Role of the Chemokine Receptor CXCR2 in Bleomycin-Induced Pulmonary Inflammation and Fibrosis

被引:115
作者
Russo, Remo C. [1 ]
Guabiraba, Rodrigo [1 ]
Garcia, Cristiana C. [1 ]
Barcelos, Luciola S. [1 ]
Roffe, Ester [1 ]
Souza, Adriano L. S. [1 ]
Amaral, Flvio A. [1 ]
Cisalpino, Daniel [1 ]
Cassali, Geovanni D. [2 ]
Doni, Andrea [3 ]
Bertini, Riccardo [4 ]
Teixeira, Mauro M. [1 ]
机构
[1] Univ Fed Minas Gerais, Lab Imunofarmacol, Dept Bioquim & Immunol, Inst Ciencias Biol, BR-30882650 Belo Horizonte, MG, Brazil
[2] Univ Fed Minas Gerais, Dept Patol Geral, Inst Ciencias Biol, BR-30882650 Belo Horizonte, MG, Brazil
[3] ICH, IRCCS, Dept Immunol & Inflammat, Milan, Italy
[4] Dompe Pharma SPA, Dept Preclin Pharmacol, Laquila, Italy
关键词
CXCR2; neutrophil; angiogenesis; bleomycin; fibrosis; REPERFUSION INJURY; MINOR COMPONENT; LUNG FIBROSIS; CELLS; NEUTROPHIL; MECHANISMS; IL-13; PROLIFERATION; ANGIOGENESIS; PATHOGENESIS;
D O I
10.1165/rcmb.2007-0364OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pulmonary fibrosis is characterized by chronic inflammation and excessive collagen deposition. Neutrophils are thought to be involved in the pathogenesis of lung fibrosis. We hypothesized that CXCR2-mediated neutrophil recruitment is essential for the cascade of events leading to bleomycin-incluced pulmonary fibrosis. CXCL1 / KC was detected as early as 6 hours after bleomycin instillation and returned to basal levels after Day 8. Neutrophils were detected in bronchoalveolar lavage and interstitium from 12 hours and peaked at Day 8 after instillation. Treatment with the CXCR2 receptor antagonist, DF2162, reduced airway neutrophil transmigration but led to an increase of neutrophils in lung parenchyma. There was a significant reduction in IL-13, IL-10, CCL5/RANTES, and active transforming growth factor (TGF)-beta(1) levels, but not on IFN-gamma and total TGF-beta(1), and enhanced granulocyte macrophage-colony-stimulating factor production in DF2162-treated animals. Notably, treatment with the CXCR2 antagonist led to an improvement of the lung pathology and reduced Collagen deposition. Using a therapeutic schedule, DF2162 administered from Days 8 to 16 after bleomycin reduced pulmonary fibrosis and levels of active TGF-beta(1) and IL-13. DF2162 treatment reduced bleomycin-incluced expression of von Willebrand Factor, a marker of angiogenesis, in the lung. In vitro, DF2162 reduced the angiogenic activity of IL-8 on human umbilical vein endothelial cells. In conclusion, we show that CXCR2 plays an important role in mediating fibrosis after bleomycin instillation. The compound blocks angiogenesis and the production of pro-angiogenic cytokines, and decreases IL-8-induced endothelial cell activation. An effect on neutrophils does not appear to account for the major effects of the blockade of CXCR2 in the system.
引用
收藏
页码:410 / 421
页数:12
相关论文
共 50 条
[1]   New molecular targets for the treatment of neutrophilic diseases [J].
Barnes, Peter J. .
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY, 2007, 119 (05) :1055-1062
[2]   Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats [J].
Barsante, M. M. ;
Cunha, T. M. ;
Allegretti, M. ;
Cattani, F. ;
Policani, F. ;
Bizzarri, C. ;
Tafuri, W. L. ;
Poole, S. ;
Cunha, F. Q. ;
Bertini, R. ;
Teixeira, M. M. .
BRITISH JOURNAL OF PHARMACOLOGY, 2008, 153 (05) :992-1002
[3]  
Belperio JA, 2000, J LEUKOCYTE BIOL, V68, P1
[4]   Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: Prevention of reperfusion injury [J].
Bertini, R ;
Allegretti, M ;
Bizzarri, C ;
Moriconi, A ;
Locati, M ;
Zampella, G ;
Cervellera, MN ;
Di Cioccio, V ;
Cesta, MC ;
Galliera, E ;
Martinez, FO ;
Di Bitondo, R ;
Troiani, G ;
Sabbatini, V ;
D'Anniballe, G ;
Anacardio, R ;
Cutrin, JC ;
Cavalieri, B ;
Mainiero, F ;
Strippoli, R ;
Villa, P ;
Di Girolamo, M ;
Martin, F ;
Gentile, M ;
Santoni, A ;
Corda, D ;
Poli, G ;
Mantovani, A ;
Ghezzi, P ;
Colotta, F .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (32) :11791-11796
[5]   The neutrophil: Function and regulation in innate and humoral immunity [J].
Burg, ND ;
Pillinger, MH .
CLINICAL IMMUNOLOGY, 2001, 99 (01) :7-17
[7]   Disorders of lung matrix remodeling [J].
Chapman, HA .
JOURNAL OF CLINICAL INVESTIGATION, 2004, 113 (02) :148-157
[8]   Bleomycins: Towards better therapeutics [J].
Chen, JY ;
Stubbe, J .
NATURE REVIEWS CANCER, 2005, 5 (02) :102-112
[9]   Chemokine regulation of normal and pathologic immune responses [J].
Christopherson, K ;
Hromas, R .
STEM CELLS, 2001, 19 (05) :388-396
[10]   Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis [J].
Chua, Felix ;
Dunsmore, Sarah E. ;
Clingen, Peter H. ;
Mutsaers, Steven E. ;
Shapiro, Steven D. ;
Segal, Anthony W. ;
Roes, Jurgen ;
Laurent, Geoffrey J. .
AMERICAN JOURNAL OF PATHOLOGY, 2007, 170 (01) :65-74