title: alpha5beta1 Integrin blockade inhibits lymphangiogenesis in airway inflammation.
abstract: The integrin alpha5beta1 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 alpha5beta1 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, alpha5 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 alpha5 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 alpha5beta1 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.
authors.affiliation: Department of Anatomy, S1363, University of California, 513 Parnassus Avenue, San Francisco, CA 94143-0452, USA.
authors.forename: Tatsuma
authors.initials: T
authors.lastname: Okazaki
authors.forename: Amy
authors.initials: A
authors.lastname: Ni
authors.forename: Oluwasheyi A
authors.initials: OA
authors.lastname: Ayeni
authors.forename: Peter
authors.initials: P
authors.lastname: Baluk
authors.forename: Li-Chin
authors.initials: LC
authors.lastname: Yao
authors.forename: Doerte
authors.initials: D
authors.lastname: Vossmeyer
authors.forename: Gunther
authors.initials: G
authors.lastname: Zischinsky
authors.forename: Grit
authors.initials: G
authors.lastname: Zahn
authors.forename: Jochen
authors.initials: J
authors.lastname: Knolle
authors.forename: Claudia
authors.initials: C
authors.lastname: Christner
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000818:Animals; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology; D042583:Lymphangiogenesis / Q000187:drug effects / Q000502:physiology*; D042601:Lymphatic Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009175:Mycoplasma Infections / Q000378:metabolism / Q000503:physiopathology; D045803:Mycoplasma pulmonis; D011014:Pneumonia / Q000378:metabolism* / Q000382:microbiology; D011422:Propionates / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D011422:Propionates