In glaucoma surgery, fibrotic processes occur, leading to impairment of liquid outflow. Activated fibroblasts are responsible for postoperative scarring. The transforming growth factor-β (TGF-β) pathway plays a key role in fibroblast function, differentiation and proliferation. The aim of this study was the characterization of the fibrotic potential of two subtypes of primary human ocular fibroblasts and the attempt to inhibit fibrotic processes specifically, without impairing cell viability. For fibrosis inhibition we focused on the small molecule pirfenidone, which has been shown to prevent pulmonary fibrosis by the decrease of the expression of TGF-β1, TGF-β2 and TGF-β3 cytokines. For in vitro examinations, isolated human primary fibroblasts from Tenon capsule and human intraconal orbital fat tissues were used. These fibroblast subpopulations were analyzed in terms of the expression of matrix components responsible for postoperative scarring. We concentrated on the expression of collagen I, III, VI and fibronectin. Additionally, we analyzed the expression of α-smooth muscle actin, which serves as a marker for fibrosis and indicates transformation of fibroblasts into myofibroblasts. Gene expression was analyzed by rtPCR and synthesized proteins were examined by immunofluorescence and Western blot methods. Proliferation of fibroblasts under different culture conditions was assessed using BrdU assay. TGF-β1 induced a significant increase of cell proliferation in both cell types. Also the expression of some fibrotic markers was elevated. In contrast, pirfenidone decreased cell proliferation and matrix synthesis in both fibroblast subpopulations. Pirfenidone slightly attenuated TGF-β1 induced expression of fibronectin and α-smooth muscle actin in fibroblast cultures, without impairing cell viability. To summarize, manipulation of the TGF-β signaling pathway by pirfenidone represents a specific antifibrotic approach with no toxic side effects in two human orbital fibroblast subtypes. We presume that pirfenidone is a promising candidate for the treatment of fibrosis following glaucoma surgery.
The famous ''Faustmann'' equation, which allows for identifying the most profitable tree species on a given unstocked piece of land, assumes constant timber prices. In reality, timber prices may fluctuate dramatically. Several authors have proven for monocultures that waiting for an acceptable timber price (reservation price) before harvesting (flexible harvest policy) increases the net present value of forest management. The first part of this paper investigates how efficient a flexible harvest strategy may be applied in mixed forests and whether the optimal species mixture is changed under such harvest policy. Mixtures of the conifer Norway spruce [Picea abies (L.) Karst] and the broadleaf European beech (Fagus sylvatica L.) were investigated. In order to evaluate mixed forests, the risks and the correlation of risks between tree species as well as the attitude towards risk of the decision-maker (risk-aversion is assumed) were considered according to the classical theory of optimal portfolio selection. In the second part we took up a recent critique on modern financial theory by Mandelbrot. Whether or not the assumption of normally distributed financial flows, which are supposed to occur under risk, would be appropriate to evaluate the risk of forest management was investigated. Market and hazard risks as well as their correlation were integrated in the evaluation of mixed forests by means of Monte-Carlo simulations (MCS). The risk of the timber price fluctuation was combined with the natural hazard risk, caused mainly by insects, snow and wind. Applying the l-r-rule, the mean net present value (NPV) from 1,000 simulations and their standard deviation were used for the optimisation. Given a low-return, risk-free interest rate to assess potential species mixtures of the Norway spruce and European beech, optimal proportions of European beech increased according to the theory of optimum portfolio selection with growing risk aversion from 0 (ignorance of risk) to 60% (great riskaversion). In relation to a fixed harvest policy, the net present value of both, Norway spruce and European beech, could be increased significantly. Since the hazard risks of European beech were substantially lower compared with the Norway spruce (relation of susceptibility 1:4) beech benefited more from the flexible harvest policy. A comparison of simulated frequency distributions of the NPV with the expected density functions under the assumption of a normal distribution revealed significant differences. Only in the case of European beech was the general shape of the simulated frequency distribution similar to a normal distribution (bell-shaped curve). However, the density of NPV close to the mean was much greater than expected under the assumption of a normal distribution. Consequently, the frequency of a negative NPV for a European beech forest was greatly overestimated when applying the normal distribution. Though the shape of the simulated frequency distribution was rather different from a normal distribution for Norway spruce the simu...
Microglia are resident immune cells of the central nervous system and play critical roles during the development, homeostasis, and pathologies of the brain. Originated from yolk sac erythromyeloid progenitors, microglia immigrate into the embryonic brain parenchyma to undergo final postnatal differentiation and maturation driven by distinct chemokines, cytokines, and growth factors. Among them, TGFβ1 is an important regulator of microglial functions, mediating homeostasis, anti-inflammation, and triggering the expression of microglial homeostatic signature genes. Since microglia studies are mainly based on rodent cells and the isolation of homeostatic microglia from human tissue is challenging, human-induced pluripotent stem cells have been successfully differentiated into microglia-like cells recently. However, employed differentiation protocols strongly vary regarding used cytokines and growth factors, culture conditions, time span, and cell yield. Moreover, the incomplete differentiation of human microglia can hamper the similarity to primary human microglia and dramatically influence the outcome of follow-up studies with these differentiated cells. This review summarizes the current knowledge of the molecular mechanisms driving rodent microglia differentiation in vivo, further compares published differentiation protocols, and highlights the potential of TGFβ as an essential maturation factor.
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