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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online March 4, 2004 as doi:10.1096/fj.03-0835fje. |
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The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania, USA
2Correspondence: The Sol Sherry Thrombosis Research Center, Temple University School of Medicine, 3400 North Broad St., Room 300, OMS, Philadelphia, PA 19140, USA. E-mail: colmanr{at}temple.edu
SPECIFIC AIM
The aim of this study was to delineate mechanisms by which bradykinin can influence development of chronic synovial inflammation in an animal model of arthritis. We hypothesize that bradykinin can regulate cell adhesion molecules (CAMs) on leukocyte, endothelial, and synovial cells.
PRINCIPAL FINDINGS
1. Bradykinin-1, bradykinin-2 and combined B1-and-B2 receptor antagonist (B-RA) treatments altered the clinical course of PG-PS-induced arthritis in Lewis rats (Fig. 1)
Thirty-three female Lewis rats were separated into five groups: negative control group (HSA; n=4); positive group (PG-PS; n=6); B1-RA (n=7), B2-RA (n=8); and combined B1 and B2-RA (n=8) treatment groups. All groups were followed for 20 days. It was found that 1) B1-RA treatment increased joint swelling; 2) B2-RA treatment did not affect disease evolution; and 3) combined B1-RA-and-B2-RA treatment neutralized aggravation of inflammation caused by B1-R blockade.
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2. Bradykinin receptor antagonist (B-RA) treatments modulated CAMs expression on leukocytes, endothelium, and synovium present in hindpaw sections from PG-PS-induced arthritis from Lewis rats (Table 1 )
Cell adhesion markers included: CD11a/LFA-1, CD11b/Mac-1, CD44/HCAM, CD54/ICAM and CD62-L/L-selectin. When compared with CAM expression on the PG-PS group, treated groups showed statistically significant changes. In the B1-RA treated group, leukocytes increased CD11b and CD54 expression, endothelium increased CD44 and CD11b expression, and synovium increased CD54 and CD11b expression. In the B2-RA treated group, leukocytes decreased CD44 and CD54 expression, endothelium CD11b decreased expression, and synovium decreased CD44 and CD11a expression. In the combined B1 and B2-RA treated group, leukocytes increased CD62L and CD11b expression and decreased CD54 expression; endothelium increased CD44, CD11a, and CD11b expression and decreased CD62-L expression; and synovium increased CD11b expression.
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CONCLUSIONS AND SIGNIFICANCE
The present study shows that PG-PS induced arthritis treated with B2 receptor antagonist evolved similarly to the disease-untreated group. By inhibiting the B1 receptor and thereby allowing B2-R activation, arthritis worsened. When both receptors were blocked, inflammation aggravated by B1-R blockade was neutralized. Thus B2-R and B1-R activation exhibit physiological antagonism. Although the B2 receptor is constitutive, B1 receptor expression is induced by and highly expressed in inflammation (Fig. 2
).
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Hindpaw joint tissue section immunohistochemistry showed that by blocking B1 receptor, thus allowing the function of B2 receptor, there was increased expression of leukocyte adhesion (CD11b) and transmigration (CD54) markers by leukocytes and synovial cells. Endothelial cells expressed increased leukocyte adhesion (CD11b) and lymphocyte homing (CD44) markers. By blocking B2 receptor and allowing the function of B1 receptor, there was decreased expression of homing (CD44) and transmigration (CD54) markers by leukocytes, decreased leukocyte adhesion markers (CD11b) by endothelium, and decreased leukocyte adhesion (CD11a) and homing (CD44) by synovium. Remaining cell adhesion molecule expression was similar to the disease-untreated group (PG-PS). When both receptors were blocked, there was decreased rolling (CD62-L), adhesion (CD11b), and transmigration (CD54) marker expression by leukocytes. There was increased leukocyte adhesion (CD11b) marker expression by synovium; while endothelial cells showed increased expression of adhesion (CD11a, CD11b) and homing (CD44). We also detected CD62-L, which may indicate prior leukocyte activation, rolling, and subsequent CD62-L shedding (soluble CD62-L).
This study shows that sequential function of bradykinin receptors is required by control and management of inflammatory responses. When inhibiting activation of B2-R, the disease process was unaffected. In contrast, by targeting B1-R and inhibiting its interaction with kinins during inflammation, the arthritic process was significantly aggravated. When both B1 and B2 receptors are blocked, aggravation of inflammation by B1-R blockade is neutralized and there is no difference from the disease-untreated model. Further studies are needed to evaluate the role of the B1 receptor agonist in this model.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0835fje; 
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