THROMBOXANE MEDIATES DIAPEDESIS AFTER ISCHEMIA BY ACTIVATION OF NEUTROPHIL ADHESION RECEPTORS INTERACTING WITH BASALLY EXPRESSED INTERCELLULAR-ADHESION MOLECULE .1.

被引:60
作者
GOLDMAN, G
WELBOURN, R
KLAUSNER, JM
VALERI, CR
SHEPRO, D
HECHTMAN, HB
机构
[1] BRIGHAM & WOMENS HOSP,DEPT SURG,75 FRANCIS ST,BOSTON,MA 02115
[2] HARVARD UNIV,SCH MED,DEPT SURG,BOSTON,MA 02115
[3] USN,BLOOD RES LAB,WASHINGTON,DC 20350
[4] BOSTON UNIV,SCH MED,CTR BIOL SCI,BOSTON,MA 02118
关键词
THROMBOXANE SYNTHESIS; THROMBOXANE RECEPTOR ANTAGONISTS; AUTHENTIC THROMBOXANE-B2; CD-18;
D O I
10.1161/01.RES.68.4.1013
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ischemic injury is characterized by neutrophil (PMN)-endothelial cell adhesion and diapedesis associated with thromboxane (TX) generation. Neutrophil-endothelial cell interaction is regulated in part by the leukocyte adhesion receptor CD 18 glycoprotein complex and the endothelial intercellular adhesion molecule-1 (ICAM-1). This study tests the role of TX in ischemia-induced diapedesis and evaluates whether the diapedesis is regulated by neutrophil or endothelial adhesion receptors. Plasma derived from rabbit hind limbs made ischemic for 3 hours (n = 6) and reperfused for 10 minutes had increased levels of TXB2 3,450 pg/ml, which was higher than sham rabbit (n = 6) values of 653 pg/ml (p < 0.05). When introduced into abraded skin chambers placed on the dorsum of other normal rabbits (n = 6), this ischemic plasma induced 1,000 pg/ml of new TX synthesis and diapedesis of 1,235 PMN/mm3. The total TX concentration and PMN accumulations in blister fluid were correlated (r = 0.88, p < 0.05). In contrast, sham rabbit plasma induced no TX synthesis and diapedesis of only 77 PMN/mm3 (p < 0.05). Administration of 50 ng/ml of authentic TXB2 into blisters induced an accumulation of 453 PMN/mm3, which was higher than that in saline controls (18 PMN/mm3) (p < 0.05). Pretreatment of normal rabbits used for the diapedesis assay (n = 4) with the TX synthetase inhibitor OKY 046 (2 mg/kg/hr) limited ischemic plasma and authentic TXB2 induced diapedesis to 142 and 76 PMN/mm3, respectively (both p < 0.05). Pretreatment of other normal rabbits (n = 4) with the TX receptor antagonist SQ 29,548 (2 mg/kg) by intravenous bolus and then 0.2 mg/kg min also reduced diapedesis induced by ischemic plasma and authentic TXB2 to 48 and 8 PMN/mm3 (both p < 0.05). In yet other rabbits (n = 9), antagonists and agonists were locally administered into the abraded skin chambers. With the saline control antagonist, ischemic plasma or authentic TXB2 led to 927 and 404 PMN/mm3. The CD 18 monoclonal antibody R 15.7 lowered ischemic plasma and authentic TXB2 induced diapedesis to 21 and 22 PMN/mm3, respectively (both p < 0.05). R 15.7 was shown to diffuse from blister and progressively bind to circulating PMNs over the 3-hour monitoring period. Local administration of the anti-ICAM-1 antibody RR 1.1 also reduced diapedesis induced by ischemic plasma and authentic TXB2 to 119 and 93 PMN/mm3, respectively (both p < 0.05). In contrast, local application of the protein synthesis inhibitor actinomycin D (3 ng) was without inhibitory effect, suggesting a lack of synthesis of new endothelial adhesion proteins. The data indicate that TX mediates diapedesis after ischemia through regulation of neutrophil but not endothelial cell adhesion receptors.
引用
收藏
页码:1013 / 1019
页数:7
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