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Lung Fibrosis (lung + fibrosis)
Kinds of Lung Fibrosis Selected AbstractsRole of Protease Activated Receptor 2 in Experimental Acute Lung Injury and Lung FibrosisTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2009Xiao Su Abstract Protease activated receptor 2 (PAR2) is widely-distributed (lung, liver, kidney, etc.) and expressed by variety of cells (i.e. leukocytes, epithelial cells, endothelial cells, and fibroblast). PAR2 may participate in many pathological processes, such as, inflammation, injury, as well as fibrosis. Therefore, in this study, we tested whether PAR2 would exert a role in acid-induced acute lung injury, E. coli pneumonia, bleomycin-induced acute lung injury and fibrosis. Acid, E. coli, or bleomycin were intratracheally instilled into the lungs of both wildtype and PAR2 knockout mice to detect differences in pulmonary edema, lung vascular permeability, lung fibrosis, and other parameters. Knockout of PAR2 did not affect the extent of pulmonary edema and lung vascular permeability in acid-induced acute lung injury. Also, both activation of PAR2 in the airspaces of the lung and deletion of PAR2 did not alter the magnitude of pulmonary edema and lung vascular permeability in E. coli pneumonia. Finally, PAR2 deficiency did not affect the severity of lung inflammation and lung fibrosis in bleomycin-induced acute lung injury and lung fibrosis models. Thus, PAR2 does not appear to play a critical role in the pathogeneses of experimental acid-induced acute lung injury, E. coli pneumonia, and bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Anat Rec, 2009. © 2009 Wiley-Liss, Inc. [source] Attenuation of Bleomycin-Induced Lung Fibrosis by Oxymatrine Is Associated with Regulation of Fibroblast Proliferation and Collagen Production in Primary CultureBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 3 2008Xiaohong Chen Oxymatrine is an alkaloid extracted from the Chinese herb Sophora japonica (Sophora flavescens Ait.) with capacities of anti-inflammation, inhibition of immune reaction, antivirus, protection against acute lung injury and antihepatic fibrosis. In this study, the effect of oxymatrine on pulmonary fibrosis was investigated using a bleomycin-induced pulmonary fibrosis mouse model. The results showed that bleomycin challenge provoked severe pulmonary fibrosis with marked increase in hydroxyproline content of lung tissue and lung fibrosis fraction, which was prevented by oxymatrine in a dose-dependent manner. In addition, bleomycin injection resulted in a marked increase of myeloperoxidase activity and malondialdehyde level that was attenuated by oxymatrine. Administration of oxymatrine inhibited the proliferation of murine lung fibroblasts, arrested the cells at G0/G1 phase and reduced the expression of cell cycle regulatory protein, cyclin D1 in vitro. Furthermore, the steady-state production of collagen and the expression of ,1(I) pro-collagen and ,2(I) pro-collagen mRNA in fibroblasts were inhibited by oxymatrine in a dose-dependent manner. These results suggested that oxymatrine may attenuate pulmonary fibrosis induced by bleomycin in mice, partly through inhibition of inflammatory response and lipid peroxidation in lung induced by bleomycin and reduction of fibroblast proliferation and collagen synthesis. [source] Regional distribution of collagen and haemosiderin in the lungs of horses with exercise-induced pulmonary haemorrhageEQUINE VETERINARY JOURNAL, Issue 6 2009F. J. Derksen Summary Reasons for performing study: Regional veno-occlusive remodelling of pulmonary veins in EIPH-affected horses, suggests that pulmonary veins may be central to pathogenesis. The current study quantified site-specific changes in vein walls, collagen and haemosiderin accumulation, and pleural vascular profiles in the lungs of horses suffering EIPH. Hypothesis: In the caudodorsal lung regions of EIPH-affected horses, there is veno-occlusive remodelling with haemosiderosis, angiogenesis and fibrosis of the interstitium, interlobular septa and pleura. Methods: Morphometric methods were used to analyse the distribution and accumulation of pulmonary collagen and haemosiderin, and to count pleural vascular profiles in the lungs of 5 EIPH-affected and 2 control horses. Results: Vein wall thickness was greatest in the dorsocaudal lung and significantly correlated with haemosiderin accumulation. Increased venous, interstitial, pleural and septal collagen; lung haemosiderin; and pleural vascular profiles occurred together and changes were most pronounced in the dorsocaudal lung. Further, haemosiderin accumulation colocalised with decreased pulmonary vein lumen size. Vein wall thickening, haemosiderin accumulation and histological score were highly correlated and these changes occurred only in the caudodorsal part of the lung. Conclusion: The colocalisation of these changes suggests that regional (caudodorsal) venous remodelling plays an important role in the pathogenesis of EIPH. Potential relevance: The results support the hypothesis that repeated bouts of venous hypertension during strenuous exercise cause regional vein wall remodelling and collagen accumulation, venous occlusion and pulmonary capillary hypertension. Subjected to these high pressures, there is capillary stress failure, bleeding, haemosiderin accumulation and, subsequently, lung fibrosis. [source] Regulation of inflammation by PPARs: a future approach to treat lung inflammatory diseases?FUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 5 2006Julien Becker Abstract Lung inflammatory diseases, such as acute lung injury (ALI), asthma, chronic obstructive pulmonary disease (COPD) and lung fibrosis, represent a major health problem worldwide. Although glucocorticoids are the most potent anti-inflammatory drug in asthma, they exhibit major side effects and have poor activity in lung inflammatory disorders such as ALI or COPD. Therefore, there is growing need for the development of alternative or new therapies to treat inflammation in the lung. Peroxisome proliferator-activated receptors (PPARs), including the three isotypes PPAR,, PPAR, (or PPAR,) and PPAR,, are transcription factors belonging to the nuclear hormone receptor superfamily. PPARs, and in particular PPAR, and PPAR,, are well known for their critical role in the regulation of energy homeostasis by controlling expression of a variety of genes involved in lipid and carbohydrate metabolism. Synthetic ligands of the two receptor isotypes, the fibrates and the thiazolidinediones, are clinically used to treat dyslipidaemia and type 2 diabetes, respectively. Recently however, PPAR, and PPAR, have been shown to exert a potent anti-inflammatory activity, mainly through their ability to downregulate pro-inflammatory gene expression and inflammatory cell functions. The present article reviews the current knowledge of the role of PPAR, and PPAR, in controlling inflammation, and presents different findings suggesting that PPAR, and PPAR, activators may be helpful in the treatment of lung inflammatory diseases. [source] Effect of IL-2-Bax, a novel interleukin-2-receptor-targeted chimeric protein, on bleomycin lung injury,INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 5 2005Michael J. Segel Summary The role of lymphocytes in the pathogenesis of lung fibrosis is not clear, but the weight of the evidence supports a pro-fibrotic effect for lymphocytes. The high-affinity interleukin-2 receptor (haIL-2R) is expressed on activated, but not quiescent, T lymphocytes. This selective expression of haIL-2R provides the basis for therapeutic strategies that target IL-2R-expressing cells. We hypothesized that elimination of activated lymphocytes by IL-2R-targeted chimeric proteins might ameliorate lung fibrosis. We investigated the effects of IL-2-Bax, a novel apoptosis-inducing IL-2R-targeted chimeric protein, on bleomycin-induced lung injury in mice. Treatment groups included (i) a single intratracheal instillation of bleomycin and twice-daily intraperitoneal injections of IL-2-Bax; (ii) intratracheal bleomycin and intraperitoneal IL-2-PE664Glu, an older-generation chimeric protein; (iii) intratracheal bleomycin/intraperitoneal PBS; (iv) intratracheal saline/intraperitoneal PBS. Lung injury was evaluated 14 days after intratracheal instillation by cell count in bronchoalveolar lavage (BAL) fluid, semi-quantitative and quantitative histomorphological measurements and by biochemical analysis of lung hydroxyproline. Bleomycin induced a BAL lymphocytosis that was significantly attenuated by IL-2-Bax and IL-2-PE664Glu. However, morphometric parameters and lung hydroxyproline were unaffected by the chimeric proteins. These results show that IL-2-Bax reduces the lymphocytic infiltration of the lungs in response to bleomycin, but this effect is not accompanied by a decrease in lung fibrosis. [source] Time course of bleomycin-induced lung fibrosisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 3 2002G. Izbicki Summary. Intratracheal instillation (IT) of bleomycin is a widely used experimental model for lung fibrosis. In this study we describe the time-course of bleomycin-induced lung fibrosis in mice using computer-assisted morphometry. C57Bl/6J mice were treated with a single IT dose of bleomycin or control saline. Animals were killed 3, 6, 14 and 21 days post-IT. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, hydroxyproline concentration in the lung, routine light microscopic examination resulting in a semiquantitative morphological index (SMI) of lung injury, and quantitative morphological measurements (fibrosis fraction and alveolar wall area fraction) aided by optimas image analysis software. Changes in BAL fluid attributed to bleomycin treatment include increased total cell count (days 14 and 21), and increased percentage of neutrophils (days 3 and 6) followed by a sustained increase in lymphocytes (days 6, 14 and 21). Hydroxyproline levels increased in bleomycin-treated mice on days 14 and 21. Median SMI grades were significantly elevated on days 3, 14 and 21. Computer-assisted morphometry demonstrated a 3-fold increase in fibrosis fraction and a 1.3-fold increase in wall area fraction in bleomycin-treated mice on day 14, with no further increase on day 21. These data also demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days after IT instillation of bleomycin, based on the observation that at 14 days the animals developed extensive fibrosis, but had less variability in the fibrotic response and lower mortality than later at 21 days. Computer-assisted morphometry provides objective and quantitative measurements that are a useful tool for the evaluation of bleomycin-induced lung injury. [source] Aging and lung injury repair: A role for bone marrow derived mesenchymal stem cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 3 2008Ana L. Mora Abstract The incidence of lung fibrosis increases with age. Aging is associated with modifications in the intracellular and extracellular environment including alteration of the extracellular matrix, imbalance of the redox state, accumulation of senescent cells and potential alteration of the recruitment of bone marrow mesenchymal stem cells. The combination of these senescence-related alterations in the lung and in bone marrow progenitor cells might be responsible of the higher susceptibility to lung fibrosis in elderly individuals. The understanding of these age related changes must be considered in the rationale for the development of therapeutic interventions to control lung injury and fibrosis. J. Cell. Biochem. 105: 641,647, 2008. © 2008 Wiley-Liss, Inc. [source] Review Article: Review: Endothelial-myofibroblast transition, a new player in diabetic renal fibrosisNEPHROLOGY, Issue 5 2010JINHUA LI ABSTRACT Diabetic nephropathy (DN) is the most common cause of chronic kidney failure and end-stage renal disease in the Western world. Studies from diabetic animal models and clinical trials have shown that inhibition of the renin-angiotensin system delays the progression of advanced DN. However, a recent large-scale clinical trial has revealed that inhibition of renin-angiotensin system in early phases of DN does not slow the decline of renal function or the development of morphological lesions, suggesting that different mechanism(s) may be involved in the different stages of DN. The role of epithelial-mesenchymal transition in renal fibrosis has been intensively investigated. Recently, endothelial-mesenchymal transition, or endothelial-myofibroblast transition (EndoMT) has emerged as another mechanism involved in both developmental and pathological processes. The essential role of EndoMT in cardiac development has been thoroughly studied. EndoMT also exists and contributes to the development and progression of cardiac fibrosis, lung fibrosis, liver fibrosis and corneal fibrosis. EndoMT is a specific form of epithelial-mesenchymal transition. During EndoMT, endothelial cells lose endothelial markers and obtain mesenchymal markers. Recent evidence from our laboratory and others suggests that EndoMT plays an important role in the development of renal fibrosis in several pathological settings, including experimental DN. This review considers the evidence supporting the occurrence of EndoMT in normal development and in pathology, as well as the latest findings suggesting EndoMT contributes to fibrosis in DN. Whether experimental findings of EndoMT will be reproduced in human studies remains to be determined. [source] Preventive effect of hochu-ekki-to, a Japanese herbal medicine, on bleomycin-induced lung injury in miceRESPIROLOGY, Issue 6 2007Shunji TAJIMA Objective: Pulmonary fibrosis is thought to be closely associated with the T-helper type-2 (Th2) immune response. Recent studies have shown that hochu-ekki-to (TJ-41), a Japanese herbal medicine, may correct the Th1/Th2 imbalance skewed to Th2. The present study was designed to investigate the preventive effect of TJ-41 on the development of bleomycin (BLM)-induced lung injury in mice. Methods: Female C57BL/6 mice were divided into a group given ordinary feed and another group given the same feed plus TJ-41 mixed in at a dose of 1 g/kg/day. Both groups were maintained on this diet for 8 weeks before and 5 weeks after administration of 2 mg/kg BLM intratracheally. Results: Mortality after BLM-induced lung injury was significantly lower in the TJ-41-treated mice. The hydroxyproline content and fluid content in the lung on day 35 was significantly lower in the TJ-41-treated mice. Histologically, TJ-41 reduced the number of infiltrating cells, thus ameliorating the destruction of the lung architecture, and attenuated the lung fibrosis score. Furthermore, TJ-41 inhibited the expression of the interleukin-5/interferon-, mRNA ratio in the lung on day 7. Conclusions: Treatment with TJ-41 partially prevented experimental lung fibrosis through the correction of the Th1/Th2 imbalance skewed to Th2. [source] Overexpression of nitric oxide synthase by the endothelium attenuates bleomycin-induced lung fibrosis and impairs MMP-9/TIMP-1 balanceRESPIROLOGY, Issue 5 2006Sho YOSHIMURA Background: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is thought to effect an anti-inflammatory response, but its mechanism is still unknown. Methods: eNOS transgenic (eNOS-TG) mice and their littermate controls (C57/BL6) were used to clarify the role of NO derived from eNOS. Bleomycin hydrochloride (1 U/body/day) or PBS was injected intraperitoneally. Results: Subpleural fibrotic changes and hydroxyproline content in the eNOS-TG mice were significantly reduced compared with those of the wild-type (WT) mice by day 56. Administration of N, -nitro- l -arginine methyl ester, a potent inhibitor of NO synthase, worsened the fibrotic response in bleomycin-treated eNOS-TG mice. Gelatinolytic activity in lung homogenates, corresponding to metalloproteinase-9 (MMP-9), was significantly increased in bleomycin-injured WT mice on day 14. In contrast, the level of tissue inhibitor of metalloproteinases-1 (TIMP-1), an endogenous MMP-9 inhibitor, was increased in the bleomycin-treated eNOS-TG mice compared with WT. Immunohistochemical analysis demonstrated that MMP-9 and TIMP-1 were strongly expressed in inflammatory cells, including subpleural fibrotic lesions. Conclusion: These data suggested that eNOS overexpression attenuates bleomycin-induced lung injury by ameliorating the MMP-9/TIMP-1 balance. [source] Role of Protease Activated Receptor 2 in Experimental Acute Lung Injury and Lung FibrosisTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 4 2009Xiao Su Abstract Protease activated receptor 2 (PAR2) is widely-distributed (lung, liver, kidney, etc.) and expressed by variety of cells (i.e. leukocytes, epithelial cells, endothelial cells, and fibroblast). PAR2 may participate in many pathological processes, such as, inflammation, injury, as well as fibrosis. Therefore, in this study, we tested whether PAR2 would exert a role in acid-induced acute lung injury, E. coli pneumonia, bleomycin-induced acute lung injury and fibrosis. Acid, E. coli, or bleomycin were intratracheally instilled into the lungs of both wildtype and PAR2 knockout mice to detect differences in pulmonary edema, lung vascular permeability, lung fibrosis, and other parameters. Knockout of PAR2 did not affect the extent of pulmonary edema and lung vascular permeability in acid-induced acute lung injury. Also, both activation of PAR2 in the airspaces of the lung and deletion of PAR2 did not alter the magnitude of pulmonary edema and lung vascular permeability in E. coli pneumonia. Finally, PAR2 deficiency did not affect the severity of lung inflammation and lung fibrosis in bleomycin-induced acute lung injury and lung fibrosis models. Thus, PAR2 does not appear to play a critical role in the pathogeneses of experimental acid-induced acute lung injury, E. coli pneumonia, and bleomycin-induced acute lung injury and pulmonary fibrosis in mice. Anat Rec, 2009. © 2009 Wiley-Liss, Inc. [source] Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosisARTHRITIS & RHEUMATISM, Issue 8 2010Ayumi Yoshizaki Objective Rapamycin, a novel macrolide immunosuppressive drug, is increasingly used as an agent for posttransplant immunosuppression and treatment of autoimmune disease. The molecular mechanism related to rapamycin-mediated immunosuppression is that rapamycin binds to FK-506 binding protein 12, and the formed complex inhibits the function of the mammalian target of rapamycin (mTOR), which in turn reduces protein phosphorylation, cell cycle progression, and cytokine production. The aim of this study was to examine the effect of rapamycin against the development of fibrosis and autoimmunity in 2 different types of systemic sclerosis (SSc) model mice. Methods Tight skin (TSK/+) mice and bleomycin- induced SSc model mice were used to evaluate the effect of rapamycin on fibrosis and immunologic abnormalities. Furthermore, the antifibrotic effect of rapamycin was assessed using TSK/+ mouse fibroblasts. Results Treatment with rapamycin reduced skin fibrosis of TSK/+ mice and skin and lung fibrosis of bleomycin-induced SSc model mice. The production of fibrogenic cytokines, such as interleukin-4 (IL-4), IL-6, IL-17, and transforming growth factor ,1, was attenuated by rapamycin. Hypergammaglobulinemia and anti,topoisomerase I antibody production were also reduced by rapamycin treatment in TSK/+ mice. In addition, mTOR expression levels were increased in TSK/+ mouse fibroblasts compared with those in wild-type mouse fibroblasts. Rapamycin treatment inhibited proliferation and collagen production of TSK/+ mouse fibroblasts in a dose-dependent manner. Conclusion This study is the first to show that rapamycin has a significant inhibitory effect on fibrosis in both TSK/+ and bleomycin-induced SSc model mice. These results suggest that rapamycin might be an attractive candidate for clinical trials in SSc patients. [source] Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagenARTHRITIS & RHEUMATISM, Issue 7 2009Markella Ponticos Objective Connective tissue growth factor (CTGF; CCN2) is overexpressed in systemic sclerosis (SSc) and has been hypothesized to be a key mediator of the pulmonary fibrosis frequently observed in this disease. CTGF is induced by transforming growth factor , (TGF,) and is a mediator of some profibrotic effects of TGF, in vitro. This study was undertaken to investigate the role of CTGF in enhanced expression of type I collagen in bleomycin-induced lung fibrosis, and to delineate the mechanisms of action underlying the effects of CTGF on Col1a2 (collagen gene type I ,2) in this mouse model and in human pulmonary fibroblasts. Methods Transgenic mice that were carrying luciferase and ,-galactosidase reporter genes driven by the Col1a2 enhancer/promoter and the CTGF promoter, respectively, were injected with bleomycin to induce lung fibrosis (or saline as control), and the extracted pulmonary fibroblasts were incubated with CTGF blocking agents. In vitro, transient transfection, promoter/reporter constructs, and electrophoretic mobility shift assays were used to determine the mechanisms of action of CTGF in pulmonary fibroblasts. Results In the mouse lung tissue, CTGF expression and promoter activity peaked 1 week after bleomycin challenge, whereas type I collagen expression and Col1a2 promoter activity peaked 2 weeks postchallenge. Fibroblasts isolated from the mouse lungs 14 days after bleomycin treatment retained a profibrotic expression pattern, characterized by greatly elevated levels of type I collagen and CTGF protein and increased promoter activity. In vitro, inhibition of CTGF by specific small interfering RNA and neutralizing antibodies reduced the collagen protein expression and Col1a2 promoter activity. Moreover, in vivo, anti-CTGF antibodies applied after bleomycin challenge significantly reduced the Col1a2 promoter activity by ,25%. The enhanced Col1a2 promoter activity in fibroblasts from bleomycin-treated lungs was partly dependent on Smad signaling, whereas CTGF acted on the Col1a2 promoter by a mechanism that was independent of the Smad binding site, but was, instead, dependent on the ERK-1/2 and JNK MAPK pathways. The CTGF effect was mapped to the proximal promoter region surrounding the inverted CCAAT box, possibly involving CREB and c-Jun. In human lung fibroblasts, the human COL1A2 promoter responded in a similar manner, and the mechanisms of action also involved ERK-1/2 and JNK signaling. Conclusion Our results clearly define a direct profibrotic effect of CTGF and demonstrate its contribution to lung fibrosis through transcriptional activation of Col1a2. Blocking strategies revealed the signaling mechanisms involved. These findings show CTGF to be a rational target for therapy in fibrotic diseases such as SSc. [source] Regulation of pulmonary inflammation and fibrosis through expression of integrins ,V,3 and ,V,5 on pulmonary T lymphocytesARTHRITIS & RHEUMATISM, Issue 5 2009Irina G. Luzina Objective Pulmonary diseases associated with fibrosis, including scleroderma lung disease, are characterized by the accumulation of T cells in the lungs. These cells are thought to facilitate lung fibrosis, but the exact mechanisms of their profibrotic action are not clear. Several ,V-containing integrins, including ,V,3 and ,V,5, have been shown to directly activate transforming growth factor , (TGF,) and promote collagen accumulation. The aim of this study was to investigate whether pulmonary T cells express profibrotic integrins and regulate collagen accumulation. Methods Expression of integrins was assessed by immunohistochemical analysis of lung tissue, by flow cytometry using bronchoalveolar lavage fluid from patients with systemic sclerosis (SSc), and in a CCL18 overexpression animal model of pulmonary T cell infiltration. Experiments in cell cultures were performed to determine whether integrin-expressing T cells are profibrotic in cocultures with pulmonary fibroblasts and, if so, through what possible mechanism. Results Lymphocytes and integrin-positive cells were present in the lungs, and pulmonary T cells expressed integrins ,V,3 and ,V,5 in patients with SSc and in the animal model. Systemic administration of neutralizing anti,integrin ,V antibody or a genetic deficiency of integrin ,3 in the CCL18 overexpression model significantly attenuated CCL18-driven pulmonary lymphocytic infiltration and collagen accumulation. Jurkat T cells overexpressing integrin ,V,3 or integrin ,V,5 in cocultures with primary pulmonary fibroblasts stimulated collagen accumulation and Smad2 nuclear translocation. Neutralizing anti-TGF, antibody attenuated the profibrotic effect of integrin-expressing T cells. Conclusion Pulmonary infiltrating T lymphocytes may express integrins ,V,3 and ,V,5 that are necessary for lymphocytic infiltration and T cell,associated TGF, activation and collagen accumulation. [source] Airway epithelium-derived transforming growth factor-, is a regulator of fibroblast proliferation in both fibrotic and normal subjectsCLINICAL & EXPERIMENTAL ALLERGY, Issue 8 2008K. E. Hostettler Summary Background In the healthy lung, airway epithelial cells (AEC) regulate fibroblast proliferation through release of soluble factors, such as prostaglandins and proteins. Fibroproliferative diseases and airway remodelling may result from an inadequate generation of suppressive factors by AEC or the inability of fibroblasts to respond to them appropriately. Objective The aim of this study was to study the effect of primary human AEC on the proliferation of fibroblasts obtained from healthy and fibrotic lungs in an interactive cell culture model. Results Conditioned medium (CM) from 14 out of 16 AEC lines significantly inhibited proliferation of normal human lung fibroblasts by 51.2±6.0%. The proliferation of fibroblasts derived from patients with lung fibrosis was equally inhibited by CM of AEC. The inhibitory effect of AEC-CM was completely reversed when fibroblasts were pre-incubated with 2.5 ,m indomethacin. Furthermore, primary human AEC, but not fibroblasts, secrete TGF-,, and the inhibitory effect of the AEC-CM was blocked by neutralizing anti-TGF-, antibodies. Conclusion These results demonstrate that AEC actively inhibit the proliferation of both normal and fibrotic fibroblasts via TGF-,, which induces the prostaglandin E2 synthesis in fibroblasts. The data indicate that proliferative lung diseases may be treated using the epithelial cell as the target of medication. [source] Development, repair and fibrosis: What is common and why it mattersRESPIROLOGY, Issue 5 2009Wei SHI ABSTRACT The complex structure of the lung is developed sequentially, initially by epithelial tube branching and later by septation of terminal air sacs with accompanying coordinated growth of a variety of lung epithelial and mesenchymal cells. Groups of transcriptional factors, peptide growth factors and their intracellular signaling regulators, as well as extracellular matrix proteins are programmed to be expressed at appropriate levels in the right place at the right time to control normal lung formation. Studies of lung development and lung repair/fibrosis to date have discovered that many of the same factors that control normal development are also key players in lung injury repair and fibrosis. Transforming growth factor-, (TGF-,) family peptide signaling is a prime example. Lack of TGF-, signaling results in abnormal lung branching morphogenesis and alveolarization during development, whereas excessive amounts of TGF-, signaling cause severe hypoplasia in the immature lung and fibrosis in mature lung. This leads us to propose the ,Goldilocks' hypothesis of regulatory signaling in lung development and injury repair that everything must be done just right! [source] | |||||||||||||||||||||||||