Imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in toluene diisocyanate induced asthma. (2004 Feb)
imbalance between matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in toluene diisocyanate induced asthma . background : toluene diisocyanate ( TDI ) induced asthma is an inflammatory disease of the airways characterized by airway remodelling due , at least in part , to an excess of extracellular matrix deposition in the airway wall . The ratio of matrix metalloproteinase 9 ( MMP 9 ) and its inhibitor , tissue inhibitor of metalloproteinase 1 ( TIMP 1 ) may be a marker of the balance between airway tissue destruction and repair . objective : We determined whether an imbalance of the MMP 9 : TIMP 1 molar ratio is present before and / or after challenge with TDI . methods : We used a murine model of TDI induced asthma to evaluate the MMP 9 and TIMP 1 balance in the lung . results : The expression of MMP 9 and TIMP 1 mrnas and proteins in the lungs increased at 7 h after TDI inhalation and continued for up to 72 h . immunohistochemical and immunocytological analyses in the lungs of TDI exposed mice revealed increases of immunoreactive MMP 9 and TIMP 1 . there were significant correlations between the levels of MMP 9 or TIMP 1 and the number of neutrophils , lymphocytes , or eosinophils . The molar ratio of MMP 9 / TIMP 1 significantly decreased at 7 h after TDI inhalation and continued up to 72 h . conclusion : these data suggest that …

The role of eosinophils in airway tissue remodelling in asthma. (2007 Dec)
The role of eosinophils in airway tissue remodelling in asthma . there is an increasing evidence that airway structural change ( termed remodelling ) is associated with the severity and chronicity of asthma . recent studies support an important role for eosinophils in the remodelling process . In particular eosinophil depletion studies have demonstrated that several aspects of remodelling are attenuated . eosinophils have been confirmed as an important source of TGF beta ( 1 ) as well as other important cytokines that can lead to the direct activation of epithelium and mesenchymal cells that are considered to drive airway remodelling . The current studies that support a role for eosinophils in airway remodelling are reviewed in article .

Allergen induced airway remodelling. (2007 May)
allergen induced airway remodelling . airway remodelling is associated with chronic asthma but it remains unclear whether it results from airway inflammation in response to allergens or immune mediated events such as viral infections . although the acute inflammation associated with asthma has been modelled extensively both in vitro and in vivo , the structural changes occurring in the lung have only recently been investigated . these in vitro , in vivo and in silico systems have been designed to examine the pathways leading to allergen induced airway remodelling and have enabled investigators to draw conclusions about the participation of key cells and molecules in the development of allergen induced airway remodelling . however , fundamental questions remain regarding the genesis of remodelling as well as the relationship between functional symptoms and pathological changes that occur . In this review the key questions relating allergen exposure to development of remodelling are discussed , as well as the steps that are being undertaken to investigate them .

Airways remodelling in asthma : no doubt , no more ? asthma is a chronic inflammatory disease of the airways … (1995 Aug)
airways remodelling in asthma : no doubt , no more ? asthma is a chronic inflammatory disease of the airways invariably associated with healing . remodelling of the airways can be demonstrated by the activation of airways macrophages , the release of growth factors and fibrogenic cytokines , the activation of fibroblasts and myofibroblast , elastolysis and elastosynthesis , collagen deposition , increased synthesis and release of extracellular matrix components , and an increased mass of smooth muscle and mucous glands . however , the control of remodelling is still poorly understood .

Reduction of matrix metalloproteinase 9 activity by the selective phosphodiesterase 4 inhibitor , RP 73 401 in sensitized mice. (2000 Dec)
reduction of matrix metalloproteinase 9 activity by the selective phosphodiesterase 4 inhibitor , RP 73 401 in sensitized mice . matrix metalloproteinases are particularly potent in degrading basement membrane collagen and other extracellular matrix components . We have investigated the effects of a selective phosphodiesterase 4 inhibitor , RP 73 401 N ( 3 , 5 dichloropyrid 4 yl ) 3 cyclopentyloxy 4 methoxybenzamide , on gelatinase ( matrix metalloproteinase 2 and matrix metalloproteinase 9 ) activity in ovalbumin sensitized and challenged mice . twenty four hours after the last challenge , matrix metalloproteinase activity was evaluated in the bronchoalveolar lavage fluids by a zymography technique , and a significant increase in matrix metalloproteinase 9 , but not matrix metalloproteinase 2 , activity was noted . When administered orally ( 0 . 3 3 mg / kg ) 1 h before each ovalbumin challenge , the selective phosphodiesterase 4 inhibitor , RP 73 401 , significantly reduced this increased matrix metalloproteinase 9 activity in bronchoalveolar lavage fluids . Our data suggest that RP 73 401 may modulate tissue remodelling associated with lung inflammatory processes including asthma .

Selective PDE4 inhibitors as potent anti inflammatory drugs for the treatment of airway diseases. (2005 Jun)
selective PDE4 inhibitors as potent anti inflammatory drugs for the treatment of airway diseases . phosphodiesterases ( PDEs ) are responsible for the breakdown of intracellular cyclic nucleotides , from which PDE4 are the major cyclic AMP metabolizing isoenzymes found in inflammatory and immune cells . This generated greatest interest on PDE4 as a potential target to treat lung inflammatory diseases . For example , cigarette smoke induced neutrophilia in BAL was dose and time dependently reduced by cilomilast . beside the undesired side effects associated with the first generation of PDE4 inhibitors , the second generation of selective inhibitors such as cilomilast and roflumilast showed clinical efficacy in asthma and chronic obstructive pulmonary diseases trials , thus re enhancing the interest on these classes of compounds . however , the ability of PDE4 inhibitors to prevent or modulate the airway remodelling remains relatively unexplored . We demonstrated that selective PDE4 inhibitor RP 73 401 reduced matrix metalloproteinase ( MMP ) 9 activity and TGF beta1 release during LPS induced lung injury in mice and that CI 1044 inhibited the production of MMP 1 and MMP 2 from human lung fibroblasts stimulated by pro inflammatory cytokines . since inflammatory diseases of the bronchial airways are associated with destruction of normal tissue structure , our data suggest a therapeutic benefit for PDE4 inhibitors in tissue remodelling associated with chronic lung diseases .

The role of mRNA stability in airway remodelling. (2005 Sep)
The role of mRNA stability in airway remodelling . As a consequence of long term exposure to inflammatory mediators , the airways of asthmatics become remodelled . airway fibrosis becomes apparent , with thickening of the lamina recticularis and increased interstitial matrix deposition being typical features of an asthmatic airway . mucus hypersecretion occurs , airway smooth muscle mass is increased and neovascularization is evident in the subepithelial mucosa . As development of a remodelled airway is correlated with deterioration of lung function in asthmatics , there is an urgent need for therapies that reduce airway inflammation and reverse structural changes in a remodelled airway . however , in order to design efficacious anti remodelling agents we first need a greater understanding of the molecular mechanism / s underlying the development of airway remodelling . To date , however , most studies have primarily focused on the transcriptional regulation of genes that promote airway remodelling . Post transcriptional mechanisms , such as control of mRNA stability , remain largely unexplored . levels of cellular mRNA transcripts are regulated by controlling the rate at which the mRNA decays , thus investigation into the mechanisms underlying mRNA stability in asthma are of critical importance . therefore , this review will present an overview of the control of mRNA stability and examine how mRNA stability may play a role in the development of airway remodelling in asthma .

What is the contribution of respiratory viruses and lung proteases to airway remodelling in asthma and chronic obstructive pulmonary disease … (2005 Nov)
What is the contribution of respiratory viruses and lung proteases to airway remodelling in asthma and chronic obstructive pulmonary disease ? It is well known that the lungs of asthmatics show airway wall remodelling and that asthma exacerbations are linked to respiratory infections . there is some evidence that respiratory infections in early childhood may increase the risk of developing asthma later in life . chronic obstructive pulmonary disease ( COPD ) , by definition , involves structural changes to the airways . however , very little is known about what role virus infections play in the development of this remodelling . This review considers the role of matrix metalloproteases and neutrophil elastase in remodelling , and whether the induction of proteases and other mediators during respiratory virus infections may contribute to the development of airway remodelling .

Role of matrix metalloproteinases in chronic rhinosinusitis. (2008 Jan)
Role of matrix metalloproteinases in chronic rhinosinusitis . purpose OF review : In this review , we discuss the role of matrix metalloproteinases and the potential therapeutic inhibition of metalloproteinases in chronic rhinosinusitis . metalloproteinases control tissue remodelling along with several other physiologic processes . failures may cause extracellular matrix deposition and sustained inflammation , which are common features in chronic rhinosinusitis . recent findings : metalloproteinases are rarely studied in chronic rhinosinusitis . upregulation of certain metalloproteinases ( gelatinases , collagenases and matrilysin ) is described in the literature . The results are partly controversial , suggesting that metalloproteinases are implicated in the destructive processes in the disease pathogenesis , but also demonstrate that they may exert an anti inflammatory function in chronic rhinosinusitis . The imbalance between metalloproteinases and the tissue inhibitor of metalloproteinases is proposed to be crucial in the extracellular matrix deposition in asthma , and it may also lead to pathologic tissue remodelling in chronic rhinosinusitis . summary : metalloproteinases are implicated in the chronic respiratory tract diseases , but little is known about their detailed functions in disease pathogenesis . metalloproteinases may serve as tools in evaluating prognosis and provide a target for novel therapies , highlighting the need for better understanding of metalloproteinase functions in chronic rhinosinusitis .

Vascular remodelling in asthma. (2008 Jan)
vascular remodelling in asthma . purpose OF review : We review the recent literature , focusing on 2006 and 2007 , to produce an update on the patho biology of angiogenesis and vascular endothelial growth factor in the asthmatic airway . recent findings : In terms of conceptual development in asthma research , airway inflammation and remodelling have been regarded as separate processes or perhaps as sequential , with early inflammation leading later to remodelling . recent insights identify a central role for vascular endothelial growth factor in stimulating both inflammation and vascular remodelling coincidentally , with the full panoply of vascular endothelial growth factor mediated events being complex and wide . Both nitric oxide and matrix metalloproteinase 9 induction may be important downstream pathogenic mechanisms . virus mediated exacerbations are a prime manifestation of the oscillating trajectory of clinical asthma . The early stimulation of vascular endothelial growth factor production is probably a central aetiological mechanism , with secondary inflammation and angiogenesis . The time scale of the latter , especially , fits with the time scale of clinico physiological changes after exacerbation . these vascular endothelial growth factor induced changes are potentially modifiable with therapy . summary : insights into the importance of vascular endothelial growth factor and angiogenesis in asthma pathogenesis now lead to potential new therapeutic possibilities and elucidate why recent advances in asthma therapeutics have been so successful .

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 .

Cytokines in chronic obstructive pulmonary disease. (2002 Oct)
cytokines in chronic obstructive pulmonary disease . chronic obstructive pulmonary disease ( COPD ) is characterized by chronic obstruction of expiratory flow affecting peripheral airways , associated with chronic bronchitis ( mucus hypersecretion with goblet cell and submucosal gland hyperplasia ) and emphysema ( destruction of airway parenchyma ) , together with fibrosis and tissue damage , and inflammation of the small airways . cytokines are extracellular signalling proteins . increased levels of interleukin ( IL ) 6 , IL 1beta , tumour necrosis factor alpha ( TNF alpha ) and IL 8 have been measured in sputum , with further increases during exacerbations , and the bronchiolar epithelium over expresses monocyte chemotactic protein ( MCP ) 1 and IL 8 . IL 8 can account for some chemotactic activity of sputum , and sputum IL 8 levels correlate with airway bacterial load and blood myeloperoxidase levels . The expression of chemokines such as regulated on activation , normal T cell expressed and secreted ( rantes ) may underlie the airway eosinophilia observed in some COPD patients . cytokines may be involved in tissue remodelling . TNF alpha and IL 1beta stimulate macrophages to produced matrix metalloproteinase 9 ( MMP 9 ) , and bronchial epithelial cells to produce extracellular matrix glycoproteins such as tenascin . increased expression of transforming growth factor beta ( tgfbeta ) and of epidermal growth factor ( EGF ) occurs in the epithelium and submucosal cells of patients with chronic bronchitis . tgfbeta and EGF …

Connective tissue growth factor : a role in airway remodelling in asthma ? 1. (2006 Jan)
connective tissue growth factor : a role in airway remodelling in asthma ? 1 . severe persistent asthma is accompanied by structural changes in the airway , referred to as remodelling . The mechanisms driving airway remodelling are poorly understood . 2 . transforming growth factor ( TGF ) beta is increased in the airways of patients with asthma . Many of the effects of TGF beta are mediated by connective tissue growth factor ( CTGF ) . 3 . overexpression of CTGF is linked to many fibrotic diseases , but its exact role in airway remodelling is unknown . 4 . connective tissue growth factor mediates cell adhesion , migration , proliferation , survival , extracellular matrix synthesis and has a role in angiogenesis . 5 . current asthma therapies do not inhibit CTGF induction . 6 . understanding the mechanisms underlying the role of CTGF in airway remodelling may lead to new therapeutic strategies for asthma .

The functional consequences of airway remodeling in asthma. (1998 May)
The functional consequences of airway remodeling in asthma . structural changes in the airway walls involving extracellular matrix remodelling are prominent features of asthma . these changes are probably driven by mediators released as a consequence of chronic allergic inflammation . It is clear that changes in the extracellular matrix have the capacity to influence airway function in asthma . however , it is not clear how each of the many changes that occur in the airway wall contribute to altered airway function in asthma . collagen deposition in the subepithelial matrix , and hyaluronan and versican deposition around and internal to the smooth muscle would be expected to oppose the effect of smooth muscle contraction . conversely , geometric considerations would result in exaggerated airway narrowing for a given degree of smooth muscle shortening , as the airway wall is thickened by the deposition of these molecules internal to the smooth muscle . elastin and cartilage reorganization and degradation in the airway walls would be expected to result in decreased airway wall stiffness and increased airway narrowing for a given amount of force generated by the smooth muscle . degradation of matrix associated with the smooth muscle may both decrease the stiffness of the parallel elastic component and uncouple smooth muscle from the load provided by lung recoil , allowing exaggerated smooth muscle shortening . increase in muscle mass may be associated with an increase , a decrease or no change in smooth muscle contractility . If an increase …

Polymorphisms of the adam33 gene are associated with accelerated lung function decline in asthma. (2004 May)
polymorphisms of the adam33 gene are associated with accelerated lung function decline in asthma . background : asthma is a genetically complex disease characterized by respiratory symptoms , intermittent airway obstruction and airway hyper responsiveness due to airway inflammation and remodelling . The adam33 gene is associated with asthma and airway hyper responsiveness and is postulated as a gene for airway remodelling . objective : To investigate whether polymorphisms of the adam33 gene are associated with accelerated lung function decline in patients with asthma . methods : In a cohort of 200 asthma patients followed over 20 years , eight single nucleotide polymorphisms of the adam33 gene were analysed to estimate their effect on annual FEV ( 1 ) decline . results : The rare allele of the S 2 polymorphism was significantly associated with excess decline in FEV ( 1 ) ( P 0 . 05 ) . conclusion : these findings suggest that a variant in adam33 is not only important in the development of asthma but also in disease progression , possibly related to enhanced airway remodelling .

Matrix metalloproteinases and their inhibitors in non neoplastic otorhinolaryngological disease. (2005 Jul)
matrix metalloproteinases and their inhibitors in non neoplastic otorhinolaryngological disease . matrix metalloproteinases ( MMPs ) are a family of zinc and calcium dependent endopeptidases that play a key role in extracellular matrix ( ECM ) degradation . MMPs are known to be important in normal remodelling processes . overexpression and activation of MMPs or an imbalance of active MMPs and tissue inhibitors of metalloproteinases ( timps ) has been linked with a number of specific disease states associated with the breakdown and remodelling of the extracellular matrix . MMPs and timps play a role in the development and progression of conditions such as acute and chronic otitis media , nasal polyposis and sjogren s disease of salivary glands . their role in allergic rhinitis has not been proven although they do appear to have a role in asthma , a condition closely linked to rhinitis . The use of a broad spectrum MMP inhibitor has been shown to alter the outcome of acute otitis media and otitis media with effusion . therapeutic strategies with anti MMP molecules are currently being developed and may play a role in modulating the course of non neoplastic otorhinolaryngological disease in the future .

Remodelling of the extracellular matrix in asthma : proteoglycan synthesis and degradation. (1998 Jun)
remodelling of the extracellular matrix in asthma : proteoglycan synthesis and degradation .

Relationship of airway wall thickening to an imbalance between matrix metalloproteinase 9 and its inhibitor in asthma. (2005 Mar)
relationship of airway wall thickening to an imbalance between matrix metalloproteinase 9 and its inhibitor in asthma . background : The balance between matrix metalloproteinase 9 ( MMP 9 ) and tissue inhibitor of metalloproteinase 1 ( TIMP 1 ) may be critical in extracellular matrix remodelling , a characteristic of asthmatic airways . An excess of TIMP 1 over MMP 9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown . recent computed tomographic ( CT ) studies indicate that airway wall thickening is associated with chronic airflow obstruction . methods : sputum levels of MMP 9 , TIMP 1 , and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness , assessed by a validated CT technique which measured wall area corrected by body surface area ( WA / BSA ) , the ratio of WA to outer wall area ( WA ) , and the absolute wall thickness corrected by radicalbsa of a segmental bronchus ( T / radicalbsa ) , was examined . results : sputum MMP 9 levels were inversely correlated with WA and TIMP 1 levels were positively correlated with WA / BSA and T / radicalbsa . The MMP 9 / TIMP 1 molar ratio was inversely correlated with WA and T / radicalbsa and positively correlated with post bronchodilator values of mid forced expiratory flow and maximum expiratory flow at the quartile of lung …

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 …

Matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics. (2004 Mar)
matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases mRNA transcripts in the bronchial secretions of asthmatics . asthma is a chronic inflammatory disease characterized by profound extracellular matrix changes referred to as bronchial remodelling . In this study , we evaluated matrix metalloproteinases ( MMPs ) and tissue inhibitors of MMPs ( timps ) mRNA expression in bronchial secretions of asthmatics and correlated MMPs modulations with the lung function as a reflection of the bronchial extracellular matrix remodelling . quantitative RT PCR was performed on cell pellets obtained from induced sputum in order to detect the mrnas for MMP 1 , 2 , 3 , 8 , 9 , 12 , 13 TIMP 1 , 2 , while semiquantitative RT PCR was performed to assess the expression of MMP 7 , monocyte chemoattractant protein 1 ( MCP 1 ) and transforming growth factor beta ( 1 ) ( TGF beta ( 1 ) ) . The mRNA transcripts for MMP 1 , TIMP 1 and monocyte chemoattractant protein 1 ( MCP 1 ) were increased in cell pellets of induced sputum from asthmatics when compared to controls ( P 0 . 05 ) , and the intensity of MMP 1 mRNA expression inversely correlated with the FEV ( 1 ) in asthmatics ( r 0 . 49 , P 0 . 05 ) . The MMP 1 mRNA / TIMP 1 mRNA ratio correlated with the levels of MCP 1 mRNA in asthmatics ( r 0 . 47 , P …