Editors' ChoicePulmonary fibrosis

A New Twist in a Fibrous Condition

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Science Translational Medicine  21 Dec 2011:
Vol. 3, Issue 114, pp. 114ec210
DOI: 10.1126/scitranslmed.3003585

Pulmonary fibrosis—progressive scarring of the lung that is often caused by chronic inflammation—is a potentially devastating complication of other diseases that can portend a grave prognosis for patients. The role of regulatory T cells (Tregs) in pulmonary fibrosis is unclear, although it has been hypothesized that because Tregs actively suppress inflammation they indirectly limit the scarring process. Now, a report by Lo Re et al. highlights how Tregs might play an unexpected pathological role in pulmonary fibrosis by serving as a key source of fibrogenic cytokines.

The investigators used a mouse model, involving pulmonary injection of silica particles, that has been established to study the lung scarring that coal miners and other workers develop after inhaling aerosolized crystalline silica. Silica treatment caused a significant increase in the number of Tregs in the lungs of experimental mice; furthermore, these Tregs stimulated undifferentiated lung fibroblasts (the cell type that secretes excessive collagen during fibrosis, causing scarring) to proliferate in vitro. Further experiments showed that transforming growth factor β (TGF-β) and platelet-derived growth factor-B (PDGF-B) mRNA transcripts were up-regulated in Tregs after silica treatment and that TGF-β stimulates PDGF-B expression in Tregs. Imatinib mesylate, a tyrosine kinase inhibitor that binds to the PDGF receptor, reduced fibroblast proliferation in co-cultures of Tregs and fibroblasts. When the researchers transferred Treg cells from silica-treated animals into the lungs of naive mice, the mice developed significant fibrosis; imatinib treatment abolished this effect.

Selective depletion of Tregs in an engineered mouse line 10 days after silica administration led to a reduction in the amount of PDGF-B and TGF-β in the lung lavage fluid (obtained by rinsing the lungs). Surprisingly, the amount of collagen deposition in Treg-depleted mice was the same as Treg cell-competent animals, perhaps because the fibrosis in Treg-depleted mice was caused by an increase in effector T cells and inflammatory cytokines. Lo Re et al. used their in vitro co-culture system to show that interleukin-4 might be important in this setting.

This study supports the use of tyrosine kinase inhibitors in patients with silica-induced pulmonary fibrosis and warrants further investigation into the role of Tregs in tissue fibrosis.

S. Lo Re et al., Platelet-derived growth factor–producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis. Am. J. Respir. Crit. Care Med. 184, 1270-1281 (2011). [Abstract]

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