Insulin-like growth factor-I receptor blockade improves outcome in mouse model of lung injury

Am J Respir Crit Care Med. 2009 Feb 1;179(3):212-9. doi: 10.1164/rccm.200802-228OC. Epub 2008 Nov 14.


Rationale: 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.

Objectives: 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.

Measurements and main 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.

Publication types

  • Comparative Study

MeSH terms

  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / therapeutic use*
  • Apoptosis
  • Bleomycin / toxicity
  • Blotting, Western
  • Bronchoalveolar Lavage Fluid / chemistry
  • Bronchoalveolar Lavage Fluid / cytology
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects
  • Fibroblasts / pathology
  • Follow-Up Studies
  • Gene Expression
  • Immunohistochemistry
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Polymerase Chain Reaction
  • Pulmonary Fibrosis / drug therapy
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • RNA, Messenger / genetics
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Treatment Outcome


  • Antibodies, Monoclonal
  • RNA, Messenger
  • Bleomycin
  • Receptor, IGF Type 1