Gene expression changes during the development of acute lung injury : Role of transforming growth factor β

• Published in: American journal of respiratory and critical care medicine Vol. 172; no. 11; pp. 1399 - 1411
• Main Authors: WESSELKAMPER, Scott C, CASE, Lisa M, LEIKAUF, George D, HENNING, Lisa N, BORCHERS, Michael T, TICHELAAR, Jay W, MASON, John M, DRAGIN, Nadine, MEDVEDOVIC, Mario, SARTOR, Maureen A, TOMLINSON, Craig R
• Format: Journal Article
• Language: English
• Published: New York, NY American Lung Association 01.12.2005; American Thoracic Society
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Biological and medical sciences; Blood and lymphatic vessels; Bronchoalveolar Lavage Fluid - chemistry; C. Critical Care; Cardiology. Vascular system; Cells, Cultured; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Enzyme-Linked Immunosorbent Assay; Female; Fibrinolysis - drug effects; Fibrinolysis - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression; Intensive care medicine; Medical sciences; Mice; Nickel - toxicity; Oligonucleotide Array Sequence Analysis; Pulmonary Surfactant-Associated Protein B - genetics; Pulmonary Surfactant-Associated Protein B - metabolism; Respiratory Distress Syndrome, Adult - drug therapy; Respiratory Distress Syndrome, Adult - genetics; Respiratory Distress Syndrome, Adult - metabolism; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA - genetics; 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; Vertebrates: blood, hematopoietic organs, reticuloendothelial system; Lung disease; Intensive care; microarray; Pulmonary surfactant; Respiratory disease; Transforming growth factor β; Extracellular matrix; Surfactant; Gene expression; Fibrinolysis; Resuscitation
• ISSN: 1073-449X; 1535-4970
• DOI: 10.1164/rccm.200502-286OC

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. To integrate molecular pathways and investigate the role of transforming growth factor beta (TGF-beta) in acute lung injury in mice. 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. 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. These data suggest that TGF-beta acts as a central mediator of acute lung injury through the alteration of several different molecular pathways.