Gene expression changes during the development of acute lung injury: role of transforming growth factor beta

Am J Respir Crit Care Med. 2005 Dec 1;172(11):1399-411. doi: 10.1164/rccm.200502-286OC. Epub 2005 Aug 11.


Rationale: Acute lung injury can occur from multiple causes, resulting in high mortality. The pathophysiology of nickel-induced acute lung injury in mice is remarkably complex, and the molecular mechanisms are uncertain.

Objectives: To integrate molecular pathways and investigate the role of transforming growth factor beta (TGF-beta) in acute lung injury in mice.

Methods: cDNA microarray analyses were used to identify lung gene expression changes after nickel exposure. MAPPFinder analysis of the microarray data was used to determine significantly altered molecular pathways. TGF-beta1 protein in bronchoalveolar lavage fluid, as well as the effect of inhibition of TGF-beta, was assessed in nickel-exposed mice. The effect of TGF-beta on surfactant-associated protein B (Sftpb) promoter activity was measured in mouse lung epithelial cells.

Measurements and main results: Genes that decreased the most after nickel exposure play important roles in lung fluid absorption or surfactant and phospholipid synthesis, and genes that increased the most were involved in TGF-beta signaling. MAPPFinder analysis further established TGF-beta signaling to be significantly altered. TGF-beta-inducible genes involved in the regulation of extracellular matrix function and fibrinolysis were significantly increased after nickel exposure, and TGF-beta1 protein was also increased in the lavage fluid. Pharmacologic inhibition of TGF-beta attenuated nickel-induced protein in bronchoalveolar lavage. In addition, treatment with TGF-beta1 dose-dependently repressed Sftpb promoter activity in vitro, and a novel TGF-beta-responsive region in the Sftpb promoter was identified.

Conclusions: These data suggest that TGF-beta acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Cells, Cultured
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibrinolysis / drug effects
  • Fibrinolysis / genetics
  • Gene Expression*
  • Mice
  • Nickel / toxicity
  • Oligonucleotide Array Sequence Analysis
  • Pulmonary Surfactant-Associated Protein B / genetics*
  • Pulmonary Surfactant-Associated Protein B / metabolism
  • RNA / genetics*
  • Respiratory Distress Syndrome / drug therapy
  • Respiratory Distress Syndrome / genetics*
  • Respiratory Distress Syndrome / metabolism
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Transforming Growth Factor beta / antagonists & inhibitors
  • Transforming Growth Factor beta / metabolism*
  • Transforming Growth Factor beta / therapeutic use
  • Transforming Growth Factor beta1


  • Pulmonary Surfactant-Associated Protein B
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • RNA
  • Nickel