TY - JOUR
T1 - α5β1 integrin blockade inhibits lymphangiogenesis in airway inflammation
AU - Okazaki, Tatsuma
AU - Ni, Amy
AU - Ayeni, Oluwasheyi A.
AU - Baluk, Peter
AU - Yao, Li Chin
AU - Vossmeyer, Doerte
AU - Zischinsky, Gunther
AU - Zahn, Grit
AU - Knolle, Jochen
AU - Christner, Claudia
AU - McDonald, Donald M.
N1 - Funding Information:
Supported in part by a grant from Jerini AG Berlin to the University of California, San Francisco (to D.M.M.). This research was supported in part by National Institutes of Health grants HL24136 and HL59157 from the National Heart, Lung, and Blood Institute , CA82923 from the National Cancer Institute, and funding from AngelWorks Foundation (to D.M.M.) Research funding was also provided by Jerini AG. T.O. was supported in part by a postdoctoral fellowship from the Uehara Memorial Foundation of Japan.
PY - 2009/6
Y1 - 2009/6
N2 - The integrin α5β1 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 α5β1 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, α5 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 α5 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 α5β1 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.
AB - The integrin α5β1 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 α5β1 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, α5 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 α5 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 α5β1 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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U2 - 10.2353/ajpath.2009.080942
DO - 10.2353/ajpath.2009.080942
M3 - Article
C2 - 19443705
AN - SCOPUS:67049114117
VL - 174
SP - 2378
EP - 2387
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 6
ER -