Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine

Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruc...
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Autor*in:	Pranav Murthy [verfasserIn] Aatur D. Singhi [verfasserIn] Mark A. Ross [verfasserIn] Patricia Loughran [verfasserIn] Pedram Paragomi [verfasserIn] Georgios I. Papachristou [verfasserIn] David C. Whitcomb [verfasserIn] Amer H. Zureikat [verfasserIn] Michael T. Lotze [verfasserIn] Herbert J. Zeh III [verfasserIn] Brian A. Boone [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone

Übergeordnetes Werk:	In: Frontiers in Immunology - Frontiers Media S.A., 2011, 10(2019)
Übergeordnetes Werk:	volume:10 ; year:2019

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fimmu.2019.00028

Katalog-ID:	DOAJ037322893

Internformat


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520			\|a Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted.
650		4	\|a neutrophil extracellular traps
650		4	\|a pancreatitis
650		4	\|a chloroquine
650		4	\|a autophagy
650		4	\|a systemic inflammatory response
650		4	\|a citrullinated histone
653		0	\|a Immunologic diseases. Allergy
700	0		\|a Aatur D. Singhi \|e verfasserin \|4 aut
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700	0		\|a Herbert J. Zeh III \|e verfasserin \|4 aut
700	0		\|a Herbert J. Zeh III \|e verfasserin \|4 aut
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Indexfelder

author_variant	p m pm a d s ads m a r mar p l pl p p pp g i p gip d c w dcw a h z ahz m t l mtl h j z i hjzi h j z i hjzi b a b bab b a b bab
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allfields	10.3389/fimmu.2019.00028 doi (DE-627)DOAJ037322893 (DE-599)DOAJ2f246b1f618e4df2a01e34b810a99c8b DE-627 ger DE-627 rakwb eng RC581-607 Pranav Murthy verfasserin aut Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted. neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone Immunologic diseases. Allergy Aatur D. Singhi verfasserin aut Mark A. Ross verfasserin aut Patricia Loughran verfasserin aut Pedram Paragomi verfasserin aut Georgios I. Papachristou verfasserin aut David C. Whitcomb verfasserin aut Amer H. Zureikat verfasserin aut Michael T. Lotze verfasserin aut Herbert J. Zeh III verfasserin aut Herbert J. Zeh III verfasserin aut Brian A. Boone verfasserin aut Brian A. Boone verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.00028 kostenfrei https://doaj.org/article/2f246b1f618e4df2a01e34b810a99c8b kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.00028/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
spelling	10.3389/fimmu.2019.00028 doi (DE-627)DOAJ037322893 (DE-599)DOAJ2f246b1f618e4df2a01e34b810a99c8b DE-627 ger DE-627 rakwb eng RC581-607 Pranav Murthy verfasserin aut Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted. neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone Immunologic diseases. Allergy Aatur D. Singhi verfasserin aut Mark A. Ross verfasserin aut Patricia Loughran verfasserin aut Pedram Paragomi verfasserin aut Georgios I. Papachristou verfasserin aut David C. Whitcomb verfasserin aut Amer H. Zureikat verfasserin aut Michael T. Lotze verfasserin aut Herbert J. Zeh III verfasserin aut Herbert J. Zeh III verfasserin aut Brian A. Boone verfasserin aut Brian A. Boone verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.00028 kostenfrei https://doaj.org/article/2f246b1f618e4df2a01e34b810a99c8b kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.00028/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfields_unstemmed	10.3389/fimmu.2019.00028 doi (DE-627)DOAJ037322893 (DE-599)DOAJ2f246b1f618e4df2a01e34b810a99c8b DE-627 ger DE-627 rakwb eng RC581-607 Pranav Murthy verfasserin aut Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted. neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone Immunologic diseases. Allergy Aatur D. Singhi verfasserin aut Mark A. Ross verfasserin aut Patricia Loughran verfasserin aut Pedram Paragomi verfasserin aut Georgios I. Papachristou verfasserin aut David C. Whitcomb verfasserin aut Amer H. Zureikat verfasserin aut Michael T. Lotze verfasserin aut Herbert J. Zeh III verfasserin aut Herbert J. Zeh III verfasserin aut Brian A. Boone verfasserin aut Brian A. Boone verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.00028 kostenfrei https://doaj.org/article/2f246b1f618e4df2a01e34b810a99c8b kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.00028/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfieldsGer	10.3389/fimmu.2019.00028 doi (DE-627)DOAJ037322893 (DE-599)DOAJ2f246b1f618e4df2a01e34b810a99c8b DE-627 ger DE-627 rakwb eng RC581-607 Pranav Murthy verfasserin aut Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted. neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone Immunologic diseases. Allergy Aatur D. Singhi verfasserin aut Mark A. Ross verfasserin aut Patricia Loughran verfasserin aut Pedram Paragomi verfasserin aut Georgios I. Papachristou verfasserin aut David C. Whitcomb verfasserin aut Amer H. Zureikat verfasserin aut Michael T. Lotze verfasserin aut Herbert J. Zeh III verfasserin aut Herbert J. Zeh III verfasserin aut Brian A. Boone verfasserin aut Brian A. Boone verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.00028 kostenfrei https://doaj.org/article/2f246b1f618e4df2a01e34b810a99c8b kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.00028/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
allfieldsSound	10.3389/fimmu.2019.00028 doi (DE-627)DOAJ037322893 (DE-599)DOAJ2f246b1f618e4df2a01e34b810a99c8b DE-627 ger DE-627 rakwb eng RC581-607 Pranav Murthy verfasserin aut Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted. neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone Immunologic diseases. Allergy Aatur D. Singhi verfasserin aut Mark A. Ross verfasserin aut Patricia Loughran verfasserin aut Pedram Paragomi verfasserin aut Georgios I. Papachristou verfasserin aut David C. Whitcomb verfasserin aut Amer H. Zureikat verfasserin aut Michael T. Lotze verfasserin aut Herbert J. Zeh III verfasserin aut Herbert J. Zeh III verfasserin aut Brian A. Boone verfasserin aut Brian A. Boone verfasserin aut In Frontiers in Immunology Frontiers Media S.A., 2011 10(2019) (DE-627)657998354 (DE-600)2606827-8 16643224 nnns volume:10 year:2019 https://doi.org/10.3389/fimmu.2019.00028 kostenfrei https://doaj.org/article/2f246b1f618e4df2a01e34b810a99c8b kostenfrei https://www.frontiersin.org/article/10.3389/fimmu.2019.00028/full kostenfrei https://doaj.org/toc/1664-3224 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 10 2019
language	English
source	In Frontiers in Immunology 10(2019) volume:10 year:2019
sourceStr	In Frontiers in Immunology 10(2019) volume:10 year:2019
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone Immunologic diseases. Allergy
isfreeaccess_bool	true
container_title	Frontiers in Immunology
authorswithroles_txt_mv	Pranav Murthy @@aut@@ Aatur D. Singhi @@aut@@ Mark A. Ross @@aut@@ Patricia Loughran @@aut@@ Pedram Paragomi @@aut@@ Georgios I. Papachristou @@aut@@ David C. Whitcomb @@aut@@ Amer H. Zureikat @@aut@@ Michael T. Lotze @@aut@@ Herbert J. Zeh III @@aut@@ Brian A. Boone @@aut@@
publishDateDaySort_date	2019-01-01T00:00:00Z
hierarchy_top_id	657998354
id	DOAJ037322893
language_de	englisch
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callnumber-first	R - Medicine
author	Pranav Murthy
spellingShingle	Pranav Murthy misc RC581-607 misc neutrophil extracellular traps misc pancreatitis misc chloroquine misc autophagy misc systemic inflammatory response misc citrullinated histone misc Immunologic diseases. Allergy Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine
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topic_title	RC581-607 Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine neutrophil extracellular traps pancreatitis chloroquine autophagy systemic inflammatory response citrullinated histone
topic	misc RC581-607 misc neutrophil extracellular traps misc pancreatitis misc chloroquine misc autophagy misc systemic inflammatory response misc citrullinated histone misc Immunologic diseases. Allergy
topic_unstemmed	misc RC581-607 misc neutrophil extracellular traps misc pancreatitis misc chloroquine misc autophagy misc systemic inflammatory response misc citrullinated histone misc Immunologic diseases. Allergy
topic_browse	misc RC581-607 misc neutrophil extracellular traps misc pancreatitis misc chloroquine misc autophagy misc systemic inflammatory response misc citrullinated histone misc Immunologic diseases. Allergy
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title	Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine
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title_full	Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine
author_sort	Pranav Murthy
journal	Frontiers in Immunology
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author_browse	Pranav Murthy Aatur D. Singhi Mark A. Ross Patricia Loughran Pedram Paragomi Georgios I. Papachristou David C. Whitcomb Amer H. Zureikat Michael T. Lotze Herbert J. Zeh III Brian A. Boone
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title_sort	enhanced neutrophil extracellular trap formation in acute pancreatitis contributes to disease severity and is reduced by chloroquine
callnumber	RC581-607
title_auth	Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine
abstract	Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted.
abstractGer	Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted.
abstract_unstemmed	Background: Neutrophil extracellular traps (NETs) are generated when activated neutrophils, driven by PAD4, release their DNA, histones, HMGB1, and other intracellular granule components. NETs play a role in acute pancreatitis, worsening pancreatic inflammation, and promoting pancreatic duct obstruction. The autophagy inhibitor chloroquine (CQ) inhibits NET formation; therefore, we investigated the impact of CQ mediated NET inhibition in murine models of pancreatitis and human correlative studies.Methods: L-arginine and choline deficient ethionine supplemented (CDE) diet models of acute pancreatitis were studied in wild type and PAD4−/− mice, incapable of forming NETs. Isolated neutrophils were stimulated to induce NET formation and visualized with fluorescence microscopy. CQ treatment (0.5 mg/ml PO) was initiated after induction of pancreatitis. Biomarkers of NET formation, including cell-free DNA, citrullinated histone H3 (CitH3), and MPO-DNA conjugates were measured in murine serum and correlative human patient serum samples.Results: We first confirmed the role of NETs in the pathophysiology of acute pancreatitis by demonstrating that PAD4−/− mice had decreased pancreatitis severity and improved survival compared to wild-type controls. Furthermore, patients with severe acute pancreatitis had elevated levels of cell-free DNA and MPO-DNA conjugates, consistent with NET formation. Neutrophils from mice with pancreatitis were more prone to NET formation and CQ decreased this propensity to form NETs. CQ significantly reduced serum cell-free DNA and citrullinated histone H3 in murine models of pancreatitis, increasing survival in both models.Conclusions: Inhibition of NETs with CQ decreases the severity of acute pancreatitis and improves survival. Translating these findings into clinical trials of acute pancreatitis is warranted.
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title_short	Enhanced Neutrophil Extracellular Trap Formation in Acute Pancreatitis Contributes to Disease Severity and Is Reduced by Chloroquine
url	https://doi.org/10.3389/fimmu.2019.00028 https://doaj.org/article/2f246b1f618e4df2a01e34b810a99c8b https://www.frontiersin.org/article/10.3389/fimmu.2019.00028/full https://doaj.org/toc/1664-3224
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author2	Aatur D. Singhi Mark A. Ross Patricia Loughran Pedram Paragomi Georgios I. Papachristou David C. Whitcomb Amer H. Zureikat Michael T. Lotze Herbert J. Zeh III Brian A. Boone
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up_date	2024-07-04T00:46:46.298Z
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