Search

Wounds that occur in adults form scars due to fibrosis, whereas those in embryos regenerate. If wound healing in embryos is mimicked in adults, scarring can be reduced. We found that mouse fetuses could regenerate tissues up to embryonic day (E) 13, but visible scars remained thereafter. This regeneration pattern requires actin cable formation at the epithelial wound margin via activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Here, we investigated whether the AMPK-activating effect of salicylate, an anti-inflammatory drug, promotes regenerative wound healing. Salicylate administration resulted in actin cable formation and complete wound regeneration in E14 fetuses, in which scarring should have normally occurred, and promoted contraction of the panniculus carnosus muscle, resulting in complete wound regeneration. In vitro, salicylate further induced actin remodeling in mouse epidermal keratinocytes in a manner dependent on cell and substrate target-specific AMPK activation and subsequent regulation of Rac1 signaling. Furthermore, salicylate promoted epithelialization, enhanced panniculus carnosus muscle contraction, and inhibited scar formation in adult mice. Administration of salicylates to wounds immediately after injury may be a novel method for preventing scarring by promoting a wound healing pattern similar to that of embryonic wounds. [ABSTRACT FROM AUTHOR]

Advanced hepatocellular carcinoma (HCC) is an important cause of cancer mortality. Epithelial-mesenchymal transition (EMT) has been shown to be an important biological process in cancer progression and metastasis. We have focused on elucidating factors that induce EMT to promote carcinogenesis and subsequent metastasis in HCC using the BNL CL.2 (BNL) and BNL 1ME A. 7R.1 (1MEA) cell lines. BNL cells are normal hepatocytes whereas the 1MEA cells are HCC cells derived from chemical transformation of the BNL cells. Their morphological characteristics were examined. Expression levels of hepatocyte growth factor (HGF), markers of EMT and mediators of HGF signaling were determined and functional characteristics were compared. BNL cells were treated with HGF and effects on EMT-marker and mediators of HGF signaling were analyzed. BNL cells display characteristic epithelial morphology whereas 1MEA cells display mesenchymal characteristics. 1MEA cells express and secrete more HGF than BNL cells. There was significantly decreased expression of E-cadherin, albumin, AAT and increased expression of fibronectin, collagen-1, vimentin, snail and slug in 1MEA cells. There was also increased expression of cyclooxygenase-2 (COX-2), Akt and phosphorylated Akt (pAkt) in 1MEA cells. Moreover, 1MEA cells had increased migratory capacity inhibited by inhibition of COX-2 and Akt but not extracellular signal regulated kinase (ERK). Molecular mesenchymal characteristics of 1MEA cells were reversed by inhibition of COX-2, Akt and ERK. Treatment of BNL cells with HGF led to decreased expression of E-cadherin and increased expression of fibronectin, vimentin, snail, slug, COX-2, Akt, pAkt and increased migration, invasiveness and clonogenicity. We conclude that development of HCC is associated with upregulation of HGF which promotes EMT and carcinogenesis via upregulation of COX-2 and Akt. Consequently, HGF signaling may be targeted for therapy in advanced and metastatic HCC. [ABSTRACT FROM AUTHOR]

Background/aims: Hepatic fibrosis is one kind of common wound-healing response to chronic liver injury. Transforming growth factor (TGF)-β(3) performs an anti-fibrosis function under certain conditions such as pancreatic fibrosis and wound healing. This study aimed at investigating the effect of TGF-β(3) on the histology in the liver of rat with liver fibrosis.Methods: Recombinantadeno-associated virus (rAAV) 2-TGF-β(3) and rAAV2-EGFP were constructed. Rats were randomly divided into normal control group, model group, negative control group and TGF-β(3) treated group. The hepatic fibrosis model was induced by CCl(4) administration. We injected a single dose of either rAAV2-TGF-β(3) or rAAV2-EGFP into the TGF-β(3) group and the negative control group. The histopathologic changes of liver were determined by hematoxylin and eosin (HE) staining and Masson staining. The expressions of type I collagen, MMP-9, MMP-2, and TIMP-1 in liver were detected by Immunohistochemical staining.Results: With the treatment of TGF-β(3), the degree of fibrosis and the deposition of collagen fiber in liver were markedly reduced, and the expression of MMP-9 was obviously increased (P < 0.001), while type I collagen and TIMP-1 were decreased (P = 0.004, P = 0.001) compared with the model group, but the expressed difference of MMP-2 had no statistical significance (P = 0.180).Conclusion: rAAV2-TGF-β(3) reduces the histopathologic damage of liver fibrosis on rats, and it may suppress the synthesis and deposition of type I collagen by regulating the expressions of matrix metalloproteinases and their inhibitors. Potentially, our findings might help with the design of a new TGF-β(3)-based therapy for hepatic fibrosis. [ABSTRACT FROM AUTHOR]

The transforming growth factor (TGF) superfamily encompasses about 30 members in mammals. The effect of TGF- subfamily members is exerted and regulated via selective pathways of synthesis and signaling that involve activation of latent TGF-, specific and high-affinity binding to cell membrane serine/threonine kinase receptors, activation of intracellular cascades that include Smad molecules and mitogen-activated protein kinases, and regulated termination of the effect by diverse mechanisms including protein degradation and transcriptional activation. Several comprehensive reviews on TGF- biology in general and on the role of this cytokine in other diseases have been published recently. In recent years an unexpected role of TGF- on lung homeostasis has been revealed. Here, we discuss the contribution of TGF- to the pathogenesis of asthma and chronic obstructive pulmonary disease, two common illnesses of the lung, as well as of lymphangioleiomyomatosis, a rare disease in women. The information we collate and integrate places TGF- at a pivotal point within complex networks that control lung physiology as well as the physiopathology of these lung diseases. [ABSTRACT FROM AUTHOR]

The surrounding extracellular matrix of airway wall tissues changes in response to mechanical stresses and hypoxia. The presence of matrix metalloproteinase-9 (MMP-9) and its inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1), is correlated with collagen degradation and tissue repair in lung disorders. The aim of this study was to evaluate the expression of MMP-9 and TIMP-1 in the lung of fetal rats with nitrofen-induced congenital diaphragmatic hernia (CDH). Administering 100 mg of nitrofen dissolved in 1 ml olive oil to pregnant Wistar rats on day 9 of gestation induced left-sided CDH in fetal rats. In control animals, the same dose of olive oil was given without nitrofen. Cesarean section was performed on day 21 of gestation. The fetuses were divided into two groups: normal controls (n = 10) and nitrofen-induced left-sided CDH (n = 10). Immunoreactivity of the staining for MMP-9 and TIMP-1 in the lung tissues was semiquantitatively analyzed using the staining scores. The relative amount of MMP-9 or TIMP-1 divided by the amount of β-actin for each lung sample was measured by using the real-time reverse-transcriptase polymerase chain reaction. The immunoreactivity of MMP-9 was significantly increased in the CDH group (n = 5) compared with the control group (n = 5) (p = 0.031). On the other hand, the immunoreactivity of TIMP-1 in the two groups was not significantly different (n = 0.134). The relative amount of MMP-9 (or TIMP-1) in the CDH group (n = 5) does not differ significantly from that in the control group (n = 5) (p = 0.059, 0.596, respectively), but the relative amount of MMP-9 is higher in the CDH group, although it is not significantly higher. On the other hand, the ratios of MMP-9 to TIMP-1 were significantly higher in the CDH group (p = 0.028). In conclusion, fetal rats with nitrofen-induced CDH, a model of respiratory disorders, manifested the excess of MMP-9 activity due to the absence of TIMP-1 that would suggest a trend toward disruption of the extracellular matrix in the CDH lung tissues. [ABSTRACT FROM AUTHOR]

Pituitary prolactin (PRL) cell gene expression and proliferation are regulated by various hormones and growth factors. Transforming growth factor beta (TGFβ) and basic fibroblast growth factor (bFGF) have been implicated in the regulation of anterior pituitary function. To study the roles of TGFβ and bFGF in anterior pituitary cell function, we analyzed normal and neoplastic pituitary cells in serum-free media. The various isoforms of TGFβ and TGFβ receptor types I, II, and III were also analyzed by reverse transcriptionpolymerase chain reaction (RT-PCR) in pituitary cells. Transforming growth factor beta 1 (TGFβ1) stimulated PRL expression and PRL cell proliferation in normal pituitary. TGFβ1 stimulated PRL expression, but inhibited proliferation in the growth hormone (GH) and PRL-producing GH cells. Estradiol 17β (E) and bFGF stimulated PRL gene expression in normal pituitary and GH cells, whereas E inhibited and bFGF stimulated TGFβ1 mRNA levels in normal pituitary PRL cells, but not in GH cells. Both normal pituitary and GH cells expressed the mRNAs for TGFβ1, TGFβ2, and TGFβ3 isoforms and for TGFβ receptors I, II, and III. These results indicate that there is a relative loss of regulatory control by growth factors in neoplastic GH cells compared to normal pituitary PRL cells. [ABSTRACT FROM AUTHOR]

The dose-effect relationships were analysed for several noncarcinogenic endpoints, such as immunological and biochemical responses at subchronic, low dose exposure of female C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD). The animals were treated i.p. with TCDD according to the initial- and maintenance-dose principle for a period of 135 days. The initial doses were 1, 10 and 100 ng TCDD/kg, the weekly maintenance doses were 0.2, 2 and 20 ng TCDD/kg, respectively. At days 23, 79 and 135 of TCDD treatment 10 animals of each dose group were killed. As immunological parameters the number of thymocytes and the pattern of thymocyte subpopulations were determined. In liver, lung and thymus, mRNA expression of TGF-α, TGF-β1, TGF-β2, TGF-β3, TNF-α, IL-1β and different CYP1 isoforms (CYP1A1, CYP1A2, CYP1B1) was analysed. In the livers, activities of 7-ethoxyresorufin-O-deethylase (EROD) and 7-methoxyresorufin-O-demethylase (MROD) were measured. TCDD content in the liver was determined. The main results are summarized as follows: (1) The TCDD doses were not sufficient to elicit dose-dependent changes of pattern of thymocyte subpopulation. (2) TCDD failed to change the mRNA expression of TGF-α, TGF-β and TNF-α, but led to an increase of IL-1β mRNA expression in liver, lung and thymus. The results show that the TCDD induced IL-1β mRNA increase is at least as sensitive a marker as the induction of CYP1A isoforms. (3) The expression of CYP1B1 mRNA remained unchanged at the doses tested, while CYP1A1 and CYP1A2 mRNA expression was dose-dependently enhanced. EROD and MROD activities in the liver paralleled the increases of CYP1A1 and CYP1A2 mRNA expression. (4) Regression analysis of the data showed that most of the parameters tested fit a linear model. (5) From the data, a benchmark dose for EROD/MROD activities in the livers of female C57BL/6 mice of about 0.03 ng TCDD/kg per day was calculated. [ABSTRACT FROM AUTHOR]