Discoidin domain receptor 1-deficient mice are resistant to bleomycin-induced lung fibrosis

被引:110
作者
Avivi-Green, Carmel [1 ]
Singal, Mayank [1 ]
Vogel, Wolfgang F. [1 ]
机构
[1] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
关键词
kinases/phosphatases; lung; signal transduction; transgenic/knockout mice;
D O I
10.1164/rccm.200603-333OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Rationale: Discoidin domain receptor 1 (DDR1) is a tyrosine kinase activated by native collagens. Based on previous findings showing increased DDR1 expression in bronchoalveolar lavage cells from patients with idiopathic pulmonary fibrosis, we hypothesized that DDR1 mediates disease progression after lung injury. Objectives: To investigate the inflammatory and fibrotic responses of DDR1 knockout and wild-type mice to bleomycin-induced lung injury. Methods: Age- and sex-matched DDR1 knockout and wild-type C57BL/6 mice received a single intratracheal instillation of 2 U/kg bleomycin or saline, respectively. After 2 wk, lung inflammation and fibrosis were assessed using immunohistochemistry, real-time polymerase chain reaction, TUNEL assay, ELISA, fluorescence-activated cell sorting, and Western blot analysis. Measurements and Main Results: Compared with wild-type animals, DDR1-null mice were largely protected against bleomycin-induced injury. Bleomycin-induced increases in Collagen protein levels and tenascin-C mRNA levels were abrogated in knockout animals. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and a cytokine ELISA. Western blot analysis of injured lung tissue revealed that DDR1-null mice failed to respond to the bleomycin insult with p38 MAPK activation, which was readily observed in wild-type mice. Conclusions: DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis. Blockade of DDR1 may therefore be a novel therapeutic intervention in patients with pulmonary fibrosis.
引用
收藏
页码:420 / 427
页数:8
相关论文
共 45 条
[1]  
ADAMSON IYR, 1974, AM J PATHOL, V77, P185
[2]  
ALVES F, 1995, ONCOGENE, V10, P609
[3]   Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice [J].
Aono, Y ;
Nishioka, Y ;
Inayama, M ;
Ugai, M ;
Kishi, J ;
Uehara, H ;
Izumi, K ;
Sone, S .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2005, 171 (11) :1279-1285
[4]   Lymphangioleiomyomatosis: A case report and review of the literature [J].
Bearz, A ;
Rupolo, M ;
Canzonieri, V ;
Balestreri, L ;
La Mura, N ;
Berretta, M ;
Colussi, AM ;
Frustaci, S .
TUMORI, 2004, 90 (05) :528-531
[5]  
BOWDEN DH, 1984, LAB INVEST, V50, P487
[6]   A catalytic antioxidant attenuates alveolar structural remodeling in bronchopulmonary dysplasia [J].
Chang, LYL ;
Subramaniam, M ;
Yoder, BA ;
Day, BJ ;
Ellison, MC ;
Sunday, ME ;
Crapo, JD .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2003, 167 (01) :57-64
[7]   Differential expression of receptor tyrosine kinases and Shc in fetal and adult rat fibroblasts: Toward defining scarless versus scarring fibroblast phenotypes [J].
Chin, GS ;
Kim, WJH ;
Lee, TY ;
Liu, W ;
Saadeh, PB ;
Lee, S ;
Levinson, H ;
Gittes, GK ;
Longaker, MT .
PLASTIC AND RECONSTRUCTIVE SURGERY, 2000, 105 (03) :972-979
[8]   Tissue repair, contraction, and the myofibroblast [J].
Desmoulière, A ;
Chaponnier, C ;
Gabbiani, G .
WOUND REPAIR AND REGENERATION, 2005, 13 (01) :7-12
[9]   Is idiopathic pulmonary fibrosis now treatable? [J].
du Bois, RM .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2005, 171 (09) :939-940
[10]   DDR1 signaling is essential to sustain Stat5 function during lactogenesis [J].
Faraci-Orf, E ;
McFadden, C ;
Vogel, WF .
JOURNAL OF CELLULAR BIOCHEMISTRY, 2006, 97 (01) :109-121