Knockdown of Burton’s tyrosine kinase confers potent protection against sepsis-induced acute lung injury

Zhou, Panyu; Ma, Bing; Xu, Shuogui; Zhang, Shijie; Tang, Haihong; Zhu, Shishu; Xiao, Shichu; Ben, Daofeng; Xia, Zhaofan

doi:10.1007/s12013-014-0050-1

Cited by 29 publications

(28 citation statements)

References 31 publications

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“…Results from the present study demonstrated that BTK inhibition via LFM-A13 treatment attenuated pulmonary capillary permeability, reduced the inflammatory response and alleviated pulmonary pathological damage in THS rats. These findings were consistent with a previous study demonstrating that following BTK knockdown, the levels of inflammatory cytokines, as well as the lung pathological scores, were reduced in mice following cecal ligation and puncture-induced sepsis (32). …”

Section: Discussionsupporting

confidence: 93%

“…BTK is expressed in all hematopoietic cells, with the exception of plasma cells and T lymphocytes (30), and it is essential for lipopolysaccharide (LPS)-induced TNF-α production in mononuclear cells (31). Additional studies have demonstrated that the downregulation of BTK expression by small interfering RNA conferred strong protective effects against sepsis-induced acute lung injury (32,33). However, whether BTK is involved in THS-induced lung injury remains unknown.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of BTK protects lungs from trauma-hemorrhagic shock-induced injury in rats

Zhang

Han

et al. 2017

Molecular Medicine Reports

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The present study aimed to investigate the role of Bruton's tyrosine kinase (BTK) in the pathogenesis of lung injury induced by trauma-hemorrhagic shock (THS), and to examine the pulmonary protective effects of BTK inhibition. Male Sprague-Dawley rats were divided into four groups (n=12/group): i) A Sham group, which received surgery without induced trauma; ii) a THS-induced injury group; iii) a THS-induced injury group that also received treatment with the BTK inhibitor LFM-A13 prior to trauma induction; and iv) a Sham group that was pretreated with LFM-A13 prior to surgery but did not receive induced trauma. The expression of phosphorylated-BTK protein in the lungs was measured by immunohistochemistry and western blot analysis. The bronchoalveolar lavage fluid (BALF) protein concentration, total leukocyte and eosinophil numbers, and the expression levels of peripheral blood proinflammatory factors were measured. Morphological alterations in the lungs were detected by hematoxylin and eosin staining. Pulmonary nitric oxide (NO) concentration and inducible NO synthase (iNOS) expression were also assessed. Activities of the nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling pathways were determined by western blotting or electrophoretic mobility shift assay. BTK was notably activated in lungs of THS rats. BALF protein concentration, total leukocytes and eosinophils, peripheral blood expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6 and monocyte chemotactic protein 1 were significantly upregulated after THS induction, and each exhibited decreased expression upon LFM-A13 treatment. THS-induced interstitial hyperplasia, edema and neutrophilic infiltration in lungs were improved by the inhibition of BTK. In addition, THS-induced NO release, iNOS overexpression, and NF-κB and MAPK signaling were suppressed by BTK inhibition. Results from the present study demonstrate that BTK may serve a pivotal role in the pathogenesis of THS-related lung injury, and the inhibition of BTK may significantly alleviate THS-induced lung damage. These results provide a potential therapeutic application for the treatment of THS-induced lung injury.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Inhibition of BTK protects lungs from trauma-hemorrhagic shock-induced injury in rats

Zhang

Han

et al. 2017

Molecular Medicine Reports

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“…29 By directly binding TLR4 upon activation, Btk activates multiple signaling pathways, including NF-κB, p38 MAPK, and iNOS, whereas Btk inhibition has been shown to protect against sepsis-induced acute lung injury. 30 Previous studies have also shown that inhibition of Btk can lead to reduced fMLP-mediated tyrosine phosphorylation, neutrophil adhesion, and chemotaxis. 31 …”

Section: Discussionmentioning

confidence: 97%

Bruton Tyrosine Kinase Inhibition Attenuates Liver Damage in a Mouse Warm Ischemia and Reperfusion Model

et al. 2017

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Background Bruton’s tyrosine kinase (Btk) is a central player in multiple signaling pathways of lymphoid and myeloid cells. Myeloid cells are crucial early effectors in organ ischemia/reperfusion injury (IRI). BTKB66 is a selective, irreversible inhibitor of Btk. In this study, we hypothesized that Btk inhibition would reduce hepatocellular injury in a murine model of liver warm hepatic ischemia and reperfusion. Methods First, BTKB66 was tested in in vitro models of LPS-mediated neutrophil and macrophage activation. Then, to assess its efficacy in vivo, BTKB66 was administered orally to mice for seven days prior to subjecting them to 90 minutes of warm hepatic ischemia followed by reperfusion for 6 or 24 hours. Clinical and pathologic features in the livers, including AST, ALT, and a panel of cytokines and chemokines, were examined. Results BTKB66 potently inhibited LPS-mediated activation of bone-marrow derived neutrophils and macrophages in vitro. It also reduced the severity of IRI as determined by AST and ALT levels, as well as immune cell infiltrates. BTKB66 significantly decreased hepatic markers of sterile inflammation, such as CXCL1, CXCL2, and CXCL10, in parallel with depression of serum markers of the myeloid cell activation, such as CCL5, CCL11, and CXCL5. Conclusion BTKB66 treatment ameliorated hepatocellular injury in a well-established model of liver partial warm ischemia and in situ reperfusion. These findings confirm that neutrophil recruitment and activation play an essential role in IR-stress, and that targeting Btk activity may provide a useful approach for preventing hepatocellular damage and improving outcomes in liver transplantation.

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“…13, 14 Given the importance of macrophage subsets in tumor development and progression, 15, 16 as well as in other chronic diseases, 17 it appears that Btk inhibition may offer a new therapeutic approach in modulating macrophage populations. 18, 19 …”

Section: Introductionmentioning

confidence: 99%

Optimized Near-IR Fluorescent Agents for in Vivo Imaging of Btk Expression

et al. 2015

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Bruton’s tyrosine kinase (Btk) is intricately involved in anti-apototic signaling pathways in cancer and in regulating innate immune response. A number of Btk inhibitors are in development for use in treating B-cell malignancies and certain immunologic diseases. To develop robust companion imaging diagnostics for in vivo use, we set up to explore the effects of red wavelength fluorochrome modifications of two highly potent irreversible Btk inhibitors, Ibrutinib and AVL-292. Surprisingly, we found that subtle chemical differences in the fluorochrome had considerable effects on target localization. Based on iterative designs, we developed a single optimized version with superb in vivo imaging characteristics enabling single cell Btk imaging in vivo. This agent (Ibrutinib-SiR-COOH) is expected to be valuable chemical tool in deciphering Btk biology in cancer and host cells in vivo.

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Knockdown of Burton’s tyrosine kinase confers potent protection against sepsis-induced acute lung injury

Cited by 29 publications

References 31 publications

Inhibition of BTK protects lungs from trauma-hemorrhagic shock-induced injury in rats

Inhibition of BTK protects lungs from trauma-hemorrhagic shock-induced injury in rats

Bruton Tyrosine Kinase Inhibition Attenuates Liver Damage in a Mouse Warm Ischemia and Reperfusion Model

Optimized Near-IR Fluorescent Agents for in Vivo Imaging of Btk Expression

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