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      SU5416 attenuated lipopolysaccharide-induced acute lung injury in mice by modulating properties of vascular endothelial cells

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          Background and aim: A potent and selective vascular endothelial growth factor receptor (VEGFR) inhibitor SU5416, has been developed for the treatment of solid human tumors. The binding of VEGF to VEGFR plays a crucial role in the pathophysiology of respiratory disorders. However, the impact of SU5416 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) remains unclear. Thus, this study aimed to illuminate the biofunction of SU5416 in the mouse model of ALI.

          Methods: Wild-type (WT) and toll-like receptor 4 (TLR4)-deficient (TLR4 −/-) C57BL/6 mice were used to establish LPS-induced ALI model. The primary pulmonary microvascular endothelial cell (PMVEC) was extracted for detection of endothelial barrier function.

          Results: LPS significantly increased the number of inflammatory cells and inflammatory cytokines in bronchoalveolar lavage fluid (BALF). In addition, LPS increased alveolar epithelial cells injury, inflammation infiltration and vascular permeability of PMVEC in WT and TLR4 −/- mice. Western blotting experiment indicated VEGF/VEGFR and TLR4/NF-κB pathways were involved in the progression of LPS-stimulated ALI. Consistent with previous research, dexamethasone treatment appeared to be an effective therapeutic for mice with ALI. Moreover, treatment with SU5416 dramatically attenuated LPS-induced immune responses in mice lung tissues via inhibiting VEGF/VEGFR and TLR4/NF-κB pathways. Finally, SU5416 also decreased vascular permeability of PMVEC in vitro.

          Conclusion: SU5416 ameliorated alveolar epithelial cells injury and histopathological changes in mice lung via inhibiting VEGF/VEGFR and TLR4/NF-κB signaling pathways. We also confirmed that SU5416 could restrain vascular permeability in PMVEC through improving the integrity of endothelial cell. These findings suggested that SU5416 may serve as a potential agent for the treatment of patients with ALI.

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          Most cited references 38

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          Toll-like receptor signaling.

           Shizuo Akira (2003)
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            Nitric oxide and virus infection

            Nitric oxide (NO) has complex and diverse functions in physiological and pathophysiological phenomena. The mechanisms of many events induced by NO are now well defined, so that a fundamental understanding of NO biology is almost established. Accumulated evidence suggests that NO and oxygen radicals such as superoxide are key molecules in the pathogenesis of various infectious diseases. NO biosynthesis, particularly through expression of an inducible NO synthase (iNOS), occurs in a variety of microbial infections. Although antimicrobial activity of NO is appreciated for bacteria and protozoa, NO has opposing effects in virus infections such as influenza virus pneumonia and certain other neurotropic virus infections. iNOS produces an excessive amount of NO for long periods, which allows generation of a highly reactive nitrogen oxide species, peroxynitrite, via a radical coupling reaction of NO with superoxide. Thus, peroxynitrite causes oxidative tissue injury through potent oxidation and nitration reactions of various biomolecules. NO also appears to affect a host's immune response, with immunopathological consequences. For example, overproduction of NO in virus infections in mice is reported to suppress type 1 helper T-cell-dependent immune responses, leading to type 2 helper T-cell-biased immunological host responses. Thus, NO may be a host response modulator rather than a simple antiviral agent. The unique biological properties of NO are further illustrated by our recent data suggesting that viral mutation and evolution may be accelerated by NO-induced oxidative stress. Here, we discuss these multiple roles of NO in pathogenesis of virus infections as related to both non-specific inflammatory responses and immunological host reactions modulated by NO during infections in vivo.
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              Transfusion-related acute lung injury: a clinical review.

              Three decades ago, transfusion-related acute lung injury (TRALI) was considered a rare complication of transfusion medicine. Nowadays, the US Food and Drug Administration acknowledge the syndrome as the leading cause of transfusion-related mortality. Understanding of the pathogenesis of TRALI has resulted in the design of preventive strategies from a blood-bank perspective. A major breakthrough in efforts to reduce the incidence of TRALI has been to exclude female donors of products with high plasma volume, resulting in a decrease of roughly two-thirds in incidence. However, this strategy has not completely eradicated the complication. In the past few years, research has identified patient-related risk factors for the onset of TRALI, which have empowered physicians to take an individualised approach to patients who need transfusion. Copyright © 2013 Elsevier Ltd. All rights reserved.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                23 May 2019
                : 13
                : 1763-1772
                [1 ]Department of Respiratory Medicine, Affiliated Hospital of Hangzhou Normal University , Hangzhou, Zhejiang, People’s Republic of China
                [2 ]Department of Clinical Medicine, Zhejiang Chinese Medical University , Hangzhou, Zhejiang, People’s Republic of China
                Author notes
                Correspondence: Xuqing HuangDepartment of Respiratory Medicine, Affiliated Hospital of Hangzhou Normal University , No. 126 Wenzhou Road, Hangzhou, Zhejiang310015, People’s Republic of ChinaTel +8 605 718 801 5050Email Xuqing_Huang311@ 123456126.com

                These authors contributed equally to this work

                © 2019 Huang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

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                Figures: 5, References: 47, Pages: 10
                Original Research


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