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Impairment of Alveolar Macrophage Transcription in Idiopathic Pulmonary Fibrosis

¹ Pulmonary–Critical Care Medicine Branch and ² Bioinformatics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Bernadette R. Gochuico, M.D., 10 Center Drive, MSC 1590, Bethesda, MD 20892-1590. E-mail: gochuicb{at}mail.nih.gov

Rationale: Alveolar macrophages are inflammatory cells that may contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF), which is characterized by excessive alveolar aggregation of cells and extracellular matrix proteins.

Objectives: To identify potential molecular mechanisms of IPF.

Methods: To examine large-scale gene expression, messenger RNA isolated from alveolar macrophages and peripheral blood mononuclear cells from subjects with IPF and normal volunteers was hybridized to cDNA filters.

Measurements and Main Results: We showed that in IPF there is global down-regulation of gene expression in alveolar macrophages but not in blood monocytes. Nuclear run-on and pulse-chase studies showed that alveolar macrophages had significantly reduced transcription (p < 0.01). No significant difference in RNA degradation was found between subjects with IPF and normal volunteers. Western blot analyses revealed that concentrations of transcription factor II-H, a general transcription factor, were significantly lower in alveolar macrophages from subjects with IPF than in those from normal volunteers (p = 0.012).

Conclusions: Impaired transcription in IPF is associated with decreased concentrations of transcription factor II-H in alveolar macrophages and may alter the intraalveolar milieu in IPF.

Key Words: monocytes/macrophages • transcription factors • TFII-H • lung

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The etiology of idiopathic pulmonary fibrosis (IPF) is unknown. There are no published reports on large-scale gene expression of alveolar macrophages in IPF. What This Study Adds to the Field In IPF there is global down-regulation of gene expression in alveolar macrophages but not in blood monocytes. Aberrant transcription is a novel molecular mechanism that may contribute to development of a profibrotic alveolar milieu in idiopathic pulmonary fibrosis.

 

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