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Yang Woo Kwon, Seung Jun Lee, Soon Chul Heo, Tae Wook Lee, Gyu Tae Park, Jung Won Yoon, Seung-Chul Kim, Ho Jin Shin, Sang Chul Lee, Jae Ho Kim
Circulating angiogenic cells (CACs) have been implicated in the repair of ischemic tissues, and their mobilization from bone marrow is known to be regulated by the activations of chemokine receptors, including CXCR2 and CXCR4. This study was conducted to investigate the role of N-acetylated proline-glycine-proline (Ac-PGP; a collagen-derived chemotactic tripeptide) on CAC mobilization and its therapeutic potential for the treatment of peripheral artery diseases. Ac-PGP was administered daily to a murine hind limb ischemia model, and the effects of Ac-PGP on blood perfusion and CAC mobilization (Sca1+ Flk1+ cells) into peripheral blood were assessed...
November 26, 2018: Stem Cells Translational Medicine
Nirmal S Sharma, Charitharth Vivek Lal, Jin-Dong Li, Xiang-Yang Lou, Liliana Viera, Tarek Abdallah, Robert W King, Jaskaran Sethi, Prashanth Kanagarajah, Ricardo Restrepo-Jaramillo, Amanda Sales-Conniff, Shi Wei, Patricia L Jackson, J Edwin Blalock, Amit Gaggar, Xin Xu
Acute respiratory distress syndrome (ARDS) is characterized by unrelenting polymorphonuclear neutrophil (PMN) inflammation and vascular permeability. The matrikine proline-glycine-proline (PGP) and acetylated PGP (Ac-PGP) have been shown to induce PMN inflammation and endothelial permeability in vitro and in vivo. In this study, we investigated the presence and role of airway PGP peptides in acute lung injury (ALI)/ARDS. Pseudomonas aeruginosa-derived lipopolysaccharide (LPS) was instilled intratracheally in mice to induce ALI, and increased Ac-PGP with neutrophil inflammation was noted...
November 1, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Nirmal S Sharma, Charitharth Vivek Lal, Jin-Dong Li, Xiang-Yang Lou, Liliana Viera, Tarek Abdallah, Robert King, Jaskaran Sethi, Prashanth Kanagarajah, Ricardo Restrepo-Jaramillo, Amanda Sales-Conniff, Shi Wei, Patricia L Jackson, J Edwin Blalock, Amit Gaggar, Xin Xu
ARDS is characterized by unrelenting PMN inflammation and vascular permeability. The matrikine proline-glycine-proline (PGP) and acetylated PGP (Ac-PGP) have been shown to induce PMN inflammation and endothelial permeability in vitro and in vivo. In this study, we investigated the presence and role of airway PGP peptides in acute lung injury (ALI)/ARDS. P. aeruginosa-derived LPS was instilled intratracheally (i.t) in mice to induce ALI and increased Ac-PGP with neutrophil inflammation was noted. The PGP inhibitory peptide, RTR (arginine-threonine-arginine), was administered (i...
August 9, 2018: American Journal of Physiology. Lung Cellular and Molecular Physiology
Ryu Watanabe, Toshihisa Maeda, Hui Zhang, Gerald J Berry, Markus Zeisbrich, Robert Brockett, Andrew E Greenstein, Lu Tian, Jörg J Goronzy, Cornelia M Weyand
RATIONALE: Giant cell arteritis (GCA)-a primary vasculitis of medium and large arteries-is associated with vessel wall damage, elastic membrane fragmentation, and vascular remodeling. Proteinases are believed to contribute to pathogenesis by degrading extracellular matrix and causing tissue injury. OBJECTIVE: The MMP (matrix metalloproteinase)-9-a type IV collagenase-is produced in the vasculitic lesions of GCA. It is unknown which pathogenic processes are MMP-9 dependent...
August 31, 2018: Circulation Research
Dhiren F Patel, Robert J Snelgrove
Matrikines are bioactive fragments of the extracellular matrix (ECM) that are fundamental in regulating a diverse array of physiological processes. The tripeptide Proline-Glycine-Proline (PGP) is a collagen-derived matrikine that has classically been described as a neutrophil chemoattractant. In this article, we describe our current understanding of the pathways that generate, degrade and modify PGP to dictate its bioavailability and stability. Additionally, we discuss our expanding appreciation of the capacity of PGP to regulate diverse cell types and biological processes, independent of its activity on neutrophils, including a putative role in wound repair...
June 30, 2018: European Respiratory Review: An Official Journal of the European Respiratory Society
Philip J O'Reilly, Qiang Ding, Samia Akthar, Guoqiang Cai, Kristopher R Genschmer, Dhiren F Patel, Patricia L Jackson, Liliana Viera, Mojtaba Roda, Morgan L Locy, Ellen A Bernstein, Clare M Lloyd, Kenneth E Bernstein, Robert J Snelgrove, J Edwin Blalock
The neutrophil chemoattractant proline-glycine-proline (PGP) is generated from collagen by matrix metalloproteinase-8/9 (MMP-8/9) and prolyl endopeptidase (PE), and it is concomitantly degraded by extracellular leukotriene A4 hydrolase (LTA4H) to limit neutrophilia. Components of cigarette smoke can acetylate PGP, yielding a species (AcPGP) that is resistant to LTA4H-mediated degradation and can, thus, support a sustained neutrophilia. In this study, we sought to elucidate if an antiinflammatory system existed to degrade AcPGP that is analogous to the PGP-LTA4H axis...
November 16, 2017: JCI Insight
Gregory A Payne, Jindong Li, Xin Xu, Patricia Jackson, Hongwei Qin, David M Pollock, J Michael Wells, Suzanne Oparil, Massoud Leesar, Rakesh P Patel, J Edwin Blalock, Amit Gaggar
The extracellular matrix (ECM) is a dynamic, bioactive structure critical to organ development, structure and function. Excessive remodeling of the ECM is a hallmark of a variety of inflammatory conditions including vascular disease. Endothelin-1 (ET1) synthesis is understood to promote cardiovascular diseases including acute cardiac transplant rejection; however, the contribution of ECM-derived chemokines (matrikines) to vascular inflammation remains poorly understood. Herein we report that the matrikine acetylated Pro-Gly-Pro (PGP) stimulates vascular inflammation through activation of endothelial CXC Chemokine Receptor 2 (CXCR2) and production of endothelin-1 both in vitro and in vivo...
August 8, 2017: Scientific Reports
Chencheng Feng, Jinyue He, Yang Zhang, Minghong Lan, Minghui Yang, Huan Liu, Bo Huang, Yong Pan, Yue Zhou
N-acetylated proline-glycine-proline (N-Ac-PGP) is a chemokine involved in inflammatory diseases and is found to accumulate in degenerative discs. N-Ac-PGP has been demonstrated to have a pro-inflammatory effect on human cartilage endplate stem cells. However, the effect of N-Ac-PGP on human intervertebral disc cells, especially nucleus pulposus (NP) cells, remains unknown. The purpose of this study was to investigate the effect of N-Ac-PGP on the expression of pro-inflammatory factors and extracellular matrix (ECM) proteases in NP cells and the molecular mechanism underlying this effect...
July 2017: International Journal of Molecular Medicine
Yang Woo Kwon, Soon Chul Heo, Tae Wook Lee, Gyu Tae Park, Jung Won Yoon, Il Ho Jang, Seung-Chul Kim, Hyun-Chang Ko, Youngjae Ryu, Hyeona Kang, Chang Man Ha, Sang Chul Lee, Jae Ho Kim
Human endothelial progenitor cells (hEPCs) are promising therapeutic resources for wound repair through stimulating neovascularization. However, the hEPCs-based cell therapy has been hampered by poor engraftment of transplanted cells. In this study, we explored the effects of N-acetylated Proline-Glycine-Proline (Ac-PGP), a degradation product of collagen, on hEPC-mediated cutaneous wound healing and neovascularization. Treatment of hEPCs with Ac-PGP increased migration, proliferation, and tube-forming activity of hEPCs in vitro...
February 23, 2017: Scientific Reports
María José Torres, Angélica Fierro, C David Pessoa-Mahana, Javier Romero-Parra, Gonzalo Cabrera, Mario Faúndez
Leukotriene A4 hydrolase is a soluble enzyme with epoxide hydrolase and aminopeptidase activities catalysing the conversion of leukotriene A4 to leukotriene B4 and the hydrolysis of the peptide proline-glycine-proline. Imbalances in leukotriene B4 synthesis are related to several pathologic conditions. Currently there are no available drugs capable to modulate the synthesis of leukotriene B4 or to block its receptors. Here we show the inhibitory profile of alpha lipoic acid on the activity of leukotriene A4 Hydrolase...
March 15, 2017: European Journal of Pharmacology
Chencheng Feng, Yang Zhang, Minghui Yang, Minghong Lan, Huan Liu, Jian Wang, Yue Zhou, Bo Huang
Intervertebral disc (IVD) cell senescence is a recognized mechanism of intervertebral disc degeneration (IDD). Elucidating the molecular mechanisms underlying disc cell senescence will contribute to understanding the pathogenesis of IDD. We previously reported that N-acetylated proline-glycine-proline (N-Ac-PGP), a matrikine, is involved in the process of IDD. However, its roles in IDD are not well understood. Here, using rat nucleus pulposus (NP) cells, we found that N-Ac-PGP induced premature senescence of NP cells by binding to CXCR1...
January 2017: Biochimica et biophysica acta. Molecular basis of disease
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...
January 2017: 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...
September 24, 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
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