Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Mice Lacking the Receptor-Like Protein Tyrosine Phosphatase CD148 Are Protected from Bleomycin-Induced Pulmonary Fibrosis.

Katsumoto1,  Tamiko R., Kim2,  Kevin K., Brumwell2,  Alexis N., Nguyen2,  John X., Zhu2,  Jing W., Looney2,  Mark R., Chapman2,  Harold A.

UCSF, South San Francisco, CA
UCSF

Purpose:

The molecular mechanisms underlying pulmonary fibrosis, one of the most morbid complications of scleroderma, remain incompletely characterized. Protein tyrosine phosphatases and kinases regulate the equilibrium of tyrosine phosphorylation signaling pathways important in cell growth and differentiation. Tyrosine kinases have been implicated in fibrosis, and studies testing the anti-fibrotic activity of tyrosine kinase inhibitors such as imatinib in scleroderma patients are underway. The receptor-like protein tyrosine phosphatase (RPTP) CD148 is widely expressed on various hematopoietic and non-hematopoietic lineages, including lung epithelial cells, endothelial cells, and fibroblasts. Given the importance of tyrosine phosphorylation pathways in fibrosis, we explored the role of CD148 in the bleomycin mouse model of pulmonary fibrosis.

Methods:

Mice with a targeted deletion of the CD148 transmembrane domain (CD148KO) have been generated by our lab and are used in all studies described. Acute lung injury was measured using extravasation of radioactive iodine-labeled albumin and wet-to-dry ratios. Fibrosis was evaluated by both Masson Trichrome staining of lung sections as well as by the Sircol Collagen Assay (Biocolor).

Results:

Following intratracheal instillation of bleomycin at a dose of 3 units/kg, WT mice showed significantly impaired survival, with 4 of 6 WT mice (67%) dying between 10–16 days, whereas none of the 8 CD148KO mice (0%) died (p=0.007). Masson Trichrome staining of lungs demonstrated markedly increased fibrosis in WT mice, whereas fibrosis was significantly attenuated in the CD148KO mice. At day #13 following a lower dose of bleomycin (2.5 U/kg), WT bleomycin-treated mice had a 4.2-fold increase in lung collagen content whereas CD148KO mice showed only a 1.7-fold increase in collagen (p=0.0009). Lung collagen levels in WT bleomycin mice (66.1+/-6.1 ug/ml) were significantly higher than in WT saline mice (15.8+/-0.8 ug/ml) (p=0.0008), whereas lung collagen levels in CD148KO bleomycin mice (46.1+/-8.2 ug/ml) vs. CD148KO saline mice (26.6+/-7.2 ug/ml) were not significantly different (p=0.157). The acute lung injury response at day #5 post bleomycin (2.5 U/kg) was equivalent between genotypes. Endothelial permeability was 1.7%+/-0.33% in WT saline mice vs. 1.5%+/-0.39% in CD148KO saline mice. Following bleomycin, the increase in endothelial permeability in WT mice to 3.9%+/-0.67% and in CD148KO mice to 3.9%+/-0.39% was equivalent between genotypes (n=4 mice per genotype).

Conclusion:

Mice lacking CD148 phosphatase activity show improved survival. Attenuation of bleomycin-induced fibrosis does not appear to be the consequence of a diminished early acute lung injury response to bleomycin. Future studies will interrogate the specific cell types mediating this response, as well as elucidating the pathways regulated by CD148 underlying this phenotype. These data suggest that inhibition of the RPTP CD148 may present an attractive anti-fibrotic therapeutic strategy.

To cite this abstract, please use the following information:
Katsumoto, Tamiko R., Kim, Kevin K., Brumwell, Alexis N., Nguyen, John X., Zhu, Jing W., Looney, Mark R., et al; Mice Lacking the Receptor-Like Protein Tyrosine Phosphatase CD148 Are Protected from Bleomycin-Induced Pulmonary Fibrosis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :609
DOI: 10.1002/art.28377

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