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Inflammation
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Polymorphonuclear neutrophil elastase can hydrolyze a variety of proteins; it solubilizes elastin, cartilage proteoglycan, and several types of collagen molecules. The elastase cleaves Types I and II collagens at the nonhelical teleopeptide region of the molecules which contains the intermolecular cross-links. The resultant depolymerization facilitates further nonspecific proteolytic action. Types III and IV collagens are hydrolyzed by the polymorphonuclear neutrophil elastase across the helical portion of the tropocollagen portion. In addition to these structural tissue components, a variety of important proteins present at the inflammatory sites can also be destroyed by elastase, such as intermediates of the kallikrein-kinin system, complement system, clotting and fibrinolytic cascades, and immunoglobulins.26,133 Cathepsin G shows chymotrypsin-like properties, and it attacks the microfibrillar components of the elastic fiber, proteoglycan molecules, and certain components of the complement, clotting, and fibrinolytic systems.
Granulocyte Protease Action: a Possible Cause of Bleeding in Leukemia
Published in László Muszbek, Hemostasis and Cancer, 2019
Often designated as cathepsin G, granulocyte chymotrypsin is a serine protease also localized in the azurophil granules.16 Molecular weight of the izoenzymes varies between 24,000 and 28,000.21 Granulocyte chymotrypsin is also inhibited by α1-protease inhibitor and α2-macroglobulin.17,22 For protein substrates chymotrypsin has a pH optimum of 7.5. Its natural substrate is cartilage proteoglycan, but it also cleaves hemoglobin and fibrinogen.20,21
α1-Antitrypsin: Structure, Function, Physiology
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
First, receptor-binding studies with [125I] peptide 105Y showed that there was a single class of receptors with a Kd (~43 nM) almost identical to that previously reported for Hep G2 cells.18 There were, however, only ~13,000 plasma membrane SEC receptor molecules on each human neutrophil compared to ~450,000 plasma membrane receptors on each human hepatoma Hep G2 cell. Second, chemotactic studies showed that peptide 105Y and pentapeptide 105C mediated neutrophil chemotaxis with maximal stimulation at 10−9 to 10−8M. The magnitude of the effect was comparable to that of the chemotactic peptide fMLP of 10−8M. The specificity of the effect was consistent with its being mediated by a SEC receptor, as shown by negative control peptides. Most importantly, the neutrophil chemotactic effect of α1-AT-elastase complexes was completely blocked by antiserum to keyhole-limpet hemocyanin-coupled peptide 105Y and antiserum to purified SEC receptor, but not by a control antiserum. Other ligands for the SEC receptor, including the amyloid-β peptide, mediated neutrophil chemotaxis. Finally, preincubation of neutrophils with peptide 105Y completely abrogated the chemotactic effect of amyloid-β peptide by inducing homologous desensitization of the SEC receptor. Thus, the SEC receptor mediates the previously recognized chemotactic effect of α1-AT-elastase complexes and the previously unrecognized chemotactic effect of amyloid-β peptide. It is also likely to mediate the recently described chemotactic effect of α1-ACT-cathepsin G complexes.87 One might also predict that it mediates any chemotactic effect of HCII-thrombin complexes, although a structurally distinct region in the amino-terminal domain of HCII has been shown to possess neutrophil chemotactic activity.109 Further studies will be necessary to determine whether two regions of HCII can mediate neutrophil chemotactic effects through two distinct receptors. Although it has not been completely excluded, there is no current evidence to suggest that other regions within the α1-AT molecule, or other serpin molecules, contribute to binding to the SEC receptor.
Trends and recent developments in pharmacotherapy of acute pancreatitis
Published in Postgraduate Medicine, 2023
Juliana Hey-Hadavi, Prasad Velisetty, Swapnali Mhatre
Low molecular weight heparin (LMWH) possesses antithrombin and anti-inflammatory activity [59]. Heparin reduces the microthrombi formation and improves the microcirculation of the pancreas [60]. Heparin administration downregulates TNF-α-induced leukocyte rolling [59] and blocks leukocyte adhesion by inhibiting the interactions between expressed adhesion molecules and endothelial cells [61]. Moreover, heparin also reduces cathepsin G-induced platelet activation by blocking protease activity [62]. Importantly, administration of LMWH in patients with moderately severe and severe AP significantly reduced local and systemic complications with no hemorrhagic complications. However, no significant difference was observed in mortality between the treatment and control groups [60]. A recent meta-analysis of 16 randomized-controlled trials (RCTs) reported that LMWH treatment improved the outcomes in patients with SAP by significantly reducing hospital stay, mortality, incidences of multiple organ failure, pancreatic pseudocyst, and operation rate. Additionally, the LMWH treatment group had lower white blood cells and C-reactive protein levels than the conventional treatment group (control), thereby highlighting the potential benefits for patients with SAP [63].
Protease-activated receptor 4 activity promotes platelet granule release and platelet-leukocyte interactions
Published in Platelets, 2019
Rachel A. Rigg, Laura D. Healy, Tiffany T. Chu, Anh T. P. Ngo, Annachiara Mitrugno, Jevgenia Zilberman-Rudenko, Joseph E. Aslan, Monica T. Hinds, Lisa Dirling Vecchiarelli, Terry K. Morgan, András Gruber, Kayla J. Temple, Craig W. Lindsley, Matthew T. Duvernay, Heidi E. Hamm, Owen J. T. McCarty
Activated PAR4 antagonists were synthesized, characterized, dissolved in dimethyl sulfoxide (DMSO), and stored the refrigerated as described previously [21]. Structure and characterization of PAR4 antagonists are described in Supplemental Figures S1-S2. All other reagents were from Sigma-Aldrich (St. Louis, MO, USA), unless stated otherwise. Hanks’ Balanced Salt Solution (HBSS) was from Corning cellgro (Manassas, VA, USA). Polymorphprep was from Axis-Shield (Oslo, Norway). PGI2 and the PAR1 inhibitor SCH 79797 were from Cayman Chemical (Ann Arbor, MI, USA). Collagen-related peptide (CRP) was from R. Farndale (Cambridge University, UK). TRAP-6 (SFLLRN-NH2) was obtained from Tocris (Bristol, UK). PPACK (D-Phe-Pro-Arg-chloromethylketone) and RBC Lysis Buffer were from Santa Cruz (Dallas, TX, USA). PAR4 activating peptide (AYPGKF-NH2) was from Abgent (San Diego, CA, USA). Human α-thrombin and human plasmin were from Haematologic Technologies (Essex Junction, VT, USA). Human cathepsin G was from Innovative Research (Novi, MI, USA). For human flow cytometry studies, anti-CD66b-PE and anti-CD14-PE/Cy7 were from BD Biosciences (Franklin Lakes, NJ, USA), and anti-CD41-FITC was from Invitrogen (Carlsbad, CA, USA). For nonhuman primate flow cytometry studies, anti-CD41-FITC was from Invitrogen, and anti-CD62P-PE and anti-CD45-APC were from BD Biosciences. Chronolume detection agent was from Chrono-Log Corporation (Havertown, PA, USA).
Regulatory role of thiol isomerases in thrombus formation
Published in Expert Review of Hematology, 2018
The major drawback of the above-described technique is that it can only identify substrates that are subject to disulfide reduction, as CXXA variants of the active motif can never exist in an oxidized state. To identify substrate proteins of PDI which require oxidation using kinetic substrate trapping, a PDI variant must retain both active site cysteine residues, but instead be modified to perform disulfide exchange much more slowly that the wild-type PDI, so that the PDI−substrate intermediates formed during the oxidoreductate reaction can be ‘frozen’ using alkylating agents, and subsequently isolated and identified. Using two such variants where His of CGHC motif was modified to either Pro (CGPC) or Arg (CGAC) in both a and a’ domains, multiple other substrates released from activated platelets have now been identified [82]. These include factor V, annexin V, heparanase, ERp57, kallekrein 14, serpin B6, tetranectin, and collagen VI, which show a bias for reduction, whereas cathepsin G, glutaredoxin-1, thioredoxin, GPIb, and fibrinogen show a bias for oxidation by PDI. Cathepsin G is an ∝-granule protein known to play a role in thrombosis [83,84]. Treating washed platelet releasate with oxidized PDI increases the activity of native cathepsin G, confirming the physiological importance of PDI-cathepsin G interaction. Similarly, inhibition of PDI activity with quercetin-3-rutinoside significantly reduced platelet factor Va generation following platelet activation, which paralleled the reduction in platelet-dependent thrombin generation, implying that PDI is involved in conversion of platelet factor V to Va, which in turn is involved in thrombin generation [85].