Metalloproteinase 2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas. (2004 Apr)
metalloproteinase 2 expression correlates with aggressiveness of cutaneous squamous cell carcinomas . matrix metalloproteinases compose a family of enzymes involved in degradation of the extracellular matrix . tumor cells must penetrate the basement membrane and traverse the extracellular matrix in order to invade surrounding structures and metastasize to distant sites . gelatinases , particularly gelatinase A ( matrix metalloproteinase 2 ) , demonstrate degradative activity against components of the basement membrane and may be involved in the progression of in situ squamous cell carcinoma lesions . matrix metalloproteinase 2 overexpression has been correlated with tumor invasiveness and metastasis in a wide variety of cancer types , including squamous cell carcinoma arising on mucous membranes . however , correlation between matrix metalloproteinase 2 overexpression and the spread and prognosis of cutaneous squamous cell carcinoma has not been characterized in the literature at present . In this study , we used immunohistochemical techniques to examine the expression of matrix metalloproteinase 2 in 10 actinic keratosis , 15 in situ , 13 invasive , 13 primary ( with documented metastatic disease ) , 11 metastatic , and 8 recurrent squamous cell carcinoma cases . We found that while the average staining intensity ( scale 0 3 , 3 being strongest ) of actinic keratosis and in situ lesions was not statistically significant ( 0 . 87 1 . 3 and 0 . 75 1 . 4 , respectively ) , the average staining intensity of invasive squamous cell carcinomas ( 1 . 6 …

Human eosinophils release matrix metalloproteinase 9 on stimulation with TNF alpha. (1999 Dec)
human eosinophils release matrix metalloproteinase 9 on stimulation with TNF alpha . background : The eosinophil is a prominent cell in allergic lung inflammation and is exposed to a range of cytokines , including TNF alpha , at the site of allergen challenge . matrix metalloproteinases ( MMPs ) and tissue inhibitors of matrix metalloproteinases ( timps ) produced by inflammatory cells are thought to play a crucial role in interstitial matrix turnover and tissue remodeling in acute and chronic lung diseases . In addition , protein kinase C is known to be important in MMP 9 expression and secretion . objective : We investigated the regulation of eosinophil derived MMP 9 and TIMP proteins by TNF alpha . methods : using RT PCR and gelatin zymography , we investigated the ability of human eosinophils to produce and secrete active MMP 9 on stimulation with TNF alpha . We also studied the production of TIMP 1 and TIMP 2 in eosinophils by using western blotting . results : The gelatinolytic activity of MMP 9 in unstimulated eosinophils was low , but it increased by 95 after TNF alpha stimulation . This increase was regulated at both the transcriptional and translational levels . The transcription inhibitor actinomycin D , the nuclear factor kappab ( nfkappab ) inhibitor N CBZ Leu Leu Leu AL , the protein synthesis inhibitor cycloheximide , and the protein kinase C inhibitor H7 significantly decreased MMP 9 activity in TNF alpha treated cells . TIMP 1 and …

Selective regulation of metalloproteinase inhibitor ( TIMP 1 ) by oncostatin M in fibroblasts in culture. (1993 Jul)
selective regulation of metalloproteinase inhibitor ( TIMP 1 ) by oncostatin M in fibroblasts in culture . tissue inhibitor of metalloproteinases ( TIMP 1 ) is a potent inhibitor of activated matrix metalloproteinases ( MMP ) such as collagenase , stromelysin , and gelatinase , and thus helps to control extracellular matrix metabolism and deposition by connective tissue cells . since various cytokines and growth factors can modify the production of MMP and TIMP 1 , we explored the action of oncostatin M ( OM ) , a unique lymphocyte and monocyte derived cytokine , on expression of these proteins . We examined the regulation of TIMP 1 expression in cultured human fibroblasts by cytokines including OM , IL 6 , leukemia inhibitory factor ( LIF ) , and IL 1 alpha . When used at levels of 5 to 50 ng / ml , OM , IL 6 , LIF , and IL 1 alpha elevated the TIMP 1 expression at the RNA level in fibroblasts of lung or synovial origin . interestingly , OM stimulation resulted in highest levels of TIMP 1 RNA and protein synthesis . however , unlike IL 1 alpha , the cytokines OM , IL 6 , and LIF did not induce MMP or PGE2 release . OM also enhanced TIMP 1 mRNA levels in the h2981 lung carcinoma and hepg2 hepatoma cell lines . The results suggest that OM as well as IL 6 and LIF , other cytokines acting through similar receptor …

The role of up regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis. (2000 Dec)
The role of up regulated serine proteases and matrix metalloproteinases in the pathogenesis of a murine model of colitis . proteinases are important at several phases of physiological and pathological inflammation , mediating cellular infiltration , cytokine activation , tissue damage , remodeling , and repair . however , little is known of their role in the pathogenesis of inflammatory bowel disease . The aim of this study was to assess the role of tissue proteases in a mouse model of colitis . proteolytic activity was analyzed , using gel and in situ zymography , in colonic tissues from severe combined immunodeficient mice with colitis induced by transfer of CD4 ( ) T lymphocytes . serine proteinase levels increased in colitic tissue , with major species of 23 kd , 30 kd , and 45 kd . Co migration and inhibition studies indicated that the 23 kd proteinase was pancreatic trypsin and that the 30 kd species was neutrophil elastase . matrix metalloproteinase ( MMP ) 9 expression , and MMP 2 and MMP 9 activation , was elevated in colitic tissues . proteinase levels followed a decreasing concentration gradient from proximal to distal colon . proteolysis was localized to infiltrating leukocytes in diseased severe combined immunodeficient mice . transmural inflammation was associated with serine proteinase and MMP activity in overlying epithelium and with marked subepithelial proteolytic activity . The results demonstrate a clear elevation in the levels and activation of proteases in colitis , potentially contributing to disease progression …

Collagenase 3 ( matrix metalloproteinase 13 ) expression is induced in oral mucosal epithelium during chronic inflammation. (1998 Jul)
collagenase 3 ( matrix metalloproteinase 13 ) expression is induced in oral mucosal epithelium during chronic inflammation . increased proliferation of mucosal epithelium during inflammation is associated with degradation of subepithelial connective tissue matrix and local invasion of the epithelial cells . Here we have studied , whether collagenase 3 ( MMP 13 ) , a collagenolytic matrix metalloproteinase with an exceptionally wide substrate specificity , is expressed in the epithelium of chronically inflamed mucosa . examination of human gingival tissue sections from subjects with chronic adult periodontitis with in situ hybridization revealed marked expression of MMP 13 in basal cells of some epithelial rete ridges expanding into connective tissue . immunohistochemical staining demonstrated that these cells also expressed strongly laminin 5 , suggesting that they are actively migrating cells . A strong signal for MMP 13 mRNA was occasionally also noted in the suprabasal epithelial cells facing the gingival pocket , whereas no collagenase 1 ( MMP 1 ) mRNA was detected in any areas of the epithelium . MMP 13 expression was also detected in fibroblast like cells associated with collagen fibers of the inflamed subepithelial connective tissue . In organ culture of human oral mucosa , MMP 13 mRNA expression was observed in epithelial cells growing into connective tissue of the specimens . regulation of MMP 13 expression was examined in cultured normal nonkeratinizing epithelial cells isolated from porcine periodontal ligament . In these cells , MMP 13 expression at the mRNA and protein level was potently …

Enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment. (2000 Sep)
enhanced production of tissue inhibitor of metalloproteinases by peripheral blood mononuclear cells of rheumatoid arthritis patients responding to methotrexate treatment . objective : To determine the effects of methotrexate ( MTX ) treatment of rheumatoid arthritis ( RA ) patients ( a ) on the circulating levels and ( b ) on the ex vivo production of matrix metalloproteinase 1 ( MMP 1 ) and tissue inhibitor of metalloproteinases 1 ( TIMP 1 ) by peripheral blood mononuclear cells ( pbmnc ) . methods : circulating levels , spontaneous ex vivo and in vitro production of MMP 1 , TIMP 1 and interleukin 6 ( IL 6 ) were assessed by immunoassays in sera and culture supernatants of pbmnc derived from 27 patients with active RA before and 3 months after beginning MTX treatment and from seven healthy subjects . The production and serum levels of MMP 1 , TIMP 1 and IL 6 were correlated to the clinical response . results : pbmnc of RA patients showing / 20 improvement of the paulus index after 3 months of MTX treatment ( responders ; n 16 ) exhibited a significantly enhanced production of spontaneous TIMP 1 ex vivo which was associated with the enhanced synthesis of IL 6 . In contrast , pbmnc of 11 patients with 20 improvement and / or progression of disease showed a marked reduction of TIMP 1 and IL 6 secretion . circulating levels of TIMP 1 remained unchanged in both groups whereas serum IL …

Hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator ( … (2001 Jan)
hepatocyte growth factor activator inhibitor type 1 is a specific cell surface binding protein of hepatocyte growth factor activator ( HGFA ) and regulates HGFA activity in the pericellular microenvironment . hepatocyte growth factor activator ( HGFA ) is responsible for proteolytic activation of the precursor form of hepatocyte growth factor in injured tissues . To date , two specific inhibitors of HGFA have been identified , namely HGFA inhibitor type 1 ( HAI 1 ) and type 2 ( HAI 2 ) / placental bikunin ( PB ) . Both inhibitors are first synthesized as integral membrane proteins having two kunitz domains and a transmembrane domain , and are subsequently released from cell surface by shedding . Here we show that an active form of HGFA is specifically complexed with membrane form HAI 1 , but not with HAI 2 / PB , on the surface of epithelial cells expressing both inhibitors . This binding required the enzyme activity of HGFA . The selective binding of HGFA to the cell surface HAI 1 was further confirmed in an engineered system using chinese hamster ovary cells , in which only the cells expressing HAI 1 retained exogenous HGFA . The binding of HGFA to HAI 1 was reversible , and no irreversible modifications affecting the enzyme activity occurred during the binding . importantly , HAI 1 and the HGFA . HAI 1 complex were quickly released from the cell surface by treatment with phorbol 12 myristate 13 acetate or interleukin …

Tissue inhibitors of metalloproteinases and metalloproteinases in atherosclerosis. (1999 Jan)
tissue inhibitors of metalloproteinases and metalloproteinases in atherosclerosis . The ability of the metalloproteinases to degrade extracellular matrix proteins is essential for the matrix remodelling that occurs during infiltration of inflammatory cells , intimal thickening , angiogenesis and plaque rupture which are a result of atherosclerosis . increased metalloproteinase activity therefore requires stimulation of metalloproteinase expression by cytokines and growth factors , activation of metalloproteinases , and downregulation of tissue inhibitors of metalloproteinases . In addition , metalloproteinases may influence atherosclerosis by processing of proteins involved in inflammation and cell growth and death and the tissue inhibitors of metalloproteinases may also play a less inhibitory role by influencing cell growth and apoptosis .

Interleukin 1 stimulation of collagenase production by cultured fibroblasts. (1983 Mar)
interleukin 1 stimulation of collagenase production by cultured fibroblasts . interleukin 1 is a monokine that exerts biological effects on a variety of target cells in vitro . In this report , interleukin 1 has been found to be capable of stimulating collagenase production by cultured dermal fibroblasts . The concentrations of interleukin 1 that stimulate fibroblast collagenase production are similar to those that stimulate mouse thymocyte proliferation . analyses by high performance liquid chromatography indicate that interleukin 1 , rather than a contaminating monokine , is responsible for this effect on fibroblasts . interleukin 1 , released in vivo by macrophages infiltrating sites of tissue damage or inflammation , may function to stimulate the release of collagenase by connective tissue fibroblasts .

Oxidised , glycated LDL selectively influences tissue inhibitor of metalloproteinase 3 gene expression and protein production in human retinal capillary … (2007 Sep)
oxidised , glycated LDL selectively influences tissue inhibitor of metalloproteinase 3 gene expression and protein production in human retinal capillary pericytes . AIMS / hypothesis : matrix metalloproteinases ( MMPs ) and their natural inhibitors , tissue inhibitor of metalloproteinases ( timps ) , regulate important biological processes including the homeostasis of the extracellular matrix , proteolysis of cell surface proteins , proteinase zymogen activation , angiogenesis and inflammation . studies have shown that their balance is altered in retinal microvascular tissues in diabetes . since LDLs modified by oxidation / glycation are implicated in the pathogenesis of diabetic vascular complications , we examined the effects of modified LDL on the gene expression and protein production of MMPs and timps in retinal pericytes . methods : quiescent human retinal pericytes were exposed to native LDL ( N LDL ) , glycated LDL ( G LDL ) and heavily oxidised and glycated LDL ( HOG LDL ) for 24 h . We studied the expression of the genes encoding MMPs and timps mrnas by analysis of microarray data and quantitative PCR , and protein levels by immunoblotting and elisa . results : microarray analysis showed that MMP1 , MMP2 , mmp11 , mmp14 and mmp25 and timp1 , timp2 , timp3 and timp4 were expressed in pericytes . Of these , only timp3 mRNA showed altered regulation , being expressed at significantly lower levels in response to HOG vs N LDL . quantitative PCR and immunoblotting of cell / matrix proteins …

An orally active matrix metalloproteinase inhibitor , ONO 4817 , reduces dextran sulfate sodium induced colitis in mice. (2004 Nov)
An orally active matrix metalloproteinase inhibitor , ONO 4817 , reduces dextran sulfate sodium induced colitis in mice . objective : Over expression of matrix metalloproteinases ( MMPs ) can accelerate tissue destruction and disrupt subsequent tissue repair . A dextran sulfate sodium ( DSS ) colitis model was established to examine the effects of MMP inhibition , by an orally active MMP inhibitor ONO 4847 , on colonic inflammation . materials AND methods : acute colitis was induced in female BALB / c mice by giving 8 DSS orally in drinking water for 7 days . The animals were randomized into groups receiving different concentrations of ONO 4847 or vehicle by oral gavage every day . mRNA levels of 4 MMPs and a tissue inhibitor of MMP ( TIMP 1 ) were measured by RT PCR in intestinal tissue isolated from mice after DSS administration . colonic mucosal injury and inflammation were evaluated clinically , biochemically , and histologically . The clinical disease activity index ( DAI ) , including body weight loss , stool consistency , and blood in feces , was examined . moreover , mucosal tumor necrosis factor ( TNF ) alpha and interferon ( IFN ) gamma were determined by immunoassay . results : The intestinal expression of MMP 3 , 7 , 9 , and 12 and TIMP 1 mRNA was upregulated after DSS administration . shortening of the colon was significantly reversed by ONO 4847 at a dose of 30 mg / kg …

Comparison of collagenase activity in eosinophil and neutrophil fractions from rat peritoneal exudates. (1977 Apr)
comparison of collagenase activity in eosinophil and neutrophil fractions from rat peritoneal exudates . The collagenase activity had been compared in extracts of eosinophils and of neutrophilss from peritoneal exudates in two groups of rats , one of which had been treated to augment the numbers of eosinophils and the other the numbers of neutrophils . The proportion of granulocytes to other cells in each preparation was increased by differential centrifugation over a continuous gradient . collagenase was extracted from the fractions in which granulocytes were concentrated and the activity assayed by the radioactive fibril method . there was at least as much collagenase in the eosinophil enriched extracts as in the neutrophil enriched extracts . It is postulated that eosinophil collagenase may have a function in the remodelling of newly synthesised collagen during the post inflammatory phase of healing , since eosinophil leucocytes appear in significant numbers within the connective tissue during this phase . This suggests a different role for eosinophil collagenase than that for neutrophil collagenase , since neutrophil are present only in the early stages of inflammation , when collagen is being degraded .

Clinical significance of gelatinases in septic arthritis of native and replaced knees. (2004 Nov)
clinical significance of gelatinases in septic arthritis of native and replaced knees . We hypothesized that more gelatinases appear in effusions of septic arthritis than aseptic arthritis . This study examined the laboratory variables of inflammation and the levels of gelatinase A and B ( matrix metalloproteinases 2 and 9 ) in 75 effusions from the knees of 37 patients with inflammatory arthritis and compared them with effusions of septic and aseptic arthritis . gelatin zymography revealed that the levels of the latent matrix metalloproteinase 9 were higher in 24 effusions of septic arthritis than in 51 effusions of aseptic arthritis . The latent matrix metalloproteinase 9 levels of septic arthritis also correlated with the neutrophil counts in effusions . significantly more activated matrix metalloproteinases 2 and 9 appeared in effusions of septic arthritis in native and replaced knees than in effusions of aseptic arthritis . A high matrix metalloproteinase 9 level and the appearance of activated matrix metalloproteinases 2 and 9 may distinguish septic from aseptic arthritis , even in cases with a low neutrophil count in the replaced knee . joint aspiration may not only reduce the bacteria counts , endotoxins , and proinflammatory cytokines , but also decrease the amount of matrix metalloproteinases in effusions that attack the extracellular matrix of native and artificial joints .

Granulocyte collagenase : selective digestion of type I relative to type III collagen. (1977 May)
granulocyte collagenase : selective digestion of type I relative to type III collagen . collagenases produced by human polymorphonuclear leukocytes , human lung fibroblasts , and rabbit pulmonary alveolar macrophages were compared in their ability to digest soluble native type I and type III collagens . while the fibroblast and macrophage collagenases attacked the two substrates at approximately equal rates , the leukocyte collagenase attacked type I collagen preferentially ( 15 : 1 ) in comparison to type III collagen . This was true with human or rabbit collagen substrates . Thus , proteolysis of collagen , particularly in acute inflammation , may have a significant role in controlling the types of collagen present in connective tissue .

Effect of high dose inhaled steroid on cells , cytokines , and proteases in induced sputum in chronic obstructive pulmonary … (1999 Dec)
effect of high dose inhaled steroid on cells , cytokines , and proteases in induced sputum in chronic obstructive pulmonary disease . inhaled corticosteroids are widely prescribed for the treatment of stable chronic obstructive pulmonary disease ( COPD ) , despite lack of proven efficacy . because COPD involves airway inflammation and probable protease antiprotease imbalance , we examined the effect of high dose fluticasone propionate on markers of activity of both pathogenetic mechanisms . thirteen patients with COPD were treated with fluticasone propionate ( 500 microg twice a day ) for 4 wk , delivered via MDI and spacer , in a double blind crossover study . there was no clinical benefit in terms of lung function or symptom scores , and induced sputum inflammatory cells , percentage neutrophils , and IL 8 levels were unchanged . sputum supernatant elastase activity , matrix metalloproteinase ( MMP ) 1 , MMP 9 , and the antiproteases secretory leukoprotease inhibitor ( SLPI ) and tissue inhibitor of metalloproteinase ( TIMP ) 1 were similarly unaffected by treatment . these results add to previous evidence that inhaled steroids have no anti inflammatory action in stable COPD . furthermore , inhaled steroids do not appear to redress the protease antiprotease imbalance that is thought to be important in the pathogenesis of airway obstruction .

Rheumatoid arthritis and its implications in temporomandibular disorders. (1993 Jun)
rheumatoid arthritis and its implications in temporomandibular disorders . rheumatoid arthritis is known to afflict the temporomandibular joint ( TMJ ) with common symptoms including pain during function , tenderness on palpation , stiffness , and crepitus . New evidence suggests that metalloproteinases may be responsible for tissue changes that occur in rheumatoid arthritis . these enzymes are collagenase , gelatinase , and proteoglycanase . antiinflammatory drugs are the first line of management for pain and inflammation in rheumatoid arthritis . This paper , however , suggests that because increased joint load is believed to cause a greater expression of destructive metalloproteinase , it is appropriate to assess even the asymptomatic temporomandibular joint and the muscles of mastication for early objective signs of dysfunction or discomfort . interceptive management , by the use of load reducing appliance therapy , may enable reduction of the expression of destructive metalloproteinase within the joint , thereby reducing joint destruction .

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 …

Matrix metalloproteinase 9 modulates intestinal injury in rats with transmural colitis. (2006 Apr)
matrix metalloproteinase 9 modulates intestinal injury in rats with transmural colitis . proteolysis and degradation of extracellular matrix by metalloproteinases ( MMPs ) may contribute to intestinal injury in inflammatory bowel disease . In the present study , we investigated the pathogenic role of gelatinases ( MMP 9 and MMP 2 ) on transmural colonic injury in a rat model of chronic colitis , which was induced by intracolonic instillation of trinitrobenzene sulfonic acid ( TNBS ) . The activity and expression of MMP 2 and MMP 9 were measured in colonic tissue and peripheral neutrophils by fluorescence , zymography , western blot , or immunohistochemistry at different time points . furthermore , myeloperoxidase content in colonic homogenates was analyzed to evaluate inflammation . finally , morphological changes were assessed following early or delayed administration of CGS 27023 A , a synthetic inhibitor of MMPs . We found that the induction of colitis led to a significant up regulation in tissue gelatinase concentration , whereas no changes in collagenase activity were observed . In addition , up regulation of pro MMP 9 , but not of pro MMP 2 , was found on Days 7 and 10 following the induction of colitis . furthermore , transmural MMP 9 was detected by immunofluorescent staining in the inflamed tissue . consistent with tissue samples , neutrophils from colitic rats showed a significantly increased activity of pro MMP 9 . finally , early but not delayed treatment with CGS 27023 A attenuated colonic …

Effect of phenytoin on collagen accumulation by human gingival fibroblasts exposed to TNF alpha in vitro. (2006 Feb)
effect of phenytoin on collagen accumulation by human gingival fibroblasts exposed to TNF alpha in vitro . objective : tumor necrosis factor ( TNF ) alpha is associated with chronic gingival inflammation and reported to induce gingival overgrowth ( GO ) , while phenytoin ( PHT ) is also known to be a causative agent of GO . We examined the synergistic effect of PHT and TNF alpha on collagen metabolism in human gingival fibroblasts ( HGFs ) . materials AND methods : HGFs were cultured with TNF alpha and PHT . quantitative real time RT PCR was employed to determine the mRNA levels for collagen , matrix metalloproteinases ( MMPs ) , tissue inhibitors of metalloproteinases ( timps ) and integrin subunits . cellular collagen endocytosis was determined using a flow cytometry . results : The proliferation of HGFs was not affected by TNF alpha or PHT individually , whereas both synergistically increased collagen accumulation in HGFs . further , collagen mRNA expression was not increased by TNF alpha or PHT , although together they markedly prevented cellular collagen endocytosis , associated with the suppression of alpha2beta1 integrin mRNA expression . The mRNA expression of MMP 1 and 2 was suppressed by PHT , while TIMP 1 mRNA expression was enhanced by both TNF alpha and PHT . conclusion : Our results suggest that TNF alpha and PHT together cause impaired collagen metabolism by suppression of enzymatic degradation with MMPs / TIMP 1 and integrin mediated endocytosis . these …

Contribution of alveolar macrophages to the response of the TIMP 3 null lung during a septic insult. (2007 Aug)
contribution of alveolar macrophages to the response of the TIMP 3 null lung during a septic insult . Mice deficient in tissue inhibitor of metalloproteinase 3 ( TIMP 3 ) develop an emphysema like phenotype involving increased pulmonary compliance , tissue degradation , and matrix metalloproteinase ( MMP ) activity . after a septic insult , they develop a further increase in compliance that is thought to be a result of heightened metalloproteinase activity produced by the alveolar macrophage , potentially modeling an emphysemic exacerbation . therefore , we hypothesized that TIMP 3 null mice lacking alveolar macrophages would not be susceptible to the altered lung function associated with a septic insult . TIMP 3 null and wild type ( WT ) mice were depleted of alveolar macrophages before the induction of a septic insult and assessed for alteration in lung mechanics , alveolar structure , metalloproteinase levels , and inflammation . The results showed that TIMP 3 null mice lacking alveolar macrophages were protected from sepsis induced alterations in lung mechanics , particularly pulmonary compliance , a finding that was supported by changes in alveolar structure . additionally , changes in lung mechanics involved primarily peripheral tissue vs . central airways as determined using the flexivent system . From investigation into possible molecules that could cause these alterations , it was found that although several proteases and inflammatory mediators were increased during the septic response , only MMP 7 was attenuated after macrophage depletion . In conclusion , the …