Amanda E Starr

Government of British Columbia, Canada, Vancouver, British Columbia, Canada

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Publications (18)123.87 Total impact

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    ABSTRACT: Decreased risk of coronary artery disease (CAD) in pre-menopausal women compared with men and post-menopausal women implicates sex steroids in cardioprotective processes. β-estradiol upregulates the liver low-density lipoprotein receptor (LDLR), which in turn decreases circulating LDL cholesterol levels, a risk factor for CAD. Conversely, LDLR protein is negatively regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). Herein, we investigated PCSK9 regulation by β-estradiol and its impact on LDLR in human hepatocarcinoma HuH7 cells grown in the presence or absence of β-estradiol. Immunoblot analysis showed an upregulation of LDLR at 3μM β-estradiol (140%) and reached 220% at 10μM β-estradiol; only at the latter dose was an increase in LDLR mRNA detected by qPCR, suggesting post-translational regulation on LDLR. No change was measured for PCSK9 mRNA or secreted protein levels by qPCR or ELISA, respectively. β-estradiol conditioned media devoid of PCSK9 failed to up-regulate LDLR. Similarly, PCSK9 knockdown cells showed no up-regulation of LDLR by β-estradiol. Together, these results indicate a requirement for the PCSK9 in the β-estradiol-induced upregulation of LDLR. A radiolabeling assay showed a significant, dose-dependent decrease in the ratio of secreted phosphoPCSK9 relative to total secreted PCSK9 with increasing β-estradiol, suggesting a change in the functional state of PCSK9 in the presence of β-estradiol. Our results indicate that the protein up-regulation of LDLR at sub-transcriptionally effective doses of β-estradiol, and its supra-transcriptional up-regulation at 10μM β-estradiol occur through an extracellular PCSK9-dependent mechanism. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    FEBS Journal 04/2015; DOI:10.1111/febs.13309 · 3.99 Impact Factor
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    ABSTRACT: Cysteine cathepsins are primarily lysosomal proteases involved in general protein turnover, but also have specific proteolytic functions in antigen presentation and bone remodeling. Cathepsins are most stable at acidic pH, although growing evidence indicates that they have physiologically relevant activity also at neutral pH. Post-translational proteolytic processing of mature chemokines is a key, yet underappreciated level of chemokine regulation. Although the role of selected serine proteases and matrix metalloproteases in chemokine processing is long known, little is reported about the role of cysteine cathepsins. Here we evaluated cleavage of CXC ELR (CXCL1, 2, 3, 5, 8) and non-ELR (CXCL9, 10, 11, 12) chemokines by cysteine cathepsins B, K, L and S at neutral pH by high resolution Tris-Tricine SDS-PAGE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Whereas cathepsin B cleaved chemokines especially in the C-terminal region, cathepsins K, L and S cleaved chemokines at the N-terminus with glycosaminoglycans modulating cathepsin processing of chemokines. The functional consequences of the cleavages were determined by Ca2+ mobilization and chemotaxis assays. We show that cysteine cathepsins inactivate and in some cases degrade non-ELR CXC chemokines CXCL9, 10, 11 and 12. In contrast, cathepsins specifically process ELR CXC chemokines CXCL1, 2, 3, 5, and 8 N-terminal to the ELR motif thereby generating agonist forms. This study suggests that cysteine cathepsins regulate chemokine activity and thereby leukocyte recruitment during protective or pathological inflammation. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 04/2015; DOI:10.1074/jbc.M115.638395 · 4.60 Impact Factor
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    ABSTRACT: Resolution of inflammation reduces pathological tissue destruction and restores tissue homeostasis. Here, we used a proteomic protease substrate discovery approach, terminal amine isotopic labeling of substrates (TAILS), to analyze the role of the macrophage-specific matrix metalloproteinase-12 (MMP12) in inflammation. In murine peritonitis, MMP12 inactivates antithrombin and activates prothrombin, prolonging the activated partial thromboplastin time. Furthermore, MMP12 inactivates complement C3 to reduce complement activation and inactivates the chemoattractant anaphylatoxins C3a and C5a, whereas iC3b and C3b opsonin cleavage increases phagocytosis. Loss of these anti-inflammatory activities in collagen-induced arthritis in Mmp12(-/-) mice leads to unresolved synovitis and extensive articular inflammation. Deep articular cartilage loss is associated with massive neutrophil infiltration and abnormal DNA neutrophil extracellular traps (NETs). The NETs are rich in fibrin and extracellular actin, which TAILS identified as MMP12 substrates. Thus, macrophage MMP12 in arthritis has multiple protective roles in countering neutrophil infiltration, clearing NETs, and dampening inflammatory pathways to prepare for the resolution of inflammation.
    Cell Reports 10/2014; 9(2). DOI:10.1016/j.celrep.2014.09.006 · 7.21 Impact Factor
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    ABSTRACT: Proteolytic processing is an irreversible posttranslational modification affecting a large portion of the proteome. Protease-cleaved mediators frequently exhibit altered activity, and biological pathways are often regulated by proteolytic processing. Many of these mechanisms have not been appreciated as being protease-dependent, and the potential in unraveling a complex new dimension of biological control is increasingly recognized. Proteases are currently believed to act individually or in isolated cascades. However, conclusive but scattered biochemical evidence indicates broader regulation of proteases by protease and inhibitor interactions. Therefore, to systematically study such interactions, we assembled curated protease cleavage and inhibition data into a global, computational representation, termed the protease web. This revealed that proteases pervasively influence the activity of other proteases directly or by cleaving intermediate proteases or protease inhibitors. The protease web spans four classes of proteases and inhibitors and so links both recently and classically described protease groups and cascades, which can no longer be viewed as operating in isolation in vivo. We demonstrated that this observation, termed reachability, is robust to alterations in the data and will only increase in the future as additional data are added. We further show how subnetworks of the web are operational in 23 different tissues reflecting different phenotypes. We applied our network to develop novel insights into biologically relevant protease interactions using cell-specific proteases of the polymorphonuclear leukocyte as a system. Predictions from the protease web on the activity of matrix metalloproteinase 8 (MMP8) and neutrophil elastase being linked by an inactivating cleavage of serpinA1 by MMP8 were validated and explain perplexing Mmp8-/- versus wild-type polymorphonuclear chemokine cleavages in vivo. Our findings supply systematically derived and validated evidence for the existence of the protease web, a network that affects the activity of most proteases and thereby influences the functional state of the proteome and cell activity.
    PLoS Biology 05/2014; 12(5):e1001869. DOI:10.1371/journal.pbio.1001869 · 11.77 Impact Factor
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    ABSTRACT: We have witnessed tremendous growth in proteomics. In the early days of proteomics, we were in awe when individual proteins were identified using mass spectrometry data. Now, thousands of proteins can be routinely identified and quantified using the latest proteomic technologies. These achievements are linked to improvements in analytical technologies whose applications have led to advancement in understanding of biological processes. The mapping of protein-protein interactions in human1 and other species, as well as efforts to systematically map post-translational modifications (PTMs: PhosphoSitePlus reports over 290,000 experimental PTMs2) have changed the way we approach biological questions. Moreover, the applications of technologies to study the temporal dynamic of these interactions and PTMs using mass spectrometry are invaluable resources to the biological community. At the same time, lessons have been learned in proteomics from some of its growing pains. The first lesson was that new technical developments, although exciting, might not be on their own sufficient for discovery from complex samples such as serum and plasma. For example, one can remember the hype around Surface Enhanced Laser Desorption-Ionization (SELDI) mass spectrometry3, which from the early to mid 2000s was going to solve the biomarker conundrum; however, because of issues of reproducibility and sample preparation it has been mired in controversy. At its peak in 2006 SELDI technology was utilized in 24% of biomarker mass spectrometry papers whereas in 2012 it was represented in only 6%. It was followed by a series of other technologies that have also underperformed for the discovery of true biomarkers. The mismatch between proteomic technologies and biomarker discovery has been a major disappointment. The second lesson was that technical difficulties are not a reason to take biological shortcuts, especially if biological conclusions are to be derived from the experiment. Technical difficulties in proteomics have led to numerous papers based solely on one biological sample, with no or insufficient controls. These articles often inferred biological conclusions that were not supported. Fortunately, recent technology improvements allow extensive and detailed proteomics studies within a few days to a few weeks. As well, people are much more aware of sample complexity and the need to further improve technologies. In the last few years we have seen a decrease in the number of journals that accept proteomic-based papers based on a single biological sample (n=1). As well, the number of proteomic papers that include orthogonal validation methods, such as Western blotting and microscopy, has increased. Clearly, continuing technological developments remain essential for proteomics. Excitingly, the number and quality of applications has increased drastically in the last few years. Here, we will review some of technologies and applications in the field of proteomics since our last review in 2011.
    Analytical Chemistry 11/2013; 86(1). DOI:10.1021/ac403551f · 5.83 Impact Factor
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    ABSTRACT: The neutrophil-specific protease membrane-type 6 matrix metalloproteinase (MT6-MMP)/MMP-25/leukolysin is implicated in multiple sclerosis and cancer yet remains poorly characterized. To characterize the biological roles of MT6-MMP, it is critical to identify its substrates for which only seven are currently known. Here, we biochemically characterized MT6-MMP, profiled its tissue inhibitor of metalloproteinase inhibitory spectrum, performed degradomics analyses, and screened 26 chemokines for cleavage using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. MT6-MMP processes seven each of the CXC and CC chemokine subfamilies. Notably, cleavage of the neutrophil chemoattractant CXCL5 activates the chemokine, thereby increasing its agonist activity, indicating a feed-forward mechanism for neutrophil recruitment. Likewise, cleavage also activated CCL15 and CCL23 to increase monocyte recruitment. Utilizing the proteomics approach proteomic identification of cleavage site specificity (PICS), we identified 286 peptidic cleavage sites spanning from P6 to P6' from which an unusual glutamate preference in P1 was identified. The degradomics screen terminal amine isotopic labeling of substrates (TAILS), which enriches for neo-N-terminal peptides of cleaved substrates, was used to identify 58 new native substrates in fibroblast secretomes after incubation with MT6-MMP. Vimentin, cystatin C, galectin-1, IGFBP-7, and secreted protein, acidic and rich in cysteine (SPARC) were among those substrates we biochemically confirmed. An extracellular "moonlighting" form of vimentin is a chemoattractant for THP-1 cells, but MT6-MMP cleavage abolished monocyte recruitment. Unexpectedly, the MT6-MMP-cleaved vimentin potently stimulated phagocytosis, which was not a property of the full-length protein. Hence, MT6-MMP regulates neutrophil and monocyte chemotaxis and by generating "eat-me" signals upon vimentin cleavage potentially increases phagocytic removal of neutrophils to resolve inflammation.
    Journal of Biological Chemistry 02/2012; 287(16):13382-95. DOI:10.1074/jbc.M111.314179 · 4.60 Impact Factor
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    ABSTRACT: Leukocyte migration and activation is orchestrated by chemokines, the cleavage of which modulates their activity and glycosaminoglycan binding and thus their roles in inflammation and immunity. Early research identified proteolysis as a means of both activating or inactivating CXC chemokines and inactivating CC chemokines. Recent evidence has shown activating cleavages of the monocyte chemoattractants CCL15 and CCL23 by incubation with synovial fluid, although the responsible proteases could not be identified. Herein we show that CCL15 is processed in human synovial fluid by matrix metalloproteinases (MMPs) and serine proteases. Furthermore, a family-wide investigation of MMP processing of all 14 monocyte-directed CC chemokines revealed that each is precisely cleaved by one or more MMPs. By MALDI-TOF-MS, 149 cleavage sites were sequenced including the first reported instance of CCL1, CCL16, and CCL17 proteolysis. Full-length CCL15-(1-92) and CCL23-(1-99) were cleaved within their unique 31 and 32-amino acid residue extended amino termini, respectively. Unlike other CCL chemokines that lose activity and become receptor antagonists upon MMP cleavage, the prominent MMP-processed products CCL15-(25-92, 28-92) and CCL23-(26-99) are stronger agonists in calcium flux and Transwell CC receptor transfectant and monocytic THP-1 migration assays. MMP processing of CCL16-(1-97) in its extended carboxyl terminus yields two products, CCL16-(8-77) and CCL16-(8-85), with both showing unexpected enhanced glycosaminoglycan binding. Hence, our study reveals for the first time that MMPs activate the long amino-terminal chemokines CCL15 and CCL23 to potent forms that have potential to increase monocyte recruitment during inflammation.
    Journal of Biological Chemistry 12/2011; 287(8):5848-60. DOI:10.1074/jbc.M111.314609 · 4.60 Impact Factor
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    ABSTRACT: The study of proteins is one of the most challenging tasks in analytical chemistry. The initial protein research focused on developing techniques that could separate and identify the primary sequence (or parts) of a protein.
    Analytical Chemistry 11/2011; 84(2):720-34. DOI:10.1021/ac202882y · 5.83 Impact Factor
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    ABSTRACT: Neutrophil accumulation is balanced by both cell infiltration and cell clearance, the controls of which are pivotal in the pathogenesis of rheumatoid arthritis (RA) and other chronic inflammatory diseases. Of the neutrophil-specific proteases, matrix metalloproteinase 8 (MMP-8; also known as neutrophil collagenase or collagenase 2) is traditionally viewed as being crucial for collagen degradation and hence cell migration and infiltration. This study was undertaken to examine the role of MMP-8 in a murine model of spontaneous RA. MMP-8(-/-) mice were backcrossed onto the Fas-defective MRL/lpr background, a mouse strain characterized by systemic autoimmunity including spontaneous autoimmune arthritis. Arthritis was induced with Freund's complete adjuvant and clinical disease and histologic parameters were assessed. MMP-8(-/-) mice had earlier and more severe joint inflammation than their MMP-8(+/+) counterparts, coupled with a massive accumulation of neutrophils in synovial tissue, an unexpected result considering the commonly held view that MMP-8 has important extracellular matrix-degradative functions. Protease and protease inhibitor analysis of MMP-8(-/-) mouse neutrophils by CLIP-CHIP microarray revealed very little additional change in protease levels except for low expression of the apoptosis initiator caspase 11. This was confirmed at the protein level in unstimulated, lipopolysaccharide-treated, and interferon-γ-treated MMP-8(-/-) mouse neutrophils. Downstream of caspase 11, the activity of the apoptosis executioner caspase 3 was consequently reduced in MMP-8(-/-) mouse neutrophils, translating to reduced neutrophil apoptosis and cell accumulation compared with wild-type mouse cells. Our findings indicate that MMP-8 is not essential for neutrophil migration in arthritis and likely other autoimmune diseases. Rather, MMP-8 is important for normal rates of neutrophil apoptosis and hence regulates cell clearance. Because MMP-8 deficiency leads to an exaggerated accumulation of neutrophil infiltrates due to delayed apoptosis and concurrent pathologic changes associated with dramatically increased neutrophil infiltration, MMP-8 is antiinflammatory and therefore a drug antitarget in the treatment of arthritis.
    Arthritis & Rheumatology 12/2010; 62(12):3645-55. DOI:10.1002/art.27757 · 7.87 Impact Factor
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    ABSTRACT: Effective proteome-wide strategies that distinguish the N-termini of proteins from the N-termini of their protease cleavage products would accelerate identification of the substrates of proteases with broad or unknown specificity. Our approach, named terminal amine isotopic labeling of substrates (TAILS), addresses this challenge by using dendritic polyglycerol aldehyde polymers that remove tryptic and C-terminal peptides. We analyze unbound naturally acetylated, cyclized or labeled N-termini from proteins and their protease cleavage products by tandem mass spectrometry, and use peptide isotope quantification to discriminate between the substrates of the protease of interest and the products of background proteolysis. We identify 731 acetylated and 132 cyclized N-termini, and 288 matrix metalloproteinase (MMP)-2 cleavage sites in mouse fibroblast secretomes. We further demonstrate the potential of our strategy to link proteases with defined biological pathways in complex samples by analyzing mouse inflammatory bronchoalveolar fluid and showing that expression of the poorly defined breast cancer protease MMP-11 in MCF-7 human breast cancer cells cleaves both endoplasmin and the immunomodulator and apoptosis inducer galectin-1.
    Nature Biotechnology 03/2010; 28(3):281-8. DOI:10.1038/nbt.1611 · 39.08 Impact Factor
  • Amanda E Starr, Christopher M Overall
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    ABSTRACT: The nature, sequence, and length of the carboxy and amino termini of chemokines are important determinants of chemokine function, being essential for both efficient haptotactic gradient formation and cognate receptor activation events of these chemotactic cytokines. Chemokines are susceptible to proteolytic cleavage in both of these regions, which usually results in dramatic changes to the chemokine bioactivity. Herein we provide techniques to assess, detect, and characterize protease activity on chemokines and the biologic outcomes.
    Methods in enzymology 02/2009; 461:281-307. DOI:10.1016/S0076-6879(09)05413-5 · 2.19 Impact Factor
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    ABSTRACT: Through the activity of macrophage-specific matrix metalloproteinase-12 (MMP-12), we found that macrophages dampen the lipopolysaccharide (LPS)-induced influx of polymorphonuclear leukocytes (PMNs)-thus providing a new mechanism for the termination of PMN recruitment in acute inflammation. MMP-12 specifically cleaves human ELR(+) CXC chemokines (CXCL1, -2, -3, -5, and -8) at E-LR, the critical receptor-binding motif or, for CXCL6, carboxyl-terminal to it. Murine (m) MMP-12 also cleaves mCXCL1, -2, and -3 at E-LR. MMP-12-cleaved mCXCL2 (macrophage-inflammatory protein-2 [MIP-2]) and mCXCL3 (dendritic cell inflammatory protein-1 [DCIP-1]) lost chemotactic activity. Furthermore, MMP-12 processed and inactivated monocyte chemotactic proteins CCL2, -7, -8, and -13 at position 4-5 generating CCR antagonists. Indeed, PMNs and macrophages in bronchoalveolar lavage fluid were significantly increased 72 hours after intranasal instillation of LPS in Mmp12(-/-) mice compared with wild type. Specificity occurred at 2 levels. Macrophage MMP-1 and MMP-9 did not cleave in the ELR motif. Second, unlike human ELR(+)CXC chemokines, mCXCL5 (LPS-induced CXC chemokine [LIX]) was not inactivated. Rather, mMMP-12 cleavage at Ser4-Val5 activated the chemokine, promoting enhanced PMN early infiltration in wild-type mice compared with Mmp12(-/-) mice 8 hours after LPS challenge in air pouches. We propose that the macrophage, specifically through MMP-12, assists in orchestrating the regulation of acute inflammatory responses by precise proteolysis of ELR(+)CXC and CC chemokines.
    Blood 10/2008; 112(8):3455-64. DOI:10.1182/blood-2007-12-129080 · 9.78 Impact Factor
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    FEBS Letters 04/2008; 582(7):1168-1168. DOI:10.1016/j.febslet.2008.02.066 · 3.34 Impact Factor
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    ABSTRACT: N-terminal truncation of chemokines by proteases including dipeptidyl peptidase (DP) IV significantly alters their biological activity; generally ablating cognate G-protein coupled receptor engagement and often generating potent receptor antagonists. DP8 is a recently recognised member of the prolyl oligopeptidase gene family that includes DPIV. Since DPIV is known to process chemokines we surveyed 27 chemokines for cleavage by DP8. We report DP8 cleavage of the N-terminal two residues of IP10 (CXCL10), ITAC (CXCL11) and SDF-1 (CXCL12). This has implications for DP8 substrate specificity. Chemokine cleavage and inactivation may occur in vivo upon cell lysis and release of DP8 or in the inactivation of internalized chemokine/receptor complexes.
    FEBS Letters 04/2008; 582(5):819-25. DOI:10.1016/j.febslet.2008.02.005 · 3.34 Impact Factor
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    ABSTRACT: We identify matrix metalloproteinase (MMP)-8, the polymorphonuclear (PMN) leukocyte collagenase, as a critical mediator initiating lipopolysaccharide (LPS)-responsiveness in vivo. PMN infiltration towards LPS is abrogated in Mmp8-null mice. MMP-8 cleaves LPS-induced CXC chemokine (LIX) at Ser4~Val5 and Lys79~Arg80. LIX bioactivity is increased upon N-terminal cleavage, enhancing intracellular calcium mobilization and chemotaxis upon binding its cognate receptor, CXCR2. As there is no difference in PMN chemotaxis in Mmp8-null mice compared with wild-type mice towards synthetic analogues of MMP-8-cleaved LIX, MMP-8 is not essential for extravasation or cell migration in collagenous matrices in vivo. However, with biochemical redundancy between MMPs 1, 2, 9, and 13, which also cleave LIX at position 4~5, it was surprising to observe such a markedly reduced PMN infiltration towards LPS and LIX in Mmp8-/- mice. This lack of physiological redundancy in vivo identifies MMP-8 as a key mediator in the regulation of innate immunity. Comparable results were found with CXCL8/IL-8 and CXCL5/ENA-78, the human orthologues of LIX. MMP-8 cleaves CXCL8 at Arg5-Ser6 and at Val7-Leu8 in CXCL5 to activate respective chemokines. Hence, rather than collagen, these PMN chemoattractants are important MMP-8 substrates in vivo; PMN-derived MMP-8 cleaves and activates LIX to execute an in cis PMN-controlled feed-forward mechanism to orchestrate the initial inflammatory response and promote LPS responsiveness in tissue.
    PLoS ONE 03/2007; 2(3). DOI:10.1371/journal.pone.0000312 · 3.53 Impact Factor
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    ABSTRACT: We report here on the influence of the platelet antagonist clopidogrel (Plavix) on bovine platelet function. We first evaluated the capacity of clopidogrel to inhibit adenosine diphosphate (ADP)-stimulated platelet function in the bovine species, using an ex vivo approach with blood from treated animals. Platelets isolated from treated calves displayed rapid and consistent reduction in function (aggregation, thromboxane production) upon ADP, but not platelet activating factor (PAF), stimulation. We then examined the possibility that clopidogrel could influence Mannheimia haemolytica pneumonia pathobiology using an experimental challenge model. We were unable to detect significant differences between clopidogrel treated and untreated animals when challenged with intra-tracheal inoculation of M. haemolytica. There was a trend towards inhibition of platelet degranulation in the affected regions of lungs from clopidogrel treated calves, and pre-treated challenged animals had similar amounts of fibrin deposition and enhanced fibrous tissue formation in their lungs when compared with control counterparts.
    The Veterinary Journal 02/2006; 171(1):126-34. DOI:10.1016/j.tvjl.2004.09.008 · 2.17 Impact Factor
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    ABSTRACT: Mannheimia haemolytica infection of the lower respiratory tract of cattle results in a bronchofibrinous pneumonia characterized by massive cellular influx and lung tissue remodeling and scarring. Since altered levels of gelatinases and their inhibitors have been detected in a variety of inflammatory conditions and are associated with tissue remodeling, we examined the presence of gelatinases in lesional and nonlesional lung tissue obtained from calves experimentally infected with M. haemolytica. Lesional tissue had elevated levels of progelatinase A and B and active gelatinase A and B when compared with nonlesional tissue obtained from the same lung lobe. In vitro, M. haemolytica products stimulated production of gelatinase B, but not its activation, by bovine monocytes. Alveolar macrophages showed constitutive production of gelatinase B but no change in response to M. haemolytica products. Bovine neutrophils exposed to M. haemolytica products also released gelatinase B, and there was a significant increase in the activated form of this enzyme. These effects were virtually identical when recombinant O-sialoglycoprotease was used to stimulate these cells. M. haemolytica products also enhanced the expression by bovine monocytes and alveolar macrophages of the tissue inhibitor of metalloproteinase 1. Our results provide evidence that matrix metalloproteinases are activated in lung lesions from cattle with shipping fever and that M. haemolytica virulence products induce production, release, and especially activation of gelatinase B by bovine inflammatory cells in vitro.
    Infection and Immunity 09/2004; 72(8):4393-400. DOI:10.1128/IAI.72.8.4393-4400.2004 · 4.16 Impact Factor
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Publication Stats

458 Citations
123.87 Total Impact Points

Institutions

  • 2015
    • Government of British Columbia, Canada
      Vancouver, British Columbia, Canada
  • 2007–2014
    • University of British Columbia - Vancouver
      • • Department of Biochemistry and Molecular Biology
      • • Life Sciences Institute (LSI)
      • • Department of Oral Biological and Medical Sciences
      Vancouver, British Columbia, Canada
  • 2011–2013
    • University of Ottawa
      • Department of Biochemistry, Microbiology and Immunology
      Ottawa, Ontario, Canada
  • 2004–2006
    • University of Guelph
      • Department of Biomedical Sciences
      Guelph, Ontario, Canada