Received for publication June 1, 2005.
Revised July 28, 2005.
Accepted for publication July 28, 2005.

Fibrotic lung fibroblasts show blunted inhibition by cAMP due to deficient CREB phosphorylation

Abstract

Pulmonary fibroblasts regulate extracellular matrix production and degradation, thus are critical for maintenance of lung structure, function and repair. In pulmonary fibrosis, fibroblasts produce excess collagen and form fibrotic foci that eventually impair lung function but the mechanisms responsible for these alterations are not known. Receptors coupled to the stimulation of cAMP production can inhibit activation of fibroblasts and, thereby, are anti-fibrotic. To test whether this signaling pathway is altered in pulmonary fibrosis, we compared the ability of normal adult human pulmonary fibroblasts to generate and respond to cAMP with that of cells isolated from lungs with idiopathic pulmonary fibrosis. Serum- and TGF- stimulated cell proliferation was inhibited ~50% by forskolin and ~100% by PGE₂ in the normal cells but substantially less in the diseased cells. Collagen synthesis was also inhibited >50% by the same drugs in the normal cells but significantly less so in the diseased cells despite responding with similar increases in cAMP production. Although expression of protein kinase A (PKA) and cAMP-stimulated PKA activity were similar in both the normal and diseased cell types, forskolin- and PGE₂-stimulated CREB phosphorylation were decreased in the diseased cell lines compared to the normal cells. cAMP-mediated activation and TGF--mediated inhibition of CREB DNA binding was also diminished in the diseased cells. Thus, pulmonary fibroblasts derived from patients with pulmonary fibrosis are refractory to the inhibition by cAMP due to altered activity of components distal to the activity of PKA, in particular the phosphorylation of CREB.

Key words: collagen, cyclic AMP, extracellular matrix, prostaglandin E2, protein kinase A, pulmonary fibrosis

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