Ligation of endothelial alpha v beta 3 integrin increases capillary hydraulic conductivity of rat lung.
Complement-mediated pulmonary edema results from increases in lung capillary hydraulic conductivity (Lp), possibly by receptor-mediated mechanisms. We considered the Lp effects of vitronectin and the vitronectin-containing complement complex SC5b-9, which ligate the integrin alpha v beta 3. Vitronectin, SC5b-9, and SC5b-9-enriched zymosan-activated serum all rapidly increased Lp, as determined by the split-drop technique in single lung capillaries of rat lung. The Lp increases were inhibited by a monospecific (LM609) and a polyclonal (R838) antibody against the alpha v beta 3 integrin but not by an irrelevant monoclonal antibody isotype matched with LM609, by a monoclonal antibody against the alpha v beta 5 integrin, or by preimmune rabbit serum. Vitronectin monomers failed to increase Lp. The tyrosine kinase blockers genistein and methyl 2,5-dihydroxycinnamate caused significant concentration-dependent inhibitions of Lp increases due to vitronectin and zymosan-activated serum. By contrast, the protein kinase C blocker calphostin C had no major effect. We conclude that (1) multivalent ligation of the luminally located alpha v beta 3 integrin of lung capillary endothelium increases transcapillary liquid flux, and (2) the dominant signal transduction pathway for this effect occurs through tyrosine kinase activation.
Tsukada
H
H
Department of Medicine, College of Physicians & Surgeons, Columbia University, St. Luke's-Roosevelt Hospital Center, New York, NY 10019, USA.
Ying
X
X
Fu
C
C
Ishikawa
S
S
McKeown-Longo
P
P
Albelda
S
S
Bhattacharya
S
S
Bray
B A
BA
Bhattacharya
J
J
D000818:Animals; D002199:Capillary Permeability; D015938:Complement Membrane Attack Complex; D003165:Complement System Proteins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D006023:Glycoproteins / Q000494:pharmacology; D008168:Lung / Q000098:blood supply*; D008833:Microcirculation / Q000502:physiology*; D011817:Rabbits; D051381:Rats; D019030:Receptors, Vitronectin / Q000502:physiology*; D019096:Vitronectin / Q000493:pharmacokinetics / Q000502:physiology
D015938:Complement Membrane Attack Complex; D006023:Glycoproteins; D019030:Receptors, Vitronectin; C047610:SC5b-9 protein complex; D019096:Vitronectin; D003165:Complement System Proteins