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Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice.

Griffiths RJ, Smith MA, Roach ML, Stock JL, Stam EJ, Milici AJ, Scampoli DN, Eskra JD, Byrum RS, Koller BH, McNeish JD - J. Exp. Med. (1997)

Bottom Line: The inflammatory response to zymosan is reduced in FLAP-deficient mice.The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals.This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer, Immunology, and Infectious Diseases, Pfizer, Inc., Groton, Connecticut 06340, USA.

ABSTRACT
Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.

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Light microscopy of  the knee joint from FLAP −/−,  +/−, and +/+ mice. In the  FLAP knockout mice (a) there is  an absence of inflammatory cells in  the synovial tissue surrounding  the joint cavity. An occasional  pannus tongue (arrow) was observed and tongues generally  lacked a large cellular component.  The femoral condyle (  f  ) articular  cartilage was intact, although regions of proteoglycan depletion  (arrowhead) were observed and  these typically coincided with the  pannus extensions. In the heterozygous mice (b), the articular  cartilage was removed down to the  tidemark (arrowheads) over large regions of the femoral condyle (  f  ).  Several pannus tongues (arrow)  and an increased inflammatory cell  influx into the surrounding synovial tissue were observed. In the  wild-type mice (c), the destruction  of the femoral condyle (  f  ) articular  cartilage (arrowheads) was much  more extensive. In addition, some  plasma proteins and cells (*) were  observed within the joint cavity.  The pannus tongues (arrow) and increased cellularity of the synovial  tissue were similar to that observed  in the heterozygous mice. Original  magnification, ×60.
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Figure 3: Light microscopy of the knee joint from FLAP −/−, +/−, and +/+ mice. In the FLAP knockout mice (a) there is an absence of inflammatory cells in the synovial tissue surrounding the joint cavity. An occasional pannus tongue (arrow) was observed and tongues generally lacked a large cellular component. The femoral condyle (  f  ) articular cartilage was intact, although regions of proteoglycan depletion (arrowhead) were observed and these typically coincided with the pannus extensions. In the heterozygous mice (b), the articular cartilage was removed down to the tidemark (arrowheads) over large regions of the femoral condyle (  f  ). Several pannus tongues (arrow) and an increased inflammatory cell influx into the surrounding synovial tissue were observed. In the wild-type mice (c), the destruction of the femoral condyle (  f  ) articular cartilage (arrowheads) was much more extensive. In addition, some plasma proteins and cells (*) were observed within the joint cavity. The pannus tongues (arrow) and increased cellularity of the synovial tissue were similar to that observed in the heterozygous mice. Original magnification, ×60.

Mentions: In the FLAP-deficient mice, there generally was an absence of inflammatory cells in the joint cavity or surrounding synovial tissue (Fig. 3 a). The articular cartilage was intact, although there were regions of extensive depletion of proteoglycans in the calcified and noncalcified cartilage. Moreover, small pannus tongues coincided with the regions of greatest proteoglycan loss in some animals. In both the heterozygous and wild-type animals (Fig. 3, b and c), the extent of disease was much more extensive. Generally, these animals contained an extensive leukocyte infiltration of the synovial connective tissue, plasma protein extravasation into the synovial cavity, and variable amounts of articular cartilage destruction.


Collagen-induced arthritis is reduced in 5-lipoxygenase-activating protein-deficient mice.

Griffiths RJ, Smith MA, Roach ML, Stock JL, Stam EJ, Milici AJ, Scampoli DN, Eskra JD, Byrum RS, Koller BH, McNeish JD - J. Exp. Med. (1997)

Light microscopy of  the knee joint from FLAP −/−,  +/−, and +/+ mice. In the  FLAP knockout mice (a) there is  an absence of inflammatory cells in  the synovial tissue surrounding  the joint cavity. An occasional  pannus tongue (arrow) was observed and tongues generally  lacked a large cellular component.  The femoral condyle (  f  ) articular  cartilage was intact, although regions of proteoglycan depletion  (arrowhead) were observed and  these typically coincided with the  pannus extensions. In the heterozygous mice (b), the articular  cartilage was removed down to the  tidemark (arrowheads) over large regions of the femoral condyle (  f  ).  Several pannus tongues (arrow)  and an increased inflammatory cell  influx into the surrounding synovial tissue were observed. In the  wild-type mice (c), the destruction  of the femoral condyle (  f  ) articular  cartilage (arrowheads) was much  more extensive. In addition, some  plasma proteins and cells (*) were  observed within the joint cavity.  The pannus tongues (arrow) and increased cellularity of the synovial  tissue were similar to that observed  in the heterozygous mice. Original  magnification, ×60.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196231&req=5

Figure 3: Light microscopy of the knee joint from FLAP −/−, +/−, and +/+ mice. In the FLAP knockout mice (a) there is an absence of inflammatory cells in the synovial tissue surrounding the joint cavity. An occasional pannus tongue (arrow) was observed and tongues generally lacked a large cellular component. The femoral condyle (  f  ) articular cartilage was intact, although regions of proteoglycan depletion (arrowhead) were observed and these typically coincided with the pannus extensions. In the heterozygous mice (b), the articular cartilage was removed down to the tidemark (arrowheads) over large regions of the femoral condyle (  f  ). Several pannus tongues (arrow) and an increased inflammatory cell influx into the surrounding synovial tissue were observed. In the wild-type mice (c), the destruction of the femoral condyle (  f  ) articular cartilage (arrowheads) was much more extensive. In addition, some plasma proteins and cells (*) were observed within the joint cavity. The pannus tongues (arrow) and increased cellularity of the synovial tissue were similar to that observed in the heterozygous mice. Original magnification, ×60.
Mentions: In the FLAP-deficient mice, there generally was an absence of inflammatory cells in the joint cavity or surrounding synovial tissue (Fig. 3 a). The articular cartilage was intact, although there were regions of extensive depletion of proteoglycans in the calcified and noncalcified cartilage. Moreover, small pannus tongues coincided with the regions of greatest proteoglycan loss in some animals. In both the heterozygous and wild-type animals (Fig. 3, b and c), the extent of disease was much more extensive. Generally, these animals contained an extensive leukocyte infiltration of the synovial connective tissue, plasma protein extravasation into the synovial cavity, and variable amounts of articular cartilage destruction.

Bottom Line: The inflammatory response to zymosan is reduced in FLAP-deficient mice.The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals.This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Cancer, Immunology, and Infectious Diseases, Pfizer, Inc., Groton, Connecticut 06340, USA.

ABSTRACT
Collagen-induced arthritis in the DBA/1 mouse is an experimental model of human rheumatoid arthritis. To examine the role of leukotrienes in the pathogenesis of this disease, we have developed embryonic stem (ES) cells from this mouse strain. Here, we report that DBA/1 mice made deficient in 5-lipoxygenase-activating protein (FLAP) by gene targeting in ES cells develop and grow normally. Zymosan-stimulated leukotriene production in the peritoneal cavity of these mice is undetectable, whereas they produce substantial amounts of prostaglandins. The inflammatory response to zymosan is reduced in FLAP-deficient mice. The severity of collagen-induced arthritis in the FLAP-deficient mice was substantially reduced when compared with wild-type or heterozygous animals. This was not due to an immunosuppressive effect, because anti-collagen antibody levels were similar in wild-type and FLAP-deficient mice. These data demonstrate that leukotrienes play an essential role in both the acute and chronic inflammatory response in mice.

Show MeSH
Related in: MedlinePlus