angiogenin and Pulmonary-Fibrosis

T helper 17 (Th17) cells that produce interleukin (IL)-17A and IL-17F have been found to participate in the development of bronchial asthma and bleomycin-induced pulmonary fibrosis. However, whether they play a causative role in the airway remodeling observed in these respiratory diseases remains unclear. Because fibrocytes are involved in tissue repair and fibrosis and are presumably precursors of lung fibroblasts and myofibroblasts, we examined the effects of IL-17A/F on fibrocyte functions. Both IL-17A and IL-17F enhanced fibrocytes' α-smooth muscle actin expression. Priming fibrocytes with IL-17A enhanced their CD40-mediated IL-6 production, whereas IL-17F-priming increased the CD40-mediated mRNA expression of collagen I, vascular endothelial growth factor, and angiogenin. CD4(+) T cells co-cultured with fibrocytes produced IL-17A, which was inhibited by blocking CD40 and CD40 ligand interactions. These findings suggest that cooperative interactions between fibrocytes and Th17 cells play an important role via CD40- and IL-17A/F-mediated signaling for collagen and proangiogenic factor production, which may lead to the extracellular matrix deposition and neovascularization seen in airway remodeling.

Topics: Actins; Asthma; Bleomycin; CD40 Antigens; Cells, Cultured; Coculture Techniques; Collagen; Fibroblasts; Humans; Interleukin-17; Interleukin-6; Lymphocyte Activation; Mesenchymal Stem Cells; Pulmonary Fibrosis; Ribonuclease, Pancreatic; RNA, Messenger; Signal Transduction; Th17 Cells; Vascular Endothelial Growth Factor A

Pulmonary fibrosis in humans can occur as a result of a large number of conditions. In idiopathic pulmonary fibrosis (IPF), pulmonary function becomes progressively compromised resulting in a high mortality rate. Currently there are no proven effective treatments for IPF. We have recently reported that IL-6 and TGF-beta(1) plays an important role in proliferation and differentiation of lung fibroblasts, and all-trans-retinoic acid (ATRA) prevented bleomycin-induced lung fibrosis through the inhibition of these cytokines. Thalidomide (Thal) has been used in the treatment of multiple myeloma through the inhibitory effect on IL-6-dependent cell growth and angiogenesis. In this study, we examined the preventive effect of Thal on bleomycin-induced pulmonary fibrosis in mice. We performed histological examinations and quantitative measurements of IL-6, TGF-beta(1), collagen type Ialpha1 (COL1A1), vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in bleomycin-treated mouse lung tissues with or without the administration of Thal. Thal histologically ameliorated bleomycin-induced fibrosis in mouse lung tissues. Thal decreased the expressions of IL-6, TGF-beta(1), VEGF, Ang-1 Ang-2, and COL1A1 mRNA in mouse lung tissues. In addition, Thal inhibited angiogenesis in the lung. In vitro studies disclosed that Thal reduced 1) production of IL-6, TGF-beta(1), VEGF, Ang-1, and collagen synthesis from human lung fibroblasts, and 2) both IL-6-dependent proliferation and TGF-beta(1)-dependent transdifferentiation of the cells, which could be the mechanism underlying the preventive effect of Thal on pulmonary fibrosis. These data may provide a rationale to explore clinical use of Thal for the prevention of pulmonary fibrosis.

Topics: Animals; Bleomycin; Cell Differentiation; Cell Line; Cell Line, Transformed; Collagen Type I; Collagen Type I, alpha 1 Chain; Female; Fibroblasts; Humans; Interleukin-6; Lung; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Proteins; Pulmonary Fibrosis; Ribonuclease, Pancreatic; RNA, Messenger; Thalidomide; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A