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Cook EA, Ogunsina O, Gao X, Majetschak M. The Chemokine (C-C Motif) Receptor 1 Antagonist BX471 Improves Fluid Resuscitation in Rat Models of Hemorrhagic Shock. Biomedicines 2025; 13:1241. [PMID: 40427068 PMCID: PMC12109411 DOI: 10.3390/biomedicines13051241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2025] [Revised: 05/07/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Background/Objectives: We reported previously that antagonists at chemokine receptors CCR2 and CCR3 have fluid-sparing effects during resuscitation from hemorrhagic shock. Because CCR1 shares several chemokine ligands with CCR2/3, we tested whether the CCR1 antagonist BX471 also reduces fluid requirements to maintain hemodynamics. Methods: Sprague Dawley rats were hemorrhaged for 30 min, followed by fluid resuscitation to maintain blood pressure for 60 min (series 1) and 180 min (series 2). Series 1: Animals received vehicle (n = 5), 0.05 μmol/kg (n = 5), or 0.5 μmol/kg (n = 4) BX471 at t = 30 min. Series 2: Animals received vehicle (n = 8) or 0.5 μmol/kg (n = 7) BX471 at t = 30 min. Hemodynamics, fluid requirements, blood gases, and lactate were monitored. Serum concentrations of CCR1 ligands (CCL3/4/5/7) were determined at baseline and at the conclusion of the experiments. Tissue (small/large intestine, lung) wet/dry (W/D) weight ratios, lung myeloperoxidase activity, and a panel of inflammation markers in tissue extracts were measured. Results: All animals could be resuscitated to target blood pressures. Series 1: A total of 0.5 μmol/kg BX471 reduced fluid requirements by more than 60% (p < 0.05 vs. vehicle and 0.05 μmol/kg BX471). Series 2: Systemic CCL3/5/7 levels increased during the experiment (p < 0.05). BX471-treatment reduced fluid requirements by more than 60% (p < 0.05) and prevented increases in CCL3/7. W/D ratios of large intestine and of the sum of all tissues were lower with BX471 treatment (p < 0.05). BX471-treatment reduced TNFα and IL6 concentrations in large intestine extracts (p < 0.05). Conclusions: Our findings suggest CCR1 as a new therapeutic target to reduce fluid requirements during resuscitation from hemorrhagic shock.
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Affiliation(s)
- Elizabeth A. Cook
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (E.A.C.); (O.O.); (X.G.)
| | - Ololade Ogunsina
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (E.A.C.); (O.O.); (X.G.)
| | - Xianlong Gao
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (E.A.C.); (O.O.); (X.G.)
| | - Matthias Majetschak
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (E.A.C.); (O.O.); (X.G.)
- Department of Molecular Pharmacology & Physiology, University of South Florida, Tampa, FL 33612, USA
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Hasan A, Repici A, Capra AP, Mannino D, Bova V, Catalfamo A, Campolo M, Paterniti I, Esposito E, Ardizzone A. CCR1 antagonist as a potential modulator of inflammatory, autophagic, and apoptotic markers in spinal cord injury. Neuropharmacology 2025; 264:110239. [PMID: 39608704 DOI: 10.1016/j.neuropharm.2024.110239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 11/15/2024] [Accepted: 11/23/2024] [Indexed: 11/30/2024]
Abstract
Spinal cord injury (SCI) leads to severe and lasting impairments in motor and sensory functions. The intense inflammatory response following SCI is a significant challenge, and autophagy has emerged as a key factor in the recovery process. The C-C chemokine receptor type 1 (CCR1), a G-protein coupled receptor, plays a crucial role in managing the chemokine response under stress. BX471, a selective and potent CCR1 antagonist, has been explored in various disease contexts for its therapeutic potential. In this study, we assessed the effects of BX471 in a mouse model of SCI. The treatment was administered at doses of 3 and 10 mg/kg, 1 h and 6 h after the injury occurred. Results showed that BX471 significantly improved tissue structure by positively influencing autophagy and reducing inflammation. Inflammatory markers, including CCR1 ligands RANTES, MIP-1α, TNF-α, and IL-1β, were measured using Western blot analysis. Additionally, histological evaluations revealed that BX471 effectively decreased infiltration and reduced astrocyte and microglial activation, supporting the idea that enhancing autophagy through CCR1 inhibition could promote neuronal survival. The highest efficacy was observed at the 10 mg/kg dose, leading to optimal out-comes across the assessments. These findings suggest that CCR1 blockade with BX471 may offer a promising therapeutic strategy for SCI, addressing a critical gap in the current pharmacological treatment options.
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Affiliation(s)
- Ahmed Hasan
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy; School of Advanced Studies, Center of Neuroscience, University of Camerino, 62032, Camerino, Italy
| | - Alberto Repici
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Deborah Mannino
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Valentina Bova
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Antonio Catalfamo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Michela Campolo
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Irene Paterniti
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy.
| | - Alessio Ardizzone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D'Alcontres, 31, 98166, Messina, Italy
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Weber SN, Nowak I, Grünhage F, Lammert F. Effects of blocking chemokine receptor CCR1 with BX471 in two models of fibrosis prevention and rescue in mice. Biochem Biophys Rep 2021; 27:101077. [PMID: 34337167 PMCID: PMC8313839 DOI: 10.1016/j.bbrep.2021.101077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 11/01/2022] Open
Abstract
Background The induction, progression and resolution of liver fibrosis are influenced by multiple chemokines. The inhibition of CCR1 signalling by a specific non-peptide inhibitor (BX471) reduces kidney fibrosis after unilateral ureteral obstruction via suppression of leukocyte recruitment in mice. However, it remains unclear whether selective CCR1 inhibition also affects hepatic fibrogenesis. Therefore we aimed to study the effect of this intervention on liver fibrosis in prevention (CCl4 administration) and rescue (ABCB4-deficient mice) mouse models. Methods In the prevention model, hepatic fibrosis was induced by repeated injections of CCl4. Additionally, the verum group was treated with subcutaneous injections of BX471, while controls received vehicle only. ABCB4 deficient mice (on the BALB/c-background) with sclerosing cholangitis and biliary fibrosis received BX471 or vehicle, respectively (rescue model). Liver histopathology was assessed after Sirius red staining of collagen, and hepatic collagen contents were measured. In addition, we performed gene expression analyses of fibrosis-related genes. Results BX471 injections were tolerated moderately well by all mice, and all mice developed hepatic fibrosis. Significant differences were neither observed in serum aminotransferase activities after 6 weeks of treatment between the two groups in the prevention nor in the rescue model. Interestingly, hepatic collagen contents were significantly higher in mice treated with BX471 in the prevention model as compared to controls but histological stages of liver sections did not differ. Of note, we observed only moderate effects on liver fibrosis in the ABCB4 knock-out model. Conclusions Our data indicate that BX471 treatment did neither affect serum and tissue markers of liver injury and fibrosis in the CCl4 model and only moderately in the Abcb4 -/- model of biliary fibrosis. The animal models indicate that treatment with BX471 alone is unlikely to exert major beneficial effects in chronic liver disease.
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Affiliation(s)
- Susanne N Weber
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Irina Nowak
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Grünhage
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany.,Hannover Health Sciences Campus, Hannover Medical School (MHH), Hannover, Germany
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Possible involvement of crosstalk between endometrial cells and mast cells in the development of endometriosis via CCL8/CCR1. Biomed Pharmacother 2020; 129:110476. [PMID: 32768961 DOI: 10.1016/j.biopha.2020.110476] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND The density and the activity of mast cells are associated with endometriosis. However, the role of mast cells on the pathogenesis of endometriosis remains unclear. Our study aims to investigate whether endometrial cells interact with mast cells and the involvement of their crosstalk in the development of endometriosis. METHODS The transwell assay was applied to investigate the effect of mast cells on the migratory ability of human primary endometrial cells. Mast cells were cocultured with endometrial epithelial and stromal cells respectively and total RNAs were isolated and subjected to mRNA sequencing. Next, the transwell assay, CCK-8, and tube formation were applied to study the role of CCL8 on the endometrial and endothelial cells in vitro. The mouse model was also established to confirm the role of CCL8 in the development and angiogenesis of endometriosis. RESULTS CCL8 was up-regulated in mast cells when cocultured with endometrial cells. CCL8 was highly expressed in the ectopic endometrium and the serum of patients with endometriosis. CCL8 promoted the migratory ability of endometrial epithelial and stromal cells and increased the proliferation, migration, and tube formation of endothelial cells. CCR1, the receptor of CCL8, was over-expressed in the ectopic endometrium and colocalized with blood vessels in ovarian endometriomas. The inhibition of CCR1 suppressed the development and angiogenesis of endometriosis in vivo. CONCLUSION The crosstalk between endometrial cells and mast cells in the development of endometriosis via CCL8/CCR1 was demonstrated, thereby providing a new treatment strategy for endometriosis.
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Abstract
The incidence of acute pancreatitis continues to increase worldwide, and it is one of the most common gastrointestinal causes for hospital admission in the USA. In the past decade, substantial advancements have been made in our understanding of the pathophysiological mechanisms of acute pancreatitis. Studies have elucidated mechanisms of calcium-mediated acinar cell injury and death and the importance of store-operated calcium entry channels and mitochondrial permeability transition pores. The cytoprotective role of the unfolded protein response and autophagy in preventing sustained endoplasmic reticulum stress, apoptosis and necrosis has also been characterized, as has the central role of unsaturated fatty acids in causing pancreatic organ failure. Characterization of these pathways has led to the identification of potential molecular targets for future therapeutic trials. At the patient level, two classification systems have been developed to classify the severity of acute pancreatitis into prognostically meaningful groups, and several landmark clinical trials have informed management strategies in areas of nutritional support and interventions for infected pancreatic necrosis that have resulted in important changes to acute pancreatitis management paradigms. In this Review, we provide a summary of recent advances in acute pancreatitis with a special emphasis on pathophysiological mechanisms and clinical management of the disorder.
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Tomankova T, Kriegova E, Liu M. Chemokine receptors and their therapeutic opportunities in diseased lung: far beyond leukocyte trafficking. Am J Physiol Lung Cell Mol Physiol 2015; 308:L603-18. [PMID: 25637606 DOI: 10.1152/ajplung.00203.2014] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 01/28/2015] [Indexed: 12/13/2022] Open
Abstract
Chemokine receptors and their chemokine ligands, key mediators of inflammatory and immune cell trafficking, are involved in the regulation of both physiological and pathological processes in the lung. The discovery that chemokine receptors/chemokines, typically expressed by inflammatory and immune cells, are also expressed in structural lung tissue cells suggests their role in mediating the restoration of lung tissue structure and functions. Thus, chemokine receptors/chemokines contribute not only to inflammatory and immune responses in the lung but also play a critical role in the regulation of lung tissue repair, regeneration, and remodeling. This review aims to summarize current state-of-the-art on chemokine receptors and their ligands in lung diseases such as chronic obstructive pulmonary disease, asthma/allergy, pulmonary fibrosis, acute lung injury, and lung infection. Furthermore, the therapeutic opportunities of chemokine receptors in aforementioned lung diseases are discussed. The review also aims to delineate the potential contribution of chemokine receptors to the processes leading to repair/regeneration of the lung tissue.
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Affiliation(s)
- Tereza Tomankova
- Faculty of Medicine and Dentistry, Department of Immunology, Palacky University Olomouc, Czech Republic; Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and
| | - Eva Kriegova
- Faculty of Medicine and Dentistry, Department of Immunology, Palacky University Olomouc, Czech Republic
| | - Mingyao Liu
- Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada; and Faculty of Medicine, Departments of Physiology, Surgery, and Medicine, Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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Li J, Yang WJ, Huang LM, Tang CW. Immunomodulatory therapies for acute pancreatitis. World J Gastroenterol 2014; 20:16935-16947. [PMID: 25493006 PMCID: PMC4258562 DOI: 10.3748/wjg.v20.i45.16935] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/24/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
It is currently difficult for conventional treatments of acute pancreatitis (AP), which primarily consist of anti-inflammatory therapies, to prevent the progression of AP or to improve its outcome. This may be because the occurrence and progression of AP, which involves various inflammatory cells and cytokines, includes a series of complex immune events. Considering the complex immune system alterations during the course of AP, it is necessary to monitor the indicators related to immune cells and inflammatory mediators and to develop more individualized interventions for AP patients using immunomodulatory therapy. This review discusses the recent advances in immunomodulatory therapies. It has been suggested that overactive inflammatory responses should be inhibited and excessive immunosuppression should be avoided in the early stages of AP. The optimal duration of anti-inflammatory therapy may be shorter than previously expected (< 24 h), and appropriate immunostimulatory therapies should be administered during the period from the 3rd d to the 14th d in the course of AP. A combination therapy of anti-inflammatory and immune-stimulating drugs would hopefully constitute an alternative to anti-inflammatory drug monotherapy. Additionally, the detection of the genotypes of critical inflammatory mediators may be useful for screening populations of AP patients at high risk of severe infections to enable the administration of early interventions to improve their prognosis.
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Shen Y, Wang D, Wang X. Role of CCR2 and IL-8 in acute lung injury: a new mechanism and therapeutic target. Expert Rev Respir Med 2014; 5:107-14. [DOI: 10.1586/ers.10.80] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Bhatia M, Zemans RL, Jeyaseelan S. Role of chemokines in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol 2012; 46:566-572. [PMID: 22323365 PMCID: PMC3361356 DOI: 10.1165/rcmb.2011-0392tr] [Citation(s) in RCA: 198] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2011] [Accepted: 02/02/2012] [Indexed: 12/11/2022] Open
Abstract
Acute lung injury (ALI) is due to an uncontrolled systemic inflammatory response resulting from direct injury to the lung or indirect injury in the setting of a systemic process. Such insults lead to the systemic inflammatory response syndrome (SIRS), which includes activation of leukocytes-alveolar macrophages and sequestered neutrophils-in the lung. Although systemic inflammatory response syndrome is a physiologic response to an insult, systemic leukocyte activation, if excessive, can lead to end organ injury, such as ALI. Excessive recruitment of leukocytes is critical to the pathogenesis of ALI, and the magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ALI. Leukocyte recruitment is a well orchestrated process that depends on the function of chemokines and their receptors. Understanding the mechanisms that contribute to leukocyte recruitment in ALI may ultimately lead to the development of effective therapeutic strategies.
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Affiliation(s)
- Madhav Bhatia
- Department of Pathology, University of Otago, 2 Riccarton Avenue, Christchurch, New Zealand.
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Grassl GA, Faustmann M, Gill N, Zbytnuik L, Merkens H, So L, Rossi FM, McNagny KM, Finlay BB. CD34 mediates intestinal inflammation in Salmonella-infected mice. Cell Microbiol 2011; 12:1562-75. [PMID: 20497179 DOI: 10.1111/j.1462-5822.2010.01488.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CD34 is a highly glycosylated sialomucin expressed on a variety of cells, ranging from vascular endothelial cells to haematopoietic stem cells. Depending on its glycosylation state, CD34 has been shown to promote or inhibit cell adhesion and migration; however, a functional role for CD34 in the gut has not been determined. Using a model of Salmonella-induced gastroenteritis, we investigated the role of CD34 in the context of infection. Upon oral infection, the number of CD34+ cells detected in the submucosa, vascular endothelium and lamina propria significantly increased in S. Typhimurium-infected C57Bl/6 mice. The pathology of S. Typhimurium-infected C57Bl/6 mice was characterized by recruitment of neutrophils to the site of inflammation, submucosal oedema and crypt destruction. In contrast, Cd34(-/-) mice showed a delayed pathology, a defect in inflammatory cell migration into the intestinal tissue and enhanced survival. Importantly, this was not due to a lack of chemotactic signals in Cd34(-/-) mice as these mice had either similar or significantly higher levels of pro-inflammatory cytokines and chemokines post infection when compared with infected C57/Bl6 control mice. In summary, we demonstrate a novel role for CD34 in enhancing migration of inflammatory cells and thereby exacerbating host-mediated immunopathology in the intestine of S. Typhimurium-infected mice.
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Affiliation(s)
- Guntram A Grassl
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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Yang X, Walton W, Cook DN, Hua X, Tilley S, Haskell CA, Horuk R, Blackstock AW, Kirby SL. The chemokine, CCL3, and its receptor, CCR1, mediate thoracic radiation-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2010; 45:127-35. [PMID: 20870892 DOI: 10.1165/rcmb.2010-0265oc] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Patients receiving thoracic radiation often develop pulmonary injury and fibrosis. Currently, there are no effective measures to prevent or treat these conditions. We tested whether blockade of the chemokine, CC chemokine ligand (CCL) 3, and its receptors, CC chemokine receptor (CCR) 1 and CCR5, can prevent radiation-induced lung inflammation and fibrosis. C57BL/6J mice received thoracic radiation, and the interaction of CCL3 with CCR1 or CCR5 was blocked using genetic techniques, or by pharmacologic intervention. Lung inflammation was assessed by histochemical staining of lung tissue and by flow cytometry. Fibrosis was measured by hydroxyproline assays and collagen staining, and lung function was studied by invasive procedures. Irradiated mice lacking CCL3 or its receptor, CCR1, did not develop the lung inflammation, fibrosis, and decline in lung function seen in irradiated wild-type mice. Pharmacologic treatment of wild-type mice with a small molecule inhibitor of CCR1 also prevented lung inflammation and fibrosis. By contrast, mice lacking CCR5 were not protected from radiation-induced injury and fibrosis. The selective interaction of CCL3 with its receptor, CCR1, is critical for radiation-induced lung inflammation and fibrosis, and these conditions can be largely prevented by a small molecule inhibitor of CCR1.
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Affiliation(s)
- Xuebin Yang
- Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Kerstjens HA, Bjermer L, Eriksson L, Dahlström K, Vestbo J. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients. Respir Med 2010; 104:1297-303. [PMID: 20466530 DOI: 10.1016/j.rmed.2010.04.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2009] [Revised: 04/08/2010] [Accepted: 04/15/2010] [Indexed: 10/19/2022]
Abstract
OBJECTIVE This study evaluated the tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in patients with COPD. METHODS This double-blind, placebo-controlled study (NCT00629239) randomised patients with moderate to severe COPD to AZD4818 300mug or placebo twice daily via Turbuhaler((R)) for 4 weeks. Safety, lung function, functional capacity and health status measures were measured. Plasma concentrations of AZD4818 were measured after the first dose and after 2 and 4 weeks' treatment. RESULTS Sixty-five patients (47 male; median age 65.6 years) received AZD4818 (n=33) or placebo (n=32). There was no statistically significant difference between AZD4818 and placebo in change from baseline to endpoint for FEV(1) (AZD4818-placebo: 0.026L, p=0.69), morning PEF (-6L/min, p=0.23), or other lung function measures. There was no difference between treatment groups in the 6-min walk test, MMRC dyspnoea index, BODE index and CCQ scores. Plasma concentrations indicated that patients were exposed to AZD4818 as expected. AZD4818 was well tolerated: 27 treatment-related adverse events (13 with AZD4818, 14 with placebo), 2 serious adverse events (both AZD4818: exacerbation [considered not treatment-related] and deep vein thrombosis [considered treatment-related]) and 11 discontinuations (7 with AZD4818). CONCLUSIONS Inhaled AZD4818 was well tolerated at 300mug twice daily for 4 weeks in patients with COPD; however, there was no indication of a beneficial treatment effect despite exposure as expected. These findings in COPD are in line with other studies reporting a lack of clinical efficacy with CCR1 antagonists in other therapy areas.
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Affiliation(s)
- Huib A Kerstjens
- Department of Pulmonary Medicine, University of Groningen, Groningen, The Netherlands.
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Yang D, Tong L, Wang D, Wang Y, Wang X, Bai C. Roles of CC chemokine receptors (CCRs) on lipopolysaccharide-induced acute lung injury. Respir Physiol Neurobiol 2010; 170:253-9. [PMID: 20152938 DOI: 10.1016/j.resp.2010.02.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2009] [Revised: 02/04/2010] [Accepted: 02/04/2010] [Indexed: 01/11/2023]
Abstract
The aim of the present study was to evaluate the effects of the CC chemokine receptor (CCR) 2b and CCR1 antagonist RS504393 as well as the roles of CCRs on lipopolysaccharide (LPS)-induced acute lung injury (ALI). In A549 cell line, treatment with RS504393 significantly inhibited the expression of CCR1, CCR2 and interleukin (IL)-8 after either LPS or tumor necrosis factor-alpha stimulation. An ALI model with intranasal LPS administration was used on C57BL/6J, CCR1, CCR2 and CCR3 knockout mice. Treatment with RS504393 had a noteworthy preventative effect on LPS-induced over-expression of IL-1beta, plasminogen activator inhibitor and CCR2. In CCR1 and CCR2-deficient animals, LPS-induced less increase of lung weight, bronchoalveolar lavage (BAL) leukocytes and IL-6 compared to the C57BL/6J and CCR3 knockout mice. This was most prominent in the CCR2 knockout mice where no LPS-induced lung edema and no increase of IL-6 in BAL fluid occurred. Our results indicate that CCR2, and to some extent CCR1, play pivotal roles in the development of ALI.
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Affiliation(s)
- Dong Yang
- Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, PR China
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Zhang X, Feng G, Jiang J, Tian H, Chen L, Cai Y, Shou Y, Ma J, Ma M, Zhu F. Effect of baicalin and octreotide on the expression levels of P-selectin protein in multiple organs of rats with severe acute pancreatitis. J Gastroenterol Hepatol 2009; 24:1753-62. [PMID: 19780886 DOI: 10.1111/j.1440-1746.2009.05902.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
AIM To investigate the effect of baicalin and octreotide on the expression levels of P-selectin protein in multiple organs of rats with severe acute pancreatitis and explore the underlying mechanism. METHODS Rats were randomly divided into sham-operated, model control, baicalin-treated and octreotide-treated groups. At 3, 6 and 12 h after operation, the mortality rates of rats, the contents of plasma endotoxin as well as serum NO and ET-1, the pathological changes in multiple organs, and the expression levels of P-selectin protein in each group were observed. RESULTS At 12 h after operation, the mortality rates of rats in treated groups were significantly lower than that in the model control group (P < 0.05), and the pathological severity scores in multiple organs in treated groups were also significantly lower than those in the model control group (P < 0.05). The contents of plasma endotoxin, serum PLA(2) (at 6 and 12 h after operation), ET-1 and NO (at 3 and 12 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05, P < 0.01 or P < 0.001). In the baicalin-treated group, the expression levels of P-selectin protein in liver (at 3 h after operation), kidney (at 3 and 6 h after operation), pancreas, lung and spleen were significantly lower than those in the model control group (P < 0.01). In the octreotide-treated group, the expression levels of this protein in lung, intestinal mucosa (at 6 and 12 h after operation), lymph nodes (at 3 and 6 h after operation), spleen and thymus were significantly lower than those in the model control group (P < 0.05). Additionally, the products of the staining intensity and positive rate of P-selectin protein in pancreas, spleen (at 3 h after operation), intestinal mucosa (at 6 h after operation), thymus (at 6 h after operation) and lung (at 6 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05). CONCLUSION Both baicalin and octreotide can exert some protective effects on multiple organs and the former is superior to the latter in protecting pancreas. Furthermore, decreasing the expression levels of P-selectin protein in these organs is one of the possible mechanisms.
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Affiliation(s)
- Xiping Zhang
- Department of General Surgery, Hangzhou First People's Hospital, China.
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Liu H, Li Y, Wang L, Chen H, Guan J, Zhou Z. Aggravation of acute pancreatitis by heparan sulfate in mice. Scand J Gastroenterol 2009; 44:626-32. [PMID: 19194821 DOI: 10.1080/00365520902745047] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Systemic inflammatory response syndrome (SIRS) is responsible for pancreatitis-associated mortality, but its initiating events are poorly understood. Possible candidates may be endogenous substances, which have previously been shown to mediate inflammatory responses. The aim of this study was to investigate whether SIRS could be exaggerated by heparan sulfate (HS) in acute pancreatitis (AP). MATERIAL AND METHODS AP was induced in mice by cerulein injection and HS was administered one hour after the final cerulein injection. The severity of pancreatitis was assessed by serum amylase activity, pancreatic edema, and pancreatic myeloperoxidase (MPO) activity. Systemic inflammation was evaluated by assessing lung injury and by measuring serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. Cytokine levels were also measured in pancreas and lung tissues. RESULTS HS did not worsen the pancreatic injury induced by cerulein. In contrast, HS exacerbated the systemic inflammation as measured by augmented lung MPO activity, increased lung TNF-alpha and IL-6 levels, and elevated serum IL-6 levels. CONCLUSIONS Our results indicate a potential role for HS in propagating pancreatic inflammation from a local process to a systemic response and thus suggest the possibility that blockade of HS might improve the outcome of SIRS in AP.
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Affiliation(s)
- Hongxiang Liu
- Institute of Digestive Surgery, West China Hospital, Sichuan University, Chengdu, China
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16
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Bonville CA, Percopo CM, Dyer KD, Gao J, Prussin C, Foster B, Rosenberg HF, Domachowske JB. Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo. BMC Immunol 2009; 10:14. [PMID: 19298652 PMCID: PMC2662797 DOI: 10.1186/1471-2172-10-14] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2008] [Accepted: 03/19/2009] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND We have shown previously that acute infection with the respiratory pathogen, pneumonia virus of mice (PVM), results in local production of the proinflammatory chemokine, CCL3, and that neutrophil recruitment in response to PVM infection is reduced dramatically in CCL3 -/- mice. RESULTS In this work, we demonstrate that CCL3-mediated neutrophil recruitment is coordinated by interferon-gamma (IFNgamma). Neutrophil recruitment in response to PVM infection was diminished five-fold in IFNgamma receptor gene-deleted mice, although neutrophils from IFNgammaR -/- mice expressed transcripts for the CCL3 receptor, CCR1 and responded functionally to CCL3 ex vivo. Similarly, in the absence of PVM infection, CCL3 overexpression alone could not elicit neutrophil recruitment in the absence of IFNgamma. Interestingly, although supplemental IFNgamma restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFNgamma -/- mice, CCL3-mediated neutrophil recruitment alone did not result in the pulmonary edema or respiratory failure characteristic of severe viral infection, suggesting that CCL3 and IFN-gamma together are sufficient to promote neutrophil recruitment but not pathologic activation. CONCLUSION Our findings reveal a heretofore unrecognized hierarchical interaction between the IFNgamma and CCL3, which demonstrate that IFNgamma is crucial for CCL3-mediated neutrophil recruitment in vivo.
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MESH Headings
- Animals
- Cell Movement/immunology
- Chemokine CCL3/genetics
- Chemokine CCL3/immunology
- Chemokine CCL3/metabolism
- Gene Expression Profiling
- Interferon-gamma/genetics
- Interferon-gamma/immunology
- Interferon-gamma/metabolism
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/pathology
- Lung/immunology
- Lung/metabolism
- Lung/pathology
- Lung/virology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Murine pneumonia virus/immunology
- Murine pneumonia virus/pathogenicity
- Neutrophils/immunology
- Neutrophils/metabolism
- Neutrophils/pathology
- Pneumovirus Infections/genetics
- Pneumovirus Infections/immunology
- Pneumovirus Infections/physiopathology
- Pulmonary Edema
- Receptors, CCR1/genetics
- Receptors, CCR1/immunology
- Receptors, CCR1/metabolism
- Receptors, Interferon/genetics
- Receptors, Interferon/immunology
- Receptors, Interferon/metabolism
- Respiratory Insufficiency
- Signal Transduction/immunology
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- T-Lymphocytes/pathology
- Interferon gamma Receptor
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Affiliation(s)
| | - Caroline M Percopo
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Kimberly D Dyer
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Jiliang Gao
- Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Calman Prussin
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Barbara Foster
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
- Proteus Technologies, 133 National Business Parkway, Suite 150, Annapolis Junction, Maryland, 20701, USA
| | - Helene F Rosenberg
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
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17
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Schaller MA, Kallal LE, Lukacs NW. A key role for CC chemokine receptor 1 in T-cell-mediated respiratory inflammation. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:386-94. [PMID: 18202190 DOI: 10.2353/ajpath.2008.070537] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
CC chemokine receptor 1 (CCR1) is found on a variety of cells in the immune system and has been shown to play an important role in the host response to pathogens. These studies used a murine model of virus-induced exacerbation of allergic airway disease to examine the role of CCR1 on T cells associated with immune responses taking place in the lung. Lungs of virally exacerbated allergic animals contained elevated levels of interferon-gamma and interleukin-13 and increased levels of CCR1 ligands CCL3 and CCL5. CCR1 expression on T cells was increased in virally exacerbated allergic animals over the level observed in mice sensitized to allergen or exposed to viral infection alone. Using mice deficient for CCR1, we observed decreased airway hyperreactivity and Th2 cytokine production from CD4(+) T cells when this receptor was absent. Transfer studies demonstrated that neither CD4(+) nor CD8(+) T cells from CCR1(-/-) mice migrated to the lymph node as efficiently as wild-type T cells. Intracellular cytokine staining in wild-type mice revealed that CCR1(+) CD4(+) and CD8(+) T cells are associated with interleukin-13 production. Thus, these studies identify CCR1 as a potential target for alleviating T-cell accumulation during exacerbation of asthmatic disease.
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18
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Liehn EA, Merx MW, Postea O, Becher S, Djalali-Talab Y, Shagdarsuren E, Kelm M, Zernecke A, Weber C. Ccr1 deficiency reduces inflammatory remodelling and preserves left ventricular function after myocardial infarction. J Cell Mol Med 2007; 12:496-506. [PMID: 18088392 PMCID: PMC3822538 DOI: 10.1111/j.1582-4934.2007.00194.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Myocardial necrosis triggers inflammatory changes and a complex cytokine cascade that are only incompletely understood. The chemokine receptor CCR1 mediates inflammatory recruitment in response to several ligands released by activated platelets and up-regulated after myocardial infarction (MI). Here, we assess the effect of CCR1 on remodelling after MI using Ccr1-deficient (Ccr1−/−) mice. MI was induced in Ccr1−/− or wild-type mice by proximal ligation of the left anterior descending (LAD). Mice were sacrificed and analysed at day 1, 4, 7, 14 and 21 after MI. While initial infarct areas and areas at risk did not differ between groups, infarct size increased to 20.6±8.4% of the left ventricle (LV) in wild-type mice by day 21 but remained at 11.2±1.2% of LV (P<0.05) in Ccr1−/− mice. This attenuation in infarct expansion was associated with preserved LV function, as analysed by isolated heart studies according to Langendorff. Left ventricular developed pressure was 84.5±19.8 mmHg in Ccr1−/− mice compared to 49.0±19.7 mmHg in wild-type mice (P<0.01) and coronary flow reserve was improved in Ccr1−/− mice. An altered post-infarct inflammatory pattern was observed in Ccr1−/− mice characterized by diminished neutrophil infiltration, accelerated monocyte/lymphocyte infiltration, decreased apoptosis, increased cell proliferation and earlier myofibroblast population in the infarcted tissue. In conclusion, functional impairment and structural remodelling after MI is reduced in the genetic absence of Ccr1 due to an abrogated early inflammatory recruitment of neutrophils and improved tissue healing, thus revealing a potential therapeutic target.
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Affiliation(s)
- E A Liehn
- Institute for Molecular Cardiovascular Research, RWTH Aachen University, Aachen, Germany
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