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Molecular imaging of Toll-like receptor 4 detects ischemia-reperfusion injury during intussusception.

ABSTRACT: We investigated the expression of Toll-like receptor 4 (TLR4) in the acute phase of intestinal I/R injury during intussusception and evaluated whether anti-TLR4 antibody-conjugated lead sulfide quantum dots (TLR4-PbS QDs) could be used to detect and monitor the injury. We first established a mouse model of I/R injury during intussusception. TLR-PbS QDs were then intravenously administered to intestinal I/R injured mice and visualized using whole-body fluorescence imaging in the second near-infrared window (NIR-II). Immunohistochemical analysis of intestinal tissue from the mice revealed that TLR4 expression was higher in the I/R injury group than the control and TAK-242 groups (5.189 ± 2.482, 1.186 ± 1.171, and 2.400 ± 0.857, respectively, P < 0.05). NIR-II fluorescence intensity was also higher in the I/R injury group than in the control and TAK-242 groups (86.415 ± 10.955, 38.975 ± 8.619, and 71.977 ± 3.838, respectively; P < 0.05). Thus, anti-TLR4-PbS QDs bound to TLR4 on the cell membranes of intestinal epithelial cells with high specificity in vitro and in vivo. These results indicate that TLR4 promotes intestinal I/R injury during intussusception and that the injury can be noninvasively imaged using TLR4-PbS QDs.

SUBMITTER: Hu ZC

PROVIDER: S-EPMC5814266 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Molecular imaging of Toll-like receptor 4 detects ischemia-reperfusion injury during intussusception.

Hu Zhang-Chun ZC Tan Ya-Lan YL Huang Shun-Gen SG Pan Peng P Liu Xiao-Bo XB Wang Jian J Guo Wan-Liang WL

Oncotarget 20171222 8

We investigated the expression of Toll-like receptor 4 (TLR4) in the acute phase of intestinal I/R injury during intussusception and evaluated whether anti-TLR4 antibody-conjugated lead sulfide quantum dots (TLR4-PbS QDs) could be used to detect and monitor the injury. We first established a mouse model of I/R injury during intussusception. TLR-PbS QDs were then intravenously administered to intestinal I/R injured mice and visualized using whole-body fluorescence imaging in the second near-infra ...[more]

PMID: 29487699

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Project description:Purpose To evaluate whether noninvasive molecular imaging technologies targeting myeloperoxidase (MPO) can reveal early inflammation associated with spinal cord injury after thoracic aortic ischemia-reperfusion (TAR) in mice. Materials and Methods The study was approved by the institutional animal care and use committee. C57BL6 mice that were 8-10 weeks old underwent TAR (n = 55) or sham (n = 26) surgery. Magnetic resonance (MR) imaging (n = 6) or single photon emission computed tomography (SPECT)/computed tomography (CT) (n = 15) studies targeting MPO activity were performed after intravenous injection of MPO sensors (bis-5-hydroxytryptamide-tetraazacyclododecane [HT]-diethyneletriaminepentaacetic acid [DTPA]-gadolinium or indium 111-bis-5-HT-DTPA, respectively). Immunohistochemistry and flow cytometry were used to identify myeloid cells and neuronal loss. Proinflammatory cytokines, keratinocyte chemoattractant (KC), and interleukin 6 (IL-6) were measured with enzyme-linked immunosorbent assay. Statistical analyses were performed by using nonparametric tests and the Pearson correlation coefficient. P < .05 was considered to indicate a significant difference. Results Myeloid cells infiltrated into the injured cord at 6 and 24 hours after TAR. MR imaging confirmed the presence of ischemic lesions associated with mild MPO-mediated enhancement in the thoracolumbar spine at 24 hours compared with the sham procedure. SPECT/CT imaging of MPO activity showed marked MPO-sensor retention at 6 hours (P = .003) that continued to increase at 24 hours after TAR (P = .0001). The number of motor neurons decreased substantially at 24 hours after TAR (P < .01), which correlated inversely with in vivo inflammatory changes detected at molecular imaging (r = 0.64, P = .0099). MPO was primarily secreted by neutrophils, followed by lymphocyte antigen 6 complexhigh monocytes and/or macrophages. There were corresponding increased levels of proinflammatory cytokines KC (P = .0001) and IL-6 (P = .0001) that mirrored changes in MPO activity. Conclusion MPO is a suitable imaging biomarker for identifying and tracking inflammatory damage in the spinal cord after TAR in a mouse model. © RSNA, 2016 Online supplemental material is available for this article.

Project description:BackgroundRenal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI.MethodsMale Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1-72 h reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.ResultsTreprostinil significantly reduced peak elevated serum creatinine (SCr) levels and accelerated normalization relative to IRI-placebo (p < 0.0001). Treatment with treprostinil also inhibited IRI-mediated renal apoptosis, mitochondrial oxidative injury (p < 0.05), and the release of cytochrome c (p < 0.01) vs. IRI-placebo. In addition, treprostinil preserved renal mitochondrial DNA copy number (p < 0.0001) and renal ATP levels (p < 0.05) to nearly those of sham-operated animals. Non-targeted semi-quantitative proteomics showed reduced levels of ATP synthase subunits in the IRI-placebo group which were restored to sham levels by treprostinil treatment (p < 0.05). Furthermore, treprostinil reduced renal IRI-induced upregulated Drp1 and pErk protein levels, and restored Sirt3 and Pgc-1α levels to baseline (p < 0.05).ConclusionsTreprostinil reduces mitochondrial-mediated renal apoptosis, inhibits mitochondria fission, and promotes mitochondria fusion, thereby accelerating mitochondrial recovery and protecting renal proximal tubules from renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI.

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Molecular imaging of Toll-like receptor 4 detects ischemia-reperfusion injury during intussusception.

Publications

Molecular imaging of Toll-like receptor 4 detects ischemia-reperfusion injury during intussusception.

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