Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis

Song, Jeong Sup; Kang, Chun; Kang, Hyeon Hui; Yoon, Hyung Kyu; Kim, Young Kyoon; Kim, Kwan Hyung; Moon, Hwa Sik; Park, Sung Hak

doi:10.3858/emm.2010.42.6.048

Cited by 90 publications

(86 citation statements)

References 52 publications

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“…Future experiments will seek to identify the specific interactions between Tregs and epithelial cells that govern overall CXCL12 expression and subsequent fibrocyte recruitment in the context of ALI. The reduction in lung collagen concentrations and fibrocytes in Rag-1 2/2 mice after CXCR4 receptor blockade with AMD3100 provides further evidence that the CXCL12-CXCR4 axis is critical in fibrocyte-mediated ALI fibroproliferation, and is consistent with previous studies that demonstrated a reduction in lung fibrosis in bleomycin models after CXCR4 or CXCL12 blockade (12,24). The lack of a significant difference in BAL cell count, protein, and lung CXCL12 concentrations between AMD3100-treated Rag-1 2/2 mice and PBS control mice, as well as the similar peak weight loss in each group, indicate that the difference in fibroproliferation did not result from reduced inflammation after LPS injury, and was instead attributable to the decrease in fibrocyte number.…”

Section: Discussionsupporting

confidence: 89%

“…AMD3100 is a nonpeptide antagonist of CXCR4 that inhibits the binding and function of CXCL12 with high affinity and specificity (23,24). Rag-1 2/2 mice received intratracheal LPS on Day 0, followed by daily intraperitoneal injections of either AMD3100 (200 mg in 250 ml) or sterile PBS (250 ml), starting on Day 0.…”

Section: Blockade Of the Cxcr4 Receptor With Amd3100 Decreased Fibropmentioning

confidence: 99%

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Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

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Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1 2/2 mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1 2/2 mice received CD4 1 CD25 1 (Tregs) or CD4 1 CD252 Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1 2/2 mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1 2/2 mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1 2/2 mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.Keywords: acute lung injury; fibroproliferative ARDS; fibrocytes; regulatory T cells; lung injury resolution Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) affect 190,000 individuals in the United States each year, accounting for 75,000 deaths (1). The only treatment that improves outcomes involves a lung-protective strategy in patients on mechanical ventilation (2). Mortality from ALI/ARDS remains as high as 44% (3).ALI/ARDS is divided into an exudative phase marked by edema fluid, hyaline membrane formation, and neutrophilic infiltration, followed in some patients by a fibroproliferative phase (4). Fibroproliferation is part of the normal repair response, and is characterized by the intra-alveolar accumulation of fibroblasts and collagen deposition. If this process is ineffective or continues unabated, patients may develop fibrosis (5). Longer durations of ARDS correspond to increased lung collagen and fibrosis, and portend worse outcomes (6). Fibroproliferative changes on biopsy and computed tomography predict mortality (7,8). The determinants of prolonged fibroproliferation and factors that govern its resolution remain poorly understood.The fibroblast is a key cell ...

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Section: Discussionsupporting

confidence: 89%

Section: Blockade Of the Cxcr4 Receptor With Amd3100 Decreased Fibropmentioning

confidence: 99%

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Garibaldi

D’Alessio

Mock

et al. 2013

Am J Respir Cell Mol Biol

155

135

View full text Add to dashboard Cite

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“…One of the most important events in the early stages of epithelial repair is the migration of ATII cells to cover the denuded area, which is followed by later proliferation and differentiation. Bone marrow-derived hematopoietic stem cells also contribute to the repair of injured lungs, and these cells are recruited to the site of injury by chemokines such as CXCL12 (11,27,52,53,60). While the role of chemokine signaling is well recognized in the recruitment of stem cells and immune cells, the role of CXCL12/CXCR4 signaling in the migration of ATII cells has not been previously shown.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2

Ghosh¹,

Makena²,

Gorantla³

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Ghosh MC, Makena PS, Gorantla V, Sinclair SE, Waters CM. CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2. Am J Physiol Lung Cell Mol Physiol 302: L846 -L856, 2012. First published February 17, 2012 doi:10.1152/ajplung.00321.2011.-Restoration of the epithelial barrier following acute lung injury is critical for recovery of lung homeostasis. After injury, alveolar type II epithelial (ATII) cells spread and migrate to cover the denuded surface and, eventually, proliferate and differentiate into type I cells. The chemokine CXCL12, also known as stromal cell-derived factor 1␣, has wellrecognized roles in organogenesis, hematopoiesis, and immune responses through its binding to the chemokine receptor CXCR4. While CXCL12/CXCR4 signaling is known to be important in immune cell migration, the role of this chemokine-receptor interaction has not been studied in alveolar epithelial repair mechanisms. In this study, we demonstrated that secretion of CXCL12 was increased in the bronchoalveolar lavage of rats ventilated with an injurious tidal volume (25 ml/kg). We also found that CXCL12 secretion was increased by primary rat ATII cells and a mouse alveolar epithelial (MLE12) cell line following scratch wounding and that both types of cells express CXCR4. CXCL12 significantly increased ATII cell migration in a scratch-wound assay. When we treated cells with a specific antagonist for CXCR4, AMD-3100, cell migration was significantly inhibited. Knockdown of CXCR4 by short hairpin RNA (shRNA) caused decreased cell migration compared with cells expressing a nonspecific shRNA. Treatment with AMD-3100 decreased matrix metalloproteinase-14 expression, increased tissue inhibitor of metalloproteinase-3 expression, decreased matrix metalloproteinase-2 activity, and prevented CXCL12-induced Rac1 activation. Similar results were obtained with shRNA knockdown of CXCR4. These findings may help identify a therapeutic target for augmenting epithelial repair following acute lung injury.

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“…Other studies reporting on the recruitment of cultured MSCs in bleomycin-induced lung injury have supported opposing roles of these cells in terms of promoting fibrosis (Rojas et al, 2005;Song et al, 2010).…”

Section: Mechanisms Of Msc and Pericyte Recruitment To Sites Of Injurymentioning

confidence: 92%

Pericytes, mesenchymal stem cells and their contributions to tissue repair

Wong

Rowley

Redpath

et al. 2015

Pharmacology & Therapeutics

148

110

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Regenerative medicine using mesenchymal stem cells for the purposes of tissue repair has garnered considerable public attention due to the potential of returning tissues and organs to a normal, healthy state after injury or damage has occurred. To achieve this, progenitor cells such as pericytes and bone marrow-derived mesenchymal stem cells can be delivered exogenously, mobilised and recruited from within the body or transplanted in the form organs and tissues grown in the laboratory from stem cells. In this review, we summarise the recent evidence supporting the use of endogenously mobilised stem cell populations to enhance tissue repair along with the use of mesenchymal stem cells and pericytes in the development of engineered tissues. Finally, we conclude with an overview of currently available therapeutic options to manipulate endogenous stem cells to promote tissue repair.

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Inhibitory effect of CXC chemokine receptor 4 antagonist AMD3100 on bleomycin induced murine pulmonary fibrosis

Cited by 90 publications

References 52 publications

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

Regulatory T Cells Reduce Acute Lung Injury Fibroproliferation by Decreasing Fibrocyte Recruitment

CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2

Pericytes, mesenchymal stem cells and their contributions to tissue repair

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