TGF-beta is a critical mediator of acute lung injury.
We have shown that the integrin alphavbeta6 activates latent TGF-beta in the lungs and skin. We show here that mice lacking this integrin are completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury (ALI). Pharmacologic inhibition of TGF-beta also protected wild-type mice from pulmonary edema induced by bleomycin or Escherichia coli endotoxin. TGF-beta directly increased alveolar epithelial permeability in vitro by a mechanism that involved depletion of intracellular glutathione. These data suggest that integrin-mediated local activation of TGF-beta is critical to the development of pulmonary edema in ALI and that blocking TGF-beta or its activation could be effective treatments for this currently untreatable disorder.
Pittet
J F
JF
Departments of Anesthesia and Surgery, University of California San Francisco, San Francisco, California 94110, USA.
Griffiths
M J
MJ
Geiser
T
T
Kaminski
N
N
Dalton
S L
SL
Huang
X
X
Brown
L A
LA
Gotwals
P J
PJ
Koteliansky
V E
VE
Matthay
M A
MA
Sheppard
D
D
D000818:Animals; D000951:Antigens, Neoplasm; D001761:Bleomycin; D015824:Blood-Air Barrier / Q000502:physiology; D002478:Cells, Cultured; D004731:Endotoxins; D005978:Glutathione / Q000378:metabolism; D016023:Integrins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases; D011650:Pulmonary Alveoli / Q000378:metabolism; D011654:Pulmonary Edema / Q000209:etiology / Q000473:pathology; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage; D012128:Respiratory Distress Syndrome / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000502:physiology*
D000951:Antigens, Neoplasm; D004731:Endotoxins; D016023:Integrins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D001761:Bleomycin; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D005978:Glutathione