Fibroblasts are the major source of extracellular connective tissue matrix, and the recruitment, accumulation, and stimulation of these cells are thought to play important roles in both normal healing and the development of fibrosis. Prostaglandin E(2) (PGE(2)) can inhibit this process by blocking fibroblast proliferation and collagen production. The aim of this study was to investigate the inhibitory effect of PGE(2) on human plasma fibronectin (hFN)- and bovine bronchial epithelial cell-conditioned medium (BBEC-CM)-induced chemotaxis of human fetal lung fibroblasts (HFL1). Using the Boyden blind well chamber technique, PGE(2) (10(-7) M) inhibited chemotaxis to hFN 40.8 +/- 5.3% (P < 0.05) and to BBEC-CM 49.7 +/- 11.7% (P < 0.05). Checkerboard analysis demonstrated inhibition of both chemotaxis and chemokinesis. The effect of PGE(2) was concentration dependent, and the inhibitory effect diminished with time. Other agents that increased fibroblast cAMP levels, including isoproterenol (10(-5) M), dibutyryl cAMP (10(-5) M), and forskolin (3 x 10(-5) M) had similar effects and inhibited chemotaxis 54.1, 95.3, and 87.0%, respectively. The inhibitory effect of PGE(2) on HFL1 cell chemotaxis was inhibited by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, which suggests a cAMP-dependent effect mediated by PKA. In summary, PGE(2) appears to inhibit fibroblast chemotaxis, perhaps by modulating the rate of fibroblast migration. Such an effect may contribute to regulation of the wound healing response after injury.

Cigarette smoking is the most clearly recognized cause of pulmonary emphysema. Since loss of lung tissue, which characterizes emphysema, represents a balance between injury and repair, we hypothesized that cigarette smoke might contribute to the development of emphysema by inhibiting fibroblast proliferation and migration. To evaluate this, we examined the effect of cigarette smoke extract (CSE) on the proliferation and migration of human lung fibroblasts in vitro. CSE inhibited fibroblast proliferation and migration at noncytotoxic concentrations. When CSE was treated to remove volatile components, it showed less inhibitory activity on fibroblast proliferation. Therefore, we also examined acrolein and acetaldehyde, which are volatile components of cigarette smoke, Micromolar concentrations of acrolein and millimolar concentrations of acetaldehyde induced significant inhibition of fibroblast proliferation. In contrast, removal of volatile components did not eliminate the inhibitory activity of CSE for fibroblast migration, although acetaldehyde and acrolein alone were also capable of inhibiting chemotaxis. Cigarette smoke-induced inhibition of fibroblast proliferation and migration may impair lung repair following lung injury, and may thus contribute to the development of pulmonary emphysema.

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Minimally invasive follicular thyroid carcinoma (MI-FTC) is characterized by limited capsular and/or vascular invasion with good long-term outcomes. However, some cases of MI-FTC show a poor prognosis because of severe distant metastasis (i.e., metastatic MI-FTC). Nonetheless, no method has been established for predicting the prognosis of MI-FTC. This study was conducted to identify novel prognostic factors for metastatic MI-FTC by the use of microRNA (miRNA). Thirty-four patients with MI-FTC were categorized into two groups: the metastatic group, M(+) (n=12) and the non-metastatic group, M(−) (n=22). In the M(+) group, distant metastasis was recognized after the initial operation established the diagnosis of MI-FTC. In the M(−) group, no distant metastasis was recognized postoperatively for ≥10 years. Using laser micro-dissection followed by quantitative real-time PCR and PCR arrays, we performed a comprehensive expression profiling of 667 miRNAs in formalin-fixed, paraffin-embedded samples from the initial MI-FTC operation. Furthermore, we assessed the potential use of miRNAs as novel biomarkers for the metastatic potential of MI-FTC by logistic regression analysis. Comprehensive quantitative analysis of miRNA expression in MI-FTC samples revealed that the miR-221/222 cluster (i.e., miR-221, miR-222 and miR-222*), miR-10b and miR-92a were significantly upregulated in the M(+) group compared with the M(−) group. Interestingly, the expression levels of these miRNAs were also shown to be upregulated in widely invasive FTC (WI-FTC; n=13) that has distant metastasis and worse prognosis, indicating a close similarity in the miRNA expression between metastatic MI-FTC and WI-FTC. Logistic regression analysis revealed that miR-10b made a significant contribution to prognosis (OR 19.759, 95% CI 1.433–272.355, p= 0.026). Our findings suggest that miR-10b is a potential prognostic factor for evaluating the metastatic potential of MI-FTC at an initial operation stage.

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