force on Antimicrobial Resistance released the "Action Plan to Combat Antimicrobial Resistance; Part 1: Domestic" to strengthen the response in the United States. The Infectious Diseases Society of America (IDSA) followed in 2004 with its own report, "Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates, A Public Health Crisis Brews," which proposed incentives to reinvigorate pharmaceutical investment in antibiotic research and development. The IDSA's subsequent lobbying efforts led to the introduction of promising legislation in the 109 th US Congress (January 2005-December 2006). Unfortunately, the legislation was not enacted. During the 110 th Congress, the IDSA has continued to work with congressional leaders on promising legislation to address antibiotic-resistant infection. Nevertheless, despite intensive public relations and lobbying efforts, it remains unclear whether sufficiently robust legislation will be enacted. In the meantime, microbes continue to become more resistant, the antibiotic pipeline continues to diminish, and the majority of the public remains unaware of this critical situation. The result of insufficient federal funding; insufficient surveillance, prevention, and control; insufficient research and development activities; misguided regulation of antibiotics in agriculture and, in particular, for food animals; and insufficient overall coordination of US (and international) efforts could mean a literal return to the preantibiotic era for many types of infections. If we are to address the antimicrobial resistance crisis, a concerted, grassroots effort led by the medical community will be required.
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            NET balancing: a problem in inflammatory lung diseases

            Olivia Z. Cheng, Nades Palaniyar, Stephen Waggoner … (2013)
            Neutrophil extracellular traps (NETs) are beneficial antimicrobial defense structures that can help fight against invading pathogens in the host. However, recent studies reveal that NETs exert adverse effects in a number of diseases including those of the lung. Many inflammatory lung diseases are characterized with a massive influx of neutrophils into the airways. Neutrophils contribute to the pathology of these diseases. To date, NETs have been identified in the lungs of cystic fibrosis (CF), acute lung injury (ALI), allergic asthma, and lungs infected with bacteria, virus, or fungi. These microbes and several host factors can stimulate NET formation, or NETosis. Different forms of NETosis have been identified and are dependent on varying types of stimuli. All of these pathways however appear to result in the formation of NETs that contain DNA, modified extracellular histones, proteases, and cytotoxic enzymes. Some of the NET components are immunogenic and damaging to host tissue. Innate immune collectins, such as pulmonary surfactant protein D (SP-D), bind NETs, and enhance the clearance of dying cells and DNA by alveolar macrophages. In many inflammatory lung diseases, bronchoalveolar SP-D levels are altered and its deficiency results in the accumulation of DNA in the lungs. Some of the other therapeutic molecules under consideration for treating NET-related diseases include DNases, antiproteases, myeloperoxidase (MPO) inhibitors, peptidylarginine deiminase-4 inhibitors, and anti-histone antibodies. NETs could provide important biological advantage for the host to fight against certain microbial infections. However, too much of a good thing can be a bad thing. Maintaining the right balance of NET formation and reducing the amount of NETs that accumulate in tissues are essential for harnessing the power of NETs with minimal damage to the hosts.
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              Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E.

              S Barger, Kristin Harmon (1997)
              A role for beta-amyloid precursor protein (beta-APP) in the development of Alzheimer's disease has been indicated by genetics, and many conditions in which beta-APP is raised have been associated with an increased risk of Alzheimer's disease or an Alzheimer's-like pathology. Inflammatory events may also contribute to Alzheimer's disease. Here we investigate whether a secreted derivative of beta-APP (sAPP-alpha) can induce inflammatory reactions in microglia, which are brain cells of monocytic lineage. We found that treatment with sAPP-alpha increased markers of activation in microglia and enhanced their production of neurotoxins. The ability of sAPP-alpha to activate microglia was blocked by prior incubation of the protein with apolipoprotein E3 but not apolipoprotein E4, a variant associated with an increased risk for Alzheimer's. A product of amyloidogenic beta-APP processing (sAPP-beta) also activated microglia. Because sAPP-beta is deficient in the neuroprotective activity shown by sAPP-alpha, our results indicate that increased amyloidogenic processing could adversely affect the balance of sAPP activities that determine neuronal viability.
              Article 0 comments Cited 132 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Qingquan Liu:
                ORCID: https://orcid.org/0000-0003-3771-1730
                profliu1@163.com
                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (doi): 10.1111/(ISSN)1582-4934
                Journal ID (publisher-id): JCMM
                Title: Journal of Cellular and Molecular Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Electronic): 27 July 2019
                Publication date (Print): September 2019
                Volume: 23
                Issue: 9 ( doiID: 10.1111/jcmm.v23.9 )
                Pages: 5868-5875
                Affiliations
                [ 1 ] Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases Beijing China
                [ 2 ] Beijing Hospital of Traditional Chinese Medicine Capital Medical University Beijing China
                [ 3 ] Beijing Institute of Traditional Chinese Medicine Beijing China
                Author notes
                [*] [* ] Correspondence

                Qingquan Liu, Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, NO. 23 Gallery back street, District of Dong Cheng, Beijing 100010, China.

                Email: profliu1@ 123456163.com

                Author information
                https://orcid.org/0000-0003-3771-1730
                Article
                Publisher ID: JCMM14529
                DOI: 10.1111/jcmm.14529
                PMC ID: 6714139
                PubMed ID: 31350813
                SO-VID: f672481e-c1f8-4b18-b31c-b03dc0391eff
                Copyright © © 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 05 March 2019
                Date revision received : 11 June 2019
                Date accepted : 15 June 2019
                Page count
                Figures: 2, Tables: 1, Pages: 8, Words: 4900
                Funding
                Funded by: National Major Scientific and Technological Special 251 Project for "Significant New Drugs Development"
                Award ID: 2013ZX09102026
                Funded by: National Natural Science Foundation of China
                Award ID: 81503399
                Funded by: Beijing Natural Science Foundation
                Award ID: 7182071
                Categories
                Subject: Review
                Subject: Reviews
                Custom metadata
                source-schema-version-number 2.0
                component-id jcmm14529
                cover-date September 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.8 mode:remove_FC converted:29.08.2019

                ScienceOpen disciplines: Molecular medicine
                Keywords: gram‐negative bacterium,pneumonia,tlr4,traditional chinese medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: gram‐negative bacterium, pneumonia, tlr4, traditional chinese medicine

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