The role and regulation of the nuclear factor kappa B signalling pathway in human labour. (2007 Apr)
The role and regulation of the nuclear factor kappa B signalling pathway in human labour . within the discipline of reproductive biology , our understanding of one of the most fundamental biological processes is lacking the cellular and molecular mechanisms that govern birth . This lack of understanding limits our ability to reduce the incidence of labour complications . The incidence of labour complications including : preterm labour ; cervical incompetence ; and post date pregnancies has not diminished in decades . The key to improving the management of human labour and delivery is an understanding of how the multiple processes that are requisite for a successful labour and delivery are coordinated to achieve a timely birth . processes of human labour include the formation of : contraction associated proteins ; inflammatory mediators ( e . g . cytokines ) ; uterotonic phospholipid metabolites ( e . g . prostaglandins ) ; and the induction of extracellular matrix ( ECM ) remodelling . increasingly , it is becoming evident that labour onset and birth are the result of cross talk between multiple components of an integrated network . This hypothesis is supported by recent data implicating various upstream regulatory pathways in the control of key labour associated processes , including the activity of enzymes involved in the formation of prostaglandins and extracellular matrix remodelling , and mediators of inflammation . clearly , the biochemical pathways involved in the formation of these mediators represent potential sites for intervention that may translate …

Modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors. (2004 Jun)
modulation of matrix metalloproteinase production from human lung fibroblasts by type 4 phosphodiesterase inhibitors . Over expression of matrix metalloproteinases by lung fibroblasts has been blamed for much of the tissue destruction associated with airway inflammation . because cyclic AMP is known to regulate fibroblast proliferation , as well as cytokine and extracellular matrix protein production , the current study was designed to evaluate the ability of three selective phosphodiesterase ( PDE ) type 4 inhibitors , rolipram , cilomilast and CI 1044 , to inhibit extracellular matrix degradation . using zymography and elisa , we found that pro MMP 2 release was enhanced following 24 h treatment of human lung fibroblast ( MRC 5 ) with TGF beta1 ( 10 ng / ml ) or TNF alpha ( 10 ng / ml ) , whereas PMA ( 0 . 02 microm ) had no effect . One hour of pre incubation with PDE4 inhibitors ( 10 microm ) induced an inhibition of TNF alpha stimulated pro MMP 2 release . zymography and immunoblotting revealed that fibroblasts cultured with PMA or TNF alpha released increased amounts of pro MMP 1 , whereas TGF beta1 had no effect . incubation with CI 1044 or cilomilast significantly prevented the TNF alpha increase in pro MMP 1 . these results suggest that PDE4 inhibitors are effective in inhibiting the pro MMP 2 and pro MMP 1 secretion induced by TNF alpha and might underline a potential therapeutic benefit of selective PDE4 inhibitors in …

Renal remodelling in dietary protein modified rat polycystic kidney disease. (1999 Sep)
renal remodelling in dietary protein modified rat polycystic kidney disease . dietary protein restriction slows progression of the Han : SPRD cy rat model of polycystic kidney disease . We undertook studies to examine the relative changes in interstitial and tubular pathology as a result of feeding an 8 casein ( LP ) diet to Han : SPRD cy rats . archival tissue from a previous study comparing LP and 20 casein ( NP ) diets was examined morphometrically after immunohistochemical or histochemical staining for apoptosis , proliferation antigens , interstitial fibrosis , and macrophage infiltration . expression of common extracellular matrix genes was measured by northern analysis . animals fed LP diet demonstrated reduced tubular epithelial remodelling compared with animals fed NP diet by both proliferating cell nuclear antigen positive cells ( 57 . 5 vs . 71 . 6 cells / mm epithelium , P 0 . 007 ) or apoptosis ( 31 . 2 vs . 35 . 6 cells / mm epithelium , P 0 . 006 ) . interstitial pathology demonstrated that LP feeding was associated with proportionately greater reductions in interstitial fibrosis ( 0 . 3 vs . 1 . 3 ml / kg body weight , P 0 . 003 ) , interstitial cellularity ( 361 vs . 604 cells / high power field , P 0 . 0002 ) , and interstitial macrophages ( 67 vs . 149 cells / high power field , P 0 . 0002 ) . northern analysis …

The involvement of matrix metalloproteinase 9 in airway inflammation of patients with acute asthma. (2001 Oct)
The involvement of matrix metalloproteinase 9 in airway inflammation of patients with acute asthma . background : bronchial asthma is an inflammatory disease of the airway characterized by airway remodelling , and is due at least in part to an excess of extracellular matrix ( ECM ) deposition in the airway wall , which leads to subepithelial collagen deposition . matrix metalloproteinase 9 ( MMP 9 ) is the major proteolytic enzyme that induces bronchial remodelling in asthma . MMP 9 is also important in the migration of inflammatory cells through basement membrane components . objectives : We evaluated whether airway inflammatory cells correlated with levels of MMP 9 in acute asthma and we examined the time course of sputum levels of MMP 9 activity in patients with spontaneous asthma exacerbation . methods : We performed zymographic analysis and checked levels of MMP 9 by means of enzyme immunoassay . MMP 9 levels were also evaluated during a spontaneous attack of asthma . results : Pro MMP 9 activities and concentrations of MMP 9 in asthmatic patients significantly exceeded those of control subjects ( P 0 . 01 ) . The activities of pro MMP 9 were significantly higher in acute asthmatic patients than in stable asthmatic patients ( P 0 . 01 ) . The elevated MMP 9 activities significantly decreased after 7 and 28 days of therapy . In acute asthmatic patients , the levels of sputum MMP 9 significantly correlated with the total macrophage neutrophil eosinophil cell …

Clinical relevance of airway remodelling in airway diseases. (2007 Jul)
clinical relevance of airway remodelling in airway diseases . asthma and chronic obstructive pulmonary disease ( COPD ) are characterised by airflow obstruction , airway remodelling ( measurable structural change ) and inflammation . The present review will examine the relationship between airway remodelling in these two conditions with respect to symptoms , abnormal lung function , airway hyperresponsiveness and decline in lung function . The potential for remodelling to be a protective response will also be discussed . asthma is associated with variable symptoms and changes in lung function and also fixed abnormalities of lung function and an increased rate of decline in lung function with age . there is a relative preservation of the relaxed airway lumen dimensions , prominent thickening of the smooth muscle layer and reduced airway distensibility . The severity of asthma is related to the degree of airway remodelling , which is most marked in cases of fatal asthma . In COPD , symptoms are persistent and predictable but also progressive and are related to fixed abnormalities of lung function . remodelling is associated with narrowing of the airway lumen and an increased thickness of the airway wall , although not usually to the extent seen in asthma . COPD is most often due to smoking where there is also remodelling of the parenchyma that may contribute to symptoms .

In vivo models of inflammation and matrix remodelling : classical to modern approaches. (2000 Nov)
In vivo models of inflammation and matrix remodelling : classical to modern approaches .

Extracellular matrix remodelling after coxsackievirus B3 induced murine myocarditis. (1992 Dec)
extracellular matrix remodelling after coxsackievirus B3 induced murine myocarditis . weanling inbred Balb / c mice were intraperitoneally inoculated with a myocarditic variant of coxsackievirus B3 . At days 1 , 2 , 4 , 6 , 8 , 10 , 14 , 24 and 30 post infection ( p . i . ) , myocardial tissue was harvested for viral infectivity titrations and histological studies , including routine techniques ( haematoxylin eosin , masson trichrome and von kossa ) and specialized procedures ( silver impregnation for reticulin , picrosirius red stain for collagen and immunoperoxidase labelling for laminin ) . virus was isolated as from day 2 , reached maximal infectivity at days 6 8 and decreased gradually to become undetectable by day 14 . early histological findings during the 1st week consisted mainly of scattered foci of necrotic myocytes showing calcium deposits ; slight mononuclear cell infiltration and fragmentation of both reticulin fibres and pericellular laminin were also present . From the 2nd up to 4th week p . i . , inflammatory reaction abated concomitantly with the gradual development of fibrosis , as evidenced by reticulin fibre thickening , irregular laminin distribution and collagen fibre increase . Our results suggest that viral induced necrosis is able to trigger marked extracellular matrix remodelling even in the case of minimal inflammation .

Pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix … (2003 Dec)
pathogenic role of matrix metalloproteases and their inhibitors in asthma and chronic obstructive pulmonary disease and therapeutic relevance of matrix metalloproteases inhibitors . matrix metalloproteinases ( MMPs ) are an at least 23 member family of calcium and zinc dependent enzymes implicated in many physiological and pathological processes . asthma , chronic obstructive pulmonary disease ( COPD ) and emphysema are diseases associated with an inflammation of the airways and lung parenchyma . In this review , we focus on the role played by MMPs in the pathogenesis of inflammation , airway remodelling and alveolar destruction , depicting the observational studies in humans and the experimental studies in animal models . during the course of asthma , MMP 2 , 8 , 9 and TIMP 1 are expressed at baseline and the allergen exposure or exacerbations of the disease lead to an increase of MMP 9 secretion being at this time much higher than that of TIMP 1 , allowing temporarily a matrix damage , possibly followed by abnormal repair . animal models suggest a predominant role for MMP 9 and MMP 12 in the pathogenesis of pulmonary inflammation and link an absence of MMP 2 to an increased parenchymal inflammation . In COPD and emphysema , human studies indicate an over secretion of MMP 2 , 8 , 9 and animal models pointout MMP 1 and MMP 12 as being key players in the pathogenesis of emphysema . taken together , these data identify specific MMP inhibition as appropriate …

Extracellular matrix remodelling : the role of matrix metalloproteinases. (2003 Jul)
extracellular matrix remodelling : the role of matrix metalloproteinases . matrix metalloproteinases ( MMPs ) are a growing family of metalloendopeptidases that cleave the protein components of the extracellular matrix and thereby play a central role in tissue remodelling . For many years following their discovery , MMPs were believed to function primarily as regulators of ECM composition and to facilitate cell migration simply by removing barriers such as collagen . It is becoming increasingly clear , however , that MMPs are implicated in the functional regulation of a host of non ECM molecules that include growth factors and their receptors , cytokines and chemokines , adhesion receptors and cell surface proteoglycans , and a variety of enzymes . MMPs therefore play an important role in the control of cellular interactions with and response to their environment in conditions that promote tissue turnover , be they physiological , such as normal development , or pathological , such as inflammation and cancer . This review summarizes some of the recent discoveries that have shed new light on the role of MMPs in physiology and disease .

Cardiac hypertrophy is enhanced in PPAR alpha / mice in response to chronic pressure overload. (2008 Mar)
cardiac hypertrophy is enhanced in PPAR alpha / mice in response to chronic pressure overload . AIMS : peroxisome proliferator activated receptor alpha ( pparalpha ) is a nuclear receptor regulating cardiac metabolism that also has anti inflammatory properties . since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis , it is anticipated that pparalpha modulates cardiac remodelling . accordingly , in this study the hypothesis was tested that the absence of pparalpha aggravates the cardiac hypertrophic response to pressure overload . methods AND results : Male pparalpha / and wild type mice were subjected to transverse aortic constriction ( TAC ) for 28 days . TAC resulted in a more pronounced increase in ventricular weight and left ventricular ( LV ) wall thickness in pparalpha / than in wild type mice . compared with sham operated mice , TAC did not affect cardiac function in wild type mice , but significantly depressed LV ejection fraction and LV contractility in pparalpha / mice . moreover , after TAC mRNA levels of hypertrophic ( atrial natriuretic factor , alpha skeletal actin ) , fibrotic ( collagen 1 , matrix metalloproteinase 2 ) , and inflammatory ( interleukin 6 , tumour necrosis factor alpha , cyclo oxygenase 2 ) marker genes were higher in pparalpha / than in wild type mice . The mRNA levels of genes involved in fatty acid metabolism ( long chain acyl CoA synthetase , hydroxyacyl CoA dehydrogenase ) were …

Inflammation , proteases and cancer. (2006 Apr)
inflammation , proteases and cancer . tumours are complex tissues composed of ever evolving neoplastic cells , matrix proteins that provide structural support and sequester biologically active molecules , and a cellular stromal component . reciprocal interactions between neoplastic cells , activated host cells and the dynamic micro environment in which they live enables tumour growth and dissemination . It has become evident that early and persistent inflammatory responses observed in or around developing neoplasms regulates many aspects of tumour development ( matrix remodelling , angiogenesis , malignant potential ) by providing diverse mediators implicated in maintaining tissue homeostasis , e . g . , soluble growth and survival factors , matrix remodelling enzymes , reactive oxygen species and other bioactive molecules . This review highlights recent insights into the role of chronic inflammation associated with cancer development and examines proteolytic pathways activated by infiltrating leukocytes during neoplastic programming of tissues .

Tissue remodelling in liver diseases. (2003 Sep)
tissue remodelling in liver diseases . tissue remodelling is a dynamic process that occurs during fetal or adult life and involves a modification of the original organization and function of a tissue . tissue remodelling is observed in physiological and pathological conditions such as during wound healing or in the mammary gland during the course of pregnancy . In this review we will discuss the remodelling occurring in the liver as a consequence of chronic inflammation , as observed in chronic hepatitis , or as a consequence of hepatocellular carcinoma ( HCC ) progression in more detail . We will consider how altered deposition and turn over of extracellular matrix ( ECM ) proteins could lead to development of liver fibrosis , and how the exacerbation of fibrosis could underlie the development of cirrhosis . The involvement of inflammatory and anti inflammatory cytokines commonly used as therapeutic agents , such as interferon a , is then evaluated with a particular focus on modulation of ECM proteolysis . finally , we analyze the role of alterations of the surrounding microenvironment including ECM , growth factors , cytokines and membrane receptors for ECM ligands in the development of HCC and in its invasive behaviour .

Redox dependent signalling by angiotensin II and vascular remodelling in hypertension. (2003 Dec)
redox dependent signalling by angiotensin II and vascular remodelling in hypertension . 1 . hypertension is associated with structural alterations of resistance arteries , a process known as remodelling ( increased media to lumen ratio ) . 2 . At the cellular level , vascular remodelling involves changes in vascular smooth muscle cell ( VSMC ) growth , cell migration , inflammation and fibrosis . these processes are mediated via multiple factors , of which angiotensin ( Ang ) II appears to be one of the most important in hypertension . 3 . angiotensin II signalling , via AT1 receptors , is upregulated in VSMC from resistance arteries of hypertensive patients and rats . This is associated with hyperactivation of vascular nadph oxidase , leading to increased generation of reactive oxygen species ( ROS ) , particularly O2 and H2O2 . 4 . reactive oxygen species function as important intracellular second messengers to activate many downstream signalling molecules , such as mitogen activated protein kinase , protein tyrosine phosphatases , protein tyrosine kinases and transcription factors . activation of these signalling cascades leads to VSMC growth and migration , modulation of endothelial function , expression of pro inflammatory mediators and modification of extracellular matrix . 5 . furthermore , ROS increase intracellular free Ca2 concentration ( Ca2 i ) , a major determinant of vascular reactivity . 6 . All these processes play major roles in vascular injury associated with hypertension . accordingly , ROS and the signalling pathways that …

Wound healing mediator production by human dermal fibroblasts grown within a collagen GAG matrix for skin repair in humans. (2003 Jun)
wound healing mediator production by human dermal fibroblasts grown within a collagen GAG matrix for skin repair in humans . Cell and tissue therapy applications in humans are being used increasingly , particularly for tissue repair . several reconstructed skin models have been proposed . wound healing involves overlapping steps of inflammation , cell migration and proliferation , neovascularisation , extracellular matrix production and remodelling . This is regulated by numerous cytokines and other soluble mediators . We have prepared dermal substitutes ( DS ) consisting of a collagen GAG , three dimensional matrix colonized by human dermal fibroblasts ( HDF ) , isolated by skin explant or enzymatic digestion of the skin for potential therapeutic use in humans . To test the functionality of these DS , we measured ( elisa ) the stimulatory effect on HDF in the matrix , of serial dilutions of human serum ( HS ) on the production of wound healing mediators : interleukin 8 ( IL 8 ) , vascular endothelial growth factor ( VEGF ) , keratinocyte growth factor ( KGF ) and tissue inhibitor of metalloproteinase 1 ( TIMP 1 ) . We observed : 1 ) . a stimulatory effect of HS on HDF production of the different mediators tested , with a dose dependent effect in the case of IL 8 and VEGF . 2 ) . A matrix potentiating effect on the production of the different mediators by HDF . 3 ) . A decrease in the production …

Tackling the EGFR in pathological tissue remodelling. (2005 Nov)
tackling the EGFR in pathological tissue remodelling . tissue remodelling is an adaptive physiological event initiated by physical and / or hormonal stimuli and characterised by extracellular matrix modifications , inflammation , cellular hypertrophy , proliferation and / or apoptosis . although its initial effects may be beneficial for the maintenance of organ function , it is evident that sustained remodelling processes can lead to pathological outcomes , such as fibrosis in asthma , and cardiac hypertrophy in heart failure . Our research is focussed upon cardiac hypertrophy and the significant contribution of the molecular pathway , termed the triple membrane passing signalling paradigm ( TMPS ) , to this phenomenon . cardiac hypertrophy describes the enlargement , but not proliferation , of cardiomyocytes in response to mechanical or hormonal factors to normalise cardiac output and accompanies other features of cardiac remodelling . As a major independent risk factor for heart failure , it is imperative that the molecular mechanisms that govern this phenotype are determined to identify possible therapeutic targets . This review will focus on the importance of matrix metalloproteases and epidermal growth factor receptors in the TMPS pathway and their potential as pharmacological targets for heart failure therapy . The evidence provided may have implications for pathological tissue remodelling in other organs .

Phagocytosis and intracellular digestion of collagen , its role in turnover and remodelling. (1996 Nov)
phagocytosis and intracellular digestion of collagen , its role in turnover and remodelling . collagens of most connective tissues are subject to continuous remodelling and turnover , a phenomenon which occurs under both physiological and pathological conditions . degradation of these proteins involves participation of a variety of proteolytic enzymes including members of the following proteinase classes : matrix metalloproteinases ( e . g . collagenase , gelatinase and stromelysin ) , cysteine proteinases ( e . g . cathepsin B and L ) and serine proteinases ( e . g . plasmin and plasminogen activator ) . convincing evidence is available indicating a pivotal role for matrix metalloproteinases , in particular collagenase , in the degradation of collagen under conditions of rapid remodelling , e . g . inflammation and involution of the uterus . under steady state conditions , such as during turnover of soft connective tissues , involvement of collagenase has yet to be demonstrated . under these circumstances collagen degradation is likely to take place particularly within the lysosomal apparatus after phagocytosis of the fibrils . We propose that this process involves the following steps : ( i ) recognition of the fibril by membrane bound receptors ( integrins ? ) , ( ii ) segregation of the fibril , ( iii ) partial digestion of the fibril and / or its surrounding non collagenous proteins by matrix metalloproteinases ( possibly gelatinase ) , and finally ( iv ) lysosomal digestion by cysteine proteinases , such …

Matrix metalloproteinases , inflammation and atherosclerosis : therapeutic perspectives. (2004 Apr)
matrix metalloproteinases , inflammation and atherosclerosis : therapeutic perspectives . matrix metalloproteinases ( MMPs ) , also called matrixins , are proteinases that participate in extracellular matrix remodelling and degradation . under normal physiological conditions , the activities of MMPs are precisely regulated at the level of transcription , of activation of the pro MMP precursor zymogens and of inhibition by endogenous inhibitors ( tissue inhibitors of metalloproteinases ; timps ) . alteration in the regulation of MMP activity is implicated in diseases such as cancer , fibrosis , arthritis and atherosclerosis . The pathological effects of MMPs and timps in cardiovascular diseases involve vascular remodelling , atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction . since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression ( including plaque disruption ) , MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and timps . This review describes the members of the MMP and TIMP families and discusses the structure , function and regulation of MMP activity ; finally , pharmacological approaches to MMP inhibition are highlighted .

Matrix metalloproteinase dysregulation in HIV infection : implications for therapeutic strategies. (2008 Feb)
matrix metalloproteinase dysregulation in HIV infection : implications for therapeutic strategies . The emerging role of immune activation and inflammation in the pathogenesis of human immunodeficiency virus ( HIV ) disease has stimulated the search for new approaches for managing HIV infection . recent evidence suggests that an imbalance between matrix metalloproteinases ( MMPs ) and endogenous tissue inhibitors of MMPs ( timps ) might contribute to HIV associated pathology by inducing remodelling of the extracellular matrix . Here , we discuss the evidence and the potential mechanisms for altered MMP or TIMP function in HIV infection and disease . furthermore , we outline the possible medical implications for the use of compounds that target MMP activity , and we propose that antiretroviral drugs , particularly HIV protease inhibitors ( PIs ) , and compounds with anti inflammatory properties , such as statins , natural omega 3 fatty acids and tetracyclines , which inhibit MMP function , might represent useful therapeutic approaches to mitigate potential MMP related damage during HIV infection .

Apoptosis and extracellular matrix remodelling in human silicosis. (2006 Aug)
apoptosis and extracellular matrix remodelling in human silicosis . AIMS : silicosis is a chronic occupational disease caused by the inhalation of free crystalline silica particles which produce inflammation and tissue destruction followed by remodelling of the extracellular matrix . apoptosis has been implicated in the development of the initial inflammation that triggers the remodelling process . Our aim was to elucidate the importance of Fas ligand ( Fas L ) in this disorder and to study the relationship between Fas L and several other inflammatory and fibrotic remodelling markers . methods AND results : We analysed 23 lung biopsies from silicotic patients and five controls , quantifying Fas L and Bcl 2 expression by inflammatory cells as well as mast cells and collagen and elastic fibres . We used immunohistochemistry and morphometry to evaluate the amount of Fas L and Bcl 2 . Our analysis revealed that the silicotic lung stage was significantly related to Fas L , mast cell and extracellular matrix remodelling . Fas L expression was inversely associated with mast cells , collagen / elastic deposition and the silicotic lung . conclusion : Fas L , mast cell staining and collagen / elastic fibre quantities in silicotic lungs are strongly related to silicosis progression .

Extracellular matrix , junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation. (2002 Aug)
extracellular matrix , junctional integrity and matrix metalloproteinase interactions in endothelial permeability regulation . vascular endothelial permeability is maintained by the regulated apposition of adherens and tight junctional proteins whose organization is controlled by several pharmacological and physiological mediators . endothelial permeability changes are associated with : ( 1 ) the spatial redistribution of surface cadherins and occludin , ( 2 ) stabilization of focal adhesive bonds and ( 3 ) the progressive activation of matrix metalloproteinases ( MMPs ) . In response to peroxide , histamine and EDTA , endothelial cells sequester VE cadherin and alter its cytoskeletal binding . simultaneously , these mediators enhance focal adhesion to the substratum . oxidants , cytokines and pharmacological mediators also trigger the activation of matrix metalloproteinases ( MMPs ) in a cytoskeleton and tyrosine phosphorylation dependent manner to degrade occludin , a well characterized tight junction element . these related in vitro phenomena appear to co operate during inflammation , to increase endothelial permeability , structurally stabilize cells while also remodelling cell junctions and substratum .