Insulin-like growth factor-I receptor blockade improves outcome in mouse model of lung injury.
BACKGROUND
The insulin-like growth factor-I (IGF-I) pathway is an important determinant of survival and proliferation in many cells. However, little is known about the role of the IGF-I pathway in lung injury. We previously showed elevated levels of IGF-I in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome. Furthermore, immunodepletion of IGF from acute respiratory distress syndrome bronchoalveolar lavage increased fibroblast apoptosis.


OBJECTIVE
We examined the effect of blockade of type 1 IGF tyrosine kinase receptor (IGF-IR) in a murine model of bleomycin-induced lung injury and fibrosis.


METHODS
Mice were treated with a monoclonal antibody against the IGF-I receptor (A12) or vehicle after intratracheal bleomycin instillation.


RESULTS
Mice treated with A12 antibody had significantly improved survival after bleomycin injury compared with control mice. Both groups of mice had a similar degree of fibrosis on days 7 and 14, but by Day 28 the A12-treated group had significantly less fibrosis. Delayed treatment with A12 also resulted in decreased fibrosis. A12-treated mice had significantly decreased apoptotic cells on Day 28 compared with control mice. We confirmed that A12 treatment induced mouse lung fibroblast apoptosis in vitro. In addition, IGF-I increased lung fibroblast migration. The primary pathway activated by IGF-I in lung fibroblasts was the insulin receptor substrate-2/phosphatidylinositol 3-kinase/Akt axis.


CONCLUSIONS
IGF-I regulated survival and migration of fibrogenic cells in the lung. Blockade of the IGF pathway increased fibroblast apoptosis and subsequent resolution of pulmonary fibrosis. Thus, IGF-IR may be a potential target for treatment of lung injury and fibrosis.
Choi
Jung-Eun
JE
Divison of Pulmonary and Critical Care Medicine, Department of Medicine, Harborview Medical Center, University of Washington, Seattle,Washington, USA.
Lee
Sung-Soon
SS
Sunde
Donald A
DA
Huizar
Isham
I
Haugk
Kathy L
KL
Thannickal
Victor J
VJ
Vittal
Ragini
R
Plymate
Stephen R
SR
Schnapp
Lynn M
LM
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005500:Follow-Up Studies; D015870:Gene Expression; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D001761:Bleomycin; D017526:Receptor, IGF Type 1