Published online before print May 14, 2009

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(American Journal of Pathology. 2009;174:2378-2387.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080942

5β1 Integrin Blockade Inhibits Lymphangiogenesis in Airway Inflammation

Tatsuma Okazaki^*, Amy Ni^*, Oluwasheyi A. Ayeni^*, Peter Baluk^*, Li-Chin Yao^*, Doerte Vossmeyer, Gunther Zischinsky, Grit Zahn, Jochen Knolle, Claudia Christner and Donald M. McDonald^*

From the Department of Anatomy,^* Cardiovascular Research Institute, and Comprehensive Cancer Center, University of California, San Francisco, California; and Jerini AG, Berlin, Germany

The integrin 5β1 has been previously implicated in tumor angiogenesis, but its role in the remodeling of both blood vessels and lymphatics during inflammation is at an early stage of understanding. We examined this issue using a selective, small-molecule inhibitor of 5β1 integrin, 2-aroylamino-3-{4-[(pyridin-2-ylaminomethyl)heterocyclyl]phenyl}propionic acid (JSM8757), in a model of sustained airway inflammation in mice with Mycoplasma pulmonis infection, which is known to be accompanied by robust blood vessel remodeling and lymphangiogenesis. The inhibitor significantly decreased the proliferation of lymphatic endothelial cells in culture and the number of lymphatic sprouts and new lymphatics in airways of mice infected for 2 weeks but did not reduce remodeling of blood vessels in the same airways. In inflamed airways, 5 integrin immunoreactivity was present on lymphatic sprouts, but not on collecting lymphatics or blood vessels, and was not found on any lymphatics of normal airways. Macrophages, potential targets of the inhibitor, did not have 5 integrin immunoreactivity in inflamed airways. In addition, macrophage recruitment, assessed in infected airways by quantitative reverse transcription-polymerase chain reaction measurements of expression of the marker protein ionized calcium-binding adapter molecule 1 (Iba1), was not reduced by JSM8757. We conclude that inhibition of the 5β1 integrin reduces lymphangiogenesis in inflamed airways after M. pulmonis infection because expression of the integrin is selectively increased on lymphatic sprouts and plays an essential role in lymphatic growth.

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