Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

Tománková, Tereza; Kriegová, Eva; Liu, Mingyao

doi:10.1152/ajplung.00203.2014

Cited by 43 publications

(28 citation statements)

References 175 publications

(168 reference statements)

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“…5). ECL1i-Dylight 550 also bound lung to macrophages (CD11b hi , CD11c low ) and a very small group of “bright” dendritic cells (CD11b hi , CD11c hi ), consistent with known CCR2 + populations (1, 2). …”

Section: Resultssupporting

confidence: 52%

“…Second, CCR2 is elevated in lung cells in ARDS, COPD, experimental asthma and pulmonary fibrosis, as well as common non-pulmonary diseases, including atherosclerosis and malignancy (6,8–10,17,25–28). Third, there is substantial evidence that genetic deletion or pharmacologic inhibition of CCR2 ameliorates disease in animal models leading to industry efforts to develop and trial CCR2 antagonists for respiratory disorders and other disease (2,18,19). …”

Section: Discussionmentioning

confidence: 99%

“…Lung inflammation is a result of the recruitment of inflammatory cells along chemokine gradients, guided by their cognate receptors (1,2). In some lung conditions, patterns of inflammatory cell recruitment can be used to diagnose diseases and direct therapeutic decisions (e.g., asthma, eosinophilic pneumonia) (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…CCR2 is a surface receptor found on most inflammatory monocytes and macrophages, as well as some dendritic cells and lymphocytes (1,2). CCR2 + inflammatory monocytes are essential early responding immune cells, and excessive or prolonged recruitment impairs resolution of inflammation and propagates disease progression (3,11,12).…”

Section: Introductionmentioning

confidence: 99%

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PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation

Liu¹,

Gunsten²,

Sultan³

et al. 2017

Radiology

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Purpose To characterize a chemokine receptor-2 (CCR2) binding peptide adapted for use as a positron emission tomography (PET) radiotracer for non-invasive detection of lung inflammation in a mouse model of lung injury and in human tissues from subjects with lung disease. Materials and Methods The study had institutional Animal and Human Studies Committees approval and patient consent. A 7-amino acid CCR2 binding peptide (ECL1i) was conjugated to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with copper-64 (64Cu) or fluorescent dye. Lung inflammation was induced by intratracheal administration of lipopolysaccharide (LPS) in wild-type (n=19) and CCR2-deficient mice (n=4), and compared to wild-type mice given control saline (n=5) by PET imaging performed following intravenous injection of 64Cu-DOTA-ECL1i. Lung immune cells and those binding fluorescently labeled ECL1i in vivo were detected by flow cytometry. Lung inflammation in tissue from subjects with non-diseased lungs donated for lung transplantation (n=11) and chronic obstructive pulmonary disease (COPD) who were undergoing lung transplant (N=16) was evaluated for CCR2 by immunostaining and autoradiography (n=6, COPD) with 64Cu-DOTA-ECL1i. Groups were compared using ANOVA, Mann Whitney U- or t-tests. Results PET images obtained in mouse lungs following injury with LPS, was significantly greater than the saline control group (mean %ID/g=4.43 vs. 0.99; P<0.001). PET signal was significantly diminished with blocking studies using non-radiolabeled ECL1i in excess (mean %ID/g=0.63; P<0.001) and in CCR2-deficient mice (mean %ID/g=0.39; P<0.001). The ECL1i signal was associated with an elevated level of mouse lung monocytes. COPD lung tissue displayed significantly elevated CCR2 levels compared to non-diseased tissue (median 12.8 vs. 1.2 percent cells/sample; P=0.002), which was detected by 64Cu-DOTA-ECL1i using autoradiography. Conclusions 64Cu-DOTA-ECL1i performed as a promising tool for PET-based detection of CCR2-directed inflammation in an animal model and in human tissues as a step toward clinical translation.

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Section: Resultssupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation

Liu¹,

Gunsten²,

Sultan³

et al. 2017

Radiology

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“…We showed that a CCR2 binding peptide can specifically detect these receptors with PET/CT imaging during lung transplantation-mediated ischemiareperfusion injury in vivo as both a monovalent peptide tracer and a multivalent nanoplatform (25). We recognize that lung stromal cells can express CCR2, which needs to be considered when interpreting CCR2 imaging results (26). However, our findings suggest that any potential contribution of such cells to the CCR2 PET signal in vivo is inconsequential compared with hematopoietic cells.…”

Section: Ischemia-reperfusion Injury-mediated Primary Graft Dysfunctimentioning

confidence: 78%

Noninvasive Imaging of CCR2+ Cells in Ischemia-Reperfusion Injury After Lung Transplantation

Liu

Luehmann

et al. 2016

American Journal of Transplantation

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Ischemia reperfusion injury-mediated primary graft dysfunction substantially hampers short- and long-term outcomes after lung transplantation. This condition continues to be diagnosed based on oxygen exchange parameters as well as radiological appearance, and therapeutic strategies are mostly supportive in nature. Identifying patients who may benefit from targeted therapy would therefore be highly desirable. Here, we show that CCR2 expression in murine lung transplant recipients promotes monocyte infiltration into pulmonary grafts and mediates graft dysfunction. We have developed new positron emission tomography imaging agents using a CCR2 binding peptide ECLi1 that can be used to monitor inflammatory responses after organ transplantation. Both 64Cu-radiolabeled ECL1i peptide radiotracer (64Cu-DOTA-ECL1i) and ECL1i-conjugated gold nanoclusters doped with 64Cu (64CuAuNCs-ECL1i) showed specific detection of CCR2, which is up-regulated during ischemia-reperfusion injury after lung transplantation. Due to its fast pharmacokinetics 64Cu-DOTA-ECL1i functioned efficiently for rapid and serial imaging of CCR2. The multivalent 64CuAuNCs-ECL1i with extended pharmacokinetics is favored for long-term CCR2 detection and potential targeted theranostics. This imaging may be applicable for diagnostic and therapeutic purposes for many immune-mediated diseases.

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Thrombin Induces CCL2 Expression in Human Lung Fibroblasts via p300 Mediated Histone Acetylation and NF‐KappaB Activation

Deng

Zhou

Deng

et al. 2017

J of Cellular Biochemistry

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Thrombin has been shown to play a key role in lung diseases such as pulmonary fibrosis via the induction of fibrotic cytokine- chemokine (CC motif) ligand-2 (CCL2) expression. We previously reported that transcription factor nuclear factor-κB (NF-κB) is responsible for thrombin-induced CCL2 expression in human lung fibroblasts (HLFs). Here, we extended our study to investigate the epigenetic regulation mechanism for thrombin-induced CCL2 expression in HLFs. HLFs were cultured in F-12 medium. CCL2 protein and mRNA levels were detected by ELISA and quantitative real-time PCR, respectively. Histone, histone acetyltransferases, and NF-κB binding to CCL2 promoter were detected by ChIP assay. NF-κB activation was detected by Western blotting. We revealed that increased binding of histone acetyltransferase p300 and acetylated histone H3 and H4 to CCL2 promoter are responsible for thrombin induced CCL2 expression in HLF cells. In addition, p300 inhibition attenuates both thrombin induced-CCL2 expression and histone H3 and H4 acetylation in HLFs, suggesting that p300 is involved in thrombin-induced CCL2 expression via hyperacetylating histone H3 and H4. Our data further showed that p300 also regulates CCL2 expression via interaction with NF-κB p65, as depletion of p300 inhibits both NF-κB p65 activation and its binding to CCL2 promoter. The findings strongly suggest that epigenetic dysregulation and the interaction between histone acetyltransferase and transcription factor may be responsible for thrombin induced-CCL2 expression in HLFs. Increased understanding of the epigenetic mechanisms of CCL2 regulation may provide opportunities for identifying novel molecular targets for therapeutic purposes. J. Cell. Biochem. 118: 4012-4019, 2017. © 2017 Wiley Periodicals, Inc.

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Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

Cited by 43 publications

References 175 publications

PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation

PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation

Noninvasive Imaging of CCR2+ Cells in Ischemia-Reperfusion Injury After Lung Transplantation

Thrombin Induces CCL2 Expression in Human Lung Fibroblasts via p300 Mediated Histone Acetylation and NF‐KappaB Activation

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