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Charitharth V Lal, Xin Xu, Patricia Jackson, Thomas P Atkinson, Ona M Faye-Petersen, Jegen Kandasamy, Ken Waites, Joseph R Biggio, Amit Gaggar, Namasivayam Ambalavanan
BACKGROUND: Premature rupture of membranes and preterm delivery are associated with Ureaplasma infection. We hypothesized that Ureaplasma induced extracellular collagen fragmentation results in production of the tripeptide PGP (proline-glycine-proline), a neutrophil chemoattractant. PGP release from collagen requires matrix metalloproteases (MMP-8/MMP-9) along with a serine protease, prolyl endopeptidase (PE). METHODS: Ureaplasma culture negative amniotic fluid (indicated preterm birth, n=8; spontaneous preterm birth, n=8) and Ureaplasma positive amniotic fluid (spontaneous preterm birth, n=8) were analyzed by electro-spray ionization-liquid chromatography tandem mass spectrometry for PGP, and for MMP-9 by zymography...
September 15, 2016: Pediatric Research
Derek W Russell, J Michael Wells, J Edwin Blalock
PURPOSE OF REVIEW: Despite decades of scientific attention, chronic obstructive pulmonary disease (COPD) remains a major cause of both morbidity and mortality worldwide with strikingly few effective drug classes available. This may be in part because COPD is actually a syndrome composed of distinct diseases with varying pathophysiology (endotypes), and therapies have not been designed to target the causal pathological processes specific to an endotype. RECENT FINDINGS: Recent work has begun to clarify the nature of these endotypes and characterize them...
March 2016: Current Opinion in Pulmonary Medicine
Jeff W Hill, Edwin M Nemoto
BACKGROUND: N-acetyl proline-glycine-proline (ac-PGP) is a matrix-derived chemokine produced through the proteolytic destruction of collagen by matrix metalloproteinases (MMPs). While upregulation and activation of MMPs and concomitant degradation of the extracellular matrix are known to be associated with neurological injury in ischemic stroke, the production of ac-PGP in stroke brain and its effects on neurons have not been investigated. FINDINGS: We examined the effects of ac-PGP on primary cortical neurons and found that it binds neuronal CXCR2 receptors, activates extracellular signal-regulated kinase 1/2 (ERK1/2), and induces apoptosis associated with caspase-3 cleavage in a dose-dependent manner...
2015: Journal of Neuroinflammation
Samia Akthar, Dhiren F Patel, Rebecca C Beale, Teresa Peiró, Xin Xu, Amit Gaggar, Patricia L Jackson, J Edwin Blalock, Clare M Lloyd, Robert J Snelgrove
Bioactive matrix fragments (matrikines) have been identified in a myriad of disorders, but their impact on the evolution of airway inflammation has not been demonstrated. We recently described a pathway where the matrikine and neutrophil chemoattractant proline-glycine-proline (PGP) could be degraded by the enzyme leukotriene A4 hydrolase (LTA4H). LTA4H classically functions in the generation of pro-inflammatory leukotriene B4, thus LTA4H exhibits opposing pro- and anti-inflammatory activities. The physiological significance of this secondary anti-inflammatory activity remains unknown...
2015: Nature Communications
Chencheng Feng, Yang Zhang, Minghui Yang, Bo Huang, Yue Zhou
The factors that regulate the migration and differentiation of cartilage endplate stem cells (CESCs) remain unknown. N-Acetylated proline-glycine-proline (N-Ac-PGP) is a chemokine that is involved in inflammatory diseases. The purpose of this study was to detect N-Ac-PGP in degenerative intervertebral discs (IVDs) and to determine its roles in the migration and differentiation of CESCs. Enzyme-linked immunosorbent assay (ELISA) and liquid chromatography-mass spectrometry results indicated that the levels of the proteases that generate N-Ac-PGP as well as N-Ac-PGP levels themselves increase with the progression of IVD degeneration...
December 2015: Stem Cells
Cornelia S Hahn, David W Scott, Xin Xu, Mojtaba Abdul Roda, Gregory A Payne, J Michael Wells, Liliana Viera, Colleen J Winstead, Preston Bratcher, Rolf W Sparidans, Frank A Redegeld, Patricia L Jackson, Gert Folkerts, J Edwin Blalock, Rakesh P Patel, Amit Gaggar
The compartmentalization and transport of proteins and solutes across the endothelium is a critical biologic function altered during inflammation and disease, leading to pathology in multiple disorders. The impact of tissue damage and subsequent extracellular matrix (ECM) fragmentation in regulating this process is unknown. We demonstrate that the collagen-derived matrikine acetylated proline-glycine-proline (N-α-PGP) serves as a critical regulator of endothelial permeability. N-α-PGP activates human endothelial cells via CXC-chemokine receptor 2 (CXCR2), triggering monolayer permeability through a discrete intracellular signaling pathway...
2015: Science Advances
Brett D Noerager, Xin Xu, Virginia A Davis, Caleb W Jones, Svetlana Okafor, Alicia Whitehead, J Edwin Blalock, Patricia L Jackson
Neutrophils (PMNs) are key mediators of inflammatory processes throughout the body. In this study, we investigated the role of acrolein, a highly reactive aldehyde that is ubiquitously present in the environment and produced endogenously at sites of inflammation, in mediating PMN-mediated degradation of collagen facilitating proline-glycine-proline (PGP) production. We treated peripheral blood neutrophils with acrolein and analyzed cell supernatants and lysates for matrix metalloproteinase-9 (MMP-9) and prolyl endopeptidase (PE), assessed their ability to break down collagen and release PGP, and assayed for the presence of leukotriene A4 hydrolase (LTA4H) and its ability to degrade PGP...
December 2015: Inflammation
J Michael Wells, Patricia L Jackson, Liliana Viera, Surya P Bhatt, Joshua Gautney, Guy Handley, R Wilson King, Xin Xu, Amit Gaggar, William C Bailey, Mark T Dransfield, J Edwin Blalock
RATIONALE: Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively...
October 15, 2015: American Journal of Respiratory and Critical Care Medicine
J Michael Wells, Amit Gaggar, J Edwin Blalock
Matrikines originate from the fragmentation of extracellular matrix proteins and regulate cellular activities by interacting with specific receptors. Matrikines are implicated in inflammation, immune responses, organ development, wound repair, angiogenesis, atherosclerosis, tumor progression and metastasis due to their ability to alter cellular migration, chemotaxis, and mitogenesis. Matrix metalloproteinases (MMPs) degrade extracellular matrix components under normal circumstances and in disease processes...
May 2015: Matrix Biology: Journal of the International Society for Matrix Biology
Arne Lucas Ten Hoeve, Mojtaba Abdul Roda, Frank Redegeld, Gert Folkerts, James Edwin Blalock, Amit Gaggar
The present review discusses the role of tri-peptide Proline -Glycine -Proline (PGP) as a potential player, biomarker and therapeutic target in this process.
2012: Tanaffos
Emilie L Setlakwe, Karen R Lemos, Anouk Lavoie-Lamoureux, Jean-David Duguay, Jean-Pierre Lavoie
The consequences on lung function and inflammation of alterations in the extracellular matrix affecting the peripheral airway wall in asthma are largely unknown. We hypothesized that remodeling of collagen and elastic fibers in the peripheral airway wall leads to airway obstruction and contributes to neutrophilic airway inflammation. Animals used were six heaves-affected horses and five controls. Large peripheral lung biopsies were obtained from horses with heaves in clinical remission (Baseline) and during disease exacerbation and from age-matched controls...
August 1, 2014: American Journal of Physiology. Lung Cellular and Molecular Physiology
J Michael Wells, Philip J O'Reilly, Tomasz Szul, Daniel I Sullivan, Guy Handley, Chris Garrett, Carmel M McNicholas, Mojtaba Abdul Roda, Bruce E Miller, Ruth Tal-Singer, Amit Gaggar, Stephen I Rennard, Patricia L Jackson, J Edwin Blalock
RATIONALE: Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated. OBJECTIVES: We investigated changes to the leukotriene A4 hydrolase (LTA4H)-proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD. METHODS: A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis...
July 1, 2014: American Journal of Respiratory and Critical Care Medicine
Mojtaba Abdul Roda, Mariam Sadik, Amit Gaggar, Matthew T Hardison, Michael J Jablonsky, Saskia Braber, James Edwin Blalock, Frank A Redegeld, Gert Folkerts, Patricia L Jackson
A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by neutrophils and present in COPD serum and sputum. Valproic acid (VPA) is an inhibitor of PE and could possibly have an effect on the severity of chronic inflammation. Here the interaction site of VPA to PE and the resulting effect on the secondary structure of PE is investigated...
2014: PloS One
Mikell Paige, Kan Wang, Marie Burdick, Sunhye Park, Josiah Cha, Erin Jeffery, Nicholas Sherman, Y Michael Shim
The leukotriene A4 hydrolase (LTA4H) is a bifunctional enzyme with epoxy hydrolase and aminopeptidase activities. We hypothesize that the LTA4H aminopeptidase activity alleviates neutrophilic inflammation, which contributes to cigarette smoke (CS)-induced emphysema by clearing proline-glycine-proline (PGP), a triamino acid chemokine known to induce chemotaxis of neutrophils. To investigate the biological contributions made by the LTA4H aminopeptidase activity in CS-induced emphysema, we exposed wild-type mice to CS over 5 mo while treating them with a vehicle or a pharmaceutical agent (4MDM) that selectively augments the LTA4H aminopeptidase without affecting the bioproduction of leukotriene B4...
June 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
Philip J O'Reilly, Patricia L Jackson, J Michael Wells, Mark T Dransfield, Paul D Scanlon, J Edwin Blalock
RATIONALE: Proline-glycine-proline (PGP), a neutrophil chemoattractant derived from the enzymatic breakdown of collagen, is elevated in sputum of patients with chronic obstructive pulmonary disease (COPD) and may contribute to disease progression. Whether sputum levels of PGP respond to therapy for COPD or predict outcomes is unknown. OBJECTIVES: We conducted a study ancillary to a multicenter trial of the efficacy of azithromycin treatment for 1 year in preventing COPD exacerbations to test whether sputum levels of PGP were altered by treatment or associated with exacerbation frequency...
2013: BMJ Open
Federica Meli, Camilla Lazzi, Erasmo Neviani, Monica Gatti
The goal of this study was to evaluate how two new hydrolysates from poultry by-products act on ten lactobacilli growth kinetics when supplemented to the growth medium. These effects were compared with ones induced by two most common commercial hydrolysates, i.e., tryptone and peptone. Growth medium, supplemented with one of new hydrolysates, 78T, as only nitrogen source, can sustain the maximum growth rate and the biomass yield in the same way of MRS, reach of different nitrogen sources. Moreover aminopeptidase activities (AA) of each strain were determined to investigate the effect of the growth condition on the modulation of aminopeptidase pattern...
January 2014: Current Microbiology
Pim J Koelink, Saskia A Overbeek, Saskia Braber, Mary E Morgan, Paul A J Henricks, Mojtaba Abdul Roda, Hein W Verspaget, Simone C Wolfkamp, Anje A te Velde, Caleb W Jones, Patricia L Jackson, J Edwin Blalock, Rolf W Sparidans, John A W Kruijtzer, Johan Garssen, Gert Folkerts, Aletta D Kraneveld
OBJECTIVE: Proline-glycine-proline (PGP) has been shown to have chemotactic effects on neutrophils via CXCR2 in several lung diseases. PGP is derived from collagen by the combined action of matrix metalloproteinase (MMP) 8 and/or MMP9 and prolyl endopeptidase (PE). We investigated the role of PGP in inflammatory bowel disease (IBD). DESIGN: In intestinal tissue from patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis, MMP8, MMP9 and PE were evaluated by ELISA, immunoblot and immunohistochemistry...
April 2014: Gut
Saskia A Overbeek, Saskia Braber, Pim J Koelink, Paul A J Henricks, Esmaeil Mortaz, Adele T LoTam Loi, Patricia L Jackson, Johan Garssen, Gerry T M Wagenaar, Wim Timens, Leo Koenderman, J Edwin Blalock, Aletta D Kraneveld, Gert Folkerts
BACKGROUND: Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD). In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP). The generation of this tripeptide is mediated by a multistep pathway involving matrix metalloproteases (MMPs) 8 and 9 and prolyl endopeptidase (PE)...
2013: PloS One
Saskia A Overbeek, Marije Kleinjan, Paul A J Henricks, Vera M Kamp, Fabio L Ricciardolo, Niki A Georgiou, Johan Garssen, Aletta D Kraneveld, Gert Folkerts
BACKGROUND: Chronic inflammation in lung diseases contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated proline-glycine-proline (N-ac-PGP). In the current study, we investigate whether N-ac-PGP influences β(2)-integrin activation and function in neutrophilic firm adhesion to endothelium. METHODS: Human polymorphonuclear leukocytes (PMNs) were isolated from fresh human blood. Subsequently, a transmigration assay was performed to evaluate the active migration of PMNs towards N-ac-PGP...
January 2013: Biochimica et Biophysica Acta
Matthew Thomas Hardison, Michael David Brown, Robert James Snelgrove, James Edwin Blalock, Patricia Jackson
Several chronic lung diseases have been linked to cigarette smoking (Chronic Obstructive Pulmonary Disease (COPD), and cancer are associated with increased tobacco use). We recently described a collagen fragment, proline-glycine-proline (PGP), chemotactic for neutrophils, that appears to play a role in COPD, cystic fibrosis, and bronchiolitis obliterans syndrome. PGP can exist in either its native or acetylated form (NAcPGP), although the mechanism of N-terminal-acetylation remains unknown. This work investigates the possibility that cigarette smoke (CS) and its components acetylate PGP, describing a possible mechanism for some of the chronic inflammation seen in tobacco-associated disease...
2012: Frontiers in Bioscience (Elite Edition)
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