Treatment of sepsis-induced acquired protein C deficiency reverses Angiotensin-converting enzyme-2 inhibition and decreases pulmonary inflammatory response

The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury i...

Celý popis

Uložené v:

Podrobná bibliografia
Vydané v:	The Journal of pharmacology and experimental therapeutics Ročník 325; číslo 1; s. 17
Hlavní autori:	Richardson, Mark A, Gupta, Akanksha, O'Brien, Lee A, Berg, David T, Gerlitz, Bruce, Syed, Samreen, Sharma, Ganesh R, Cramer, Martin S, Heuer, Josef G, Galbreath, Elizabeth J, Grinnell, Brian W
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.04.2008
Predmet:	Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors - pharmacology Angiotensin-Converting Enzyme Inhibitors - therapeutic use Animals Gene Expression Regulation - drug effects Macrophage Inflammatory Proteins - genetics Nitric Oxide Synthase Type II - genetics Peptidyl-Dipeptidase A - drug effects Plasminogen Activator Inhibitor 1 - genetics Protein C Deficiency - drug therapy Protein C Deficiency - etiology Rats Respiratory Distress Syndrome - drug therapy Sepsis - complications Systemic Inflammatory Response Syndrome - drug therapy
ISSN:	1521-0103, 1521-0103
On-line prístup:	Zistit podrobnosti o prístupe
Tagy:	Pridať tag Žiadne tagy, Buďte prvý, kto otaguje tento záznam!

Abstract	The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury is unclear. We hypothesized that low PC induced by sepsis would associate with increased pulmonary injury and that replacement with activated protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, we examined the role of acquired PC deficiency on acute lung injury assessed by analyzing changes in pulmonary pathology, chemokine response, inducible nitric-oxide synthase (iNOS), and the angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in lung inflammation and drivers of pulmonary injury, including angiotensin (Ang) II, thymus and activation-regulated chemokine, plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the macrophage inflammatory protein family chemokine response, iNOS expression, and PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat sepsis model and provide support for the concept of APC as a replacement therapy in acute lung injury associated with acquired PC deficiency.
AbstractList	The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury is unclear. We hypothesized that low PC induced by sepsis would associate with increased pulmonary injury and that replacement with activated protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, we examined the role of acquired PC deficiency on acute lung injury assessed by analyzing changes in pulmonary pathology, chemokine response, inducible nitric-oxide synthase (iNOS), and the angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in lung inflammation and drivers of pulmonary injury, including angiotensin (Ang) II, thymus and activation-regulated chemokine, plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the macrophage inflammatory protein family chemokine response, iNOS expression, and PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat sepsis model and provide support for the concept of APC as a replacement therapy in acute lung injury associated with acquired PC deficiency. The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury is unclear. We hypothesized that low PC induced by sepsis would associate with increased pulmonary injury and that replacement with activated protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, we examined the role of acquired PC deficiency on acute lung injury assessed by analyzing changes in pulmonary pathology, chemokine response, inducible nitric-oxide synthase (iNOS), and the angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in lung inflammation and drivers of pulmonary injury, including angiotensin (Ang) II, thymus and activation-regulated chemokine, plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the macrophage inflammatory protein family chemokine response, iNOS expression, and PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat sepsis model and provide support for the concept of APC as a replacement therapy in acute lung injury associated with acquired PC deficiency.The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. However, the association of acquired PC deficiency with the pathophysiology of lung injury is unclear. We hypothesized that low PC induced by sepsis would associate with increased pulmonary injury and that replacement with activated protein C (APC) would reverse the activation of pathways associated with injury. Using a cecal ligation and puncture (CLP) model of polymicrobial sepsis, we examined the role of acquired PC deficiency on acute lung injury assessed by analyzing changes in pulmonary pathology, chemokine response, inducible nitric-oxide synthase (iNOS), and the angiotensin pathway. Acquired PC deficiency was strongly associated with an increase in lung inflammation and drivers of pulmonary injury, including angiotensin (Ang) II, thymus and activation-regulated chemokine, plasminogen activator inhibitor (PAI)-1, and iNOS. In contrast, the protective factor angiotensin-converting enzyme (ACE)-2 was significantly suppressed in animals with acquired PC deficiency. The endothelial protein C receptor, required for the cytoprotective signaling of APC, was significantly increased post-CLP, suggesting a compensatory up-regulation of the signaling receptor. Treatment of septic animals with APC reduced pulmonary pathology, suppressed the macrophage inflammatory protein family chemokine response, iNOS expression, and PAI-1 activity and up-regulated ACE-2 expression with concomitant reduction in AngII peptide. These data demonstrate a clear link between acquired PC deficiency and pulmonary inflammatory response in the rat sepsis model and provide support for the concept of APC as a replacement therapy in acute lung injury associated with acquired PC deficiency.
Author	Berg, David T Syed, Samreen Sharma, Ganesh R Gupta, Akanksha O'Brien, Lee A Heuer, Josef G Grinnell, Brian W Richardson, Mark A Gerlitz, Bruce Galbreath, Elizabeth J Cramer, Martin S
Author_xml	– sequence: 1 givenname: Mark A surname: Richardson fullname: Richardson, Mark A organization: Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA – sequence: 2 givenname: Akanksha surname: Gupta fullname: Gupta, Akanksha – sequence: 3 givenname: Lee A surname: O'Brien fullname: O'Brien, Lee A – sequence: 4 givenname: David T surname: Berg fullname: Berg, David T – sequence: 5 givenname: Bruce surname: Gerlitz fullname: Gerlitz, Bruce – sequence: 6 givenname: Samreen surname: Syed fullname: Syed, Samreen – sequence: 7 givenname: Ganesh R surname: Sharma fullname: Sharma, Ganesh R – sequence: 8 givenname: Martin S surname: Cramer fullname: Cramer, Martin S – sequence: 9 givenname: Josef G surname: Heuer fullname: Heuer, Josef G – sequence: 10 givenname: Elizabeth J surname: Galbreath fullname: Galbreath, Elizabeth J – sequence: 11 givenname: Brian W surname: Grinnell fullname: Grinnell, Brian W
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/18182560$$D View this record in MEDLINE/PubMed
BookMark	eNpNkE1PwzAMhiM0xD7gzA3lxK0jSdt0O04TX9IkLuNcpakzMrVO16RI46_wZ8nEkDjZsh-_tt8pGaFDIOSWsznnInvYdxDmnBVznjLJlhdkwnPBE8ZZOvqXj8nU-z1jPMtkekXGfMEXIpdsQr63PajQAgbqDPXQeesTi_WgoaZKHwbbx6TrXQCLdE1rMFZbQH2kPXxC78HTFe5s7KO3mGiHsRos7ijg17GFRFCLH7aywTqkCusooePO02A3NK1D1R8jYhrVtiq4_iTsO4cersmlUY2Hm3Ockfenx-36Jdm8Pb-uV5tEp0UeEl5k9aJKQS7zWqdLWUllRFaZlCmR60oXkEEqs4pBIRa8ikYZZngevShMroCJGbn_1Y1vHgbwoWyt19A0CsENvixYxmSkI3h3BoeqhbrsetvG68s_O8UPqEN-Ew
CitedBy_id	crossref_primary_10_1111_j_1476_5381_2009_00251_x crossref_primary_10_1007_s00011_020_01401_6 crossref_primary_10_1016_j_resp_2011_11_009 crossref_primary_10_5937_afmnai40_41219 crossref_primary_10_1016_j_ejphar_2020_173545 crossref_primary_10_1186_s13054_020_03077_0 crossref_primary_10_1097_MRM_0000000000000336 crossref_primary_10_1160_TH11_06_0438 crossref_primary_10_1186_cc7128 crossref_primary_10_1016_j_etp_2010_04_002 crossref_primary_10_1515_CCLM_2010_369 crossref_primary_10_3390_jcm9103137 crossref_primary_10_1016_j_intimp_2025_115192 crossref_primary_10_3390_vetsci9090496 crossref_primary_10_1007_s00277_020_04366_y crossref_primary_10_1007_s40995_022_01400_8 crossref_primary_10_1016_j_pharmthera_2020_107750 crossref_primary_10_22159_ijpps_2025v17i8_54583 crossref_primary_10_1517_14728220903460332
ContentType	Journal Article
DBID	CGR CUY CVF ECM EIF NPM 7X8
DOI	10.1124/jpet.107.130609
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) MEDLINE - Academic
DatabaseTitleList	MEDLINE MEDLINE - Academic
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: 7X8 name: MEDLINE - Academic url: https://search.proquest.com/medline sourceTypes: Aggregation Database
DeliveryMethod	no_fulltext_linktorsrc
Discipline	Pharmacy, Therapeutics, & Pharmacology
EISSN	1521-0103
ExternalDocumentID	18182560
Genre	Journal Article
GroupedDBID	--- -~X .55 .GJ 0R~ 18M 2WC 3O- 4.4 53G 5GY 5RE 5VS 8WZ A6W AALRI AAXUO AAYOK ABCQX ABIVO ABJNI ABOCM ABSQV ACGFO ACGFS ACNCT ADBBV ADCOW ADIYS AENEX AERNN AETEA AFFNX AFOSN AGFXO AI. ALMA_UNASSIGNED_HOLDINGS BAWUL BTFSW CGR CS3 CUY CVF DIK DU5 E3Z EBS ECM EIF EJD F5P F9R FDB GX1 H13 HZ~ INIJC KQ8 L7B LSO M41 MJL MVM NPM O9- OHT P2P R.V R0Z RHI ROL RPT TR2 UQL VH1 W8F WH7 WOQ X7M YBU YHG YQT ZGI ZXP 7X8
ID	FETCH-LOGICAL-c375t-174d8b3e695dc396b6af24bf30a25cbc7e4e364b0e7281b306f0f151447f5ae02
IEDL.DBID	7X8
ISICitedReferencesCount	23
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000254064800003&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	1521-0103
IngestDate	Sat Sep 27 16:57:36 EDT 2025 Sat Mar 08 01:25:19 EST 2025
IsPeerReviewed	true
IsScholarly	true
Issue	1
Language	English
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c375t-174d8b3e695dc396b6af24bf30a25cbc7e4e364b0e7281b306f0f151447f5ae02
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
PMID	18182560
PQID	70406447
PQPubID	23479
ParticipantIDs	proquest_miscellaneous_70406447 pubmed_primary_18182560
PublicationCentury	2000
PublicationDate	2008-Apr 20080401
PublicationDateYYYYMMDD	2008-04-01
PublicationDate_xml	– month: 04 year: 2008 text: 2008-Apr
PublicationDecade	2000
PublicationPlace	United States
PublicationPlace_xml	– name: United States
PublicationTitle	The Journal of pharmacology and experimental therapeutics
PublicationTitleAlternate	J Pharmacol Exp Ther
PublicationYear	2008
SSID	ssj0014463
Score	2.012097
Snippet	The protein C (PC) pathway plays an important role in vascular and immune function, and acquired deficiency during sepsis is associated with increased...
SourceID	proquest pubmed
SourceType	Aggregation Database Index Database
StartPage	17
SubjectTerms	Angiotensin-Converting Enzyme 2 Angiotensin-Converting Enzyme Inhibitors - pharmacology Angiotensin-Converting Enzyme Inhibitors - therapeutic use Animals Gene Expression Regulation - drug effects Macrophage Inflammatory Proteins - genetics Nitric Oxide Synthase Type II - genetics Peptidyl-Dipeptidase A - drug effects Plasminogen Activator Inhibitor 1 - genetics Protein C Deficiency - drug therapy Protein C Deficiency - etiology Rats Respiratory Distress Syndrome - drug therapy Sepsis - complications Systemic Inflammatory Response Syndrome - drug therapy
Title	Treatment of sepsis-induced acquired protein C deficiency reverses Angiotensin-converting enzyme-2 inhibition and decreases pulmonary inflammatory response
URI	https://www.ncbi.nlm.nih.gov/pubmed/18182560 https://www.proquest.com/docview/70406447
Volume	325
WOSCitedRecordID	wos000254064800003&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText
inHoldings	1
isFullTextHit
isPrint
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1NT9wwELVo4dBLC4W2lI_6gDittdk4sR0JCaEViAurPSzS3la2Yy-pirMlgLT8Ff5sZ5yN9kYPXKIcYivJTDxvMs9vCDnRxpdZ4gG5qTxnmeAZ07qwzHqVysGgMEa1zSbkaKSm02K8Qc66vTBIq-zWxLhQl7XFf-R9Cd4GsVueL_4y7BmFtdVVA40PZJMDkEFCl5yuawiQ6ER6PQQoht0MVsI-END6vwGRQt4qsReySN5AlzHKXH153_1tk88rdEkvWnfYIRsufCWn41aeetmjk_Vuq6ZHT-l4LVy93CWvk451TmtPG7doqoZBzg7WL6m2yBmGk6jsUAU6pKVD-Qncu0lRCArZIPQizKs6suIDi4x2VCmYUxdelveOpbQKd5WJNDGqQwlTIGrFgYunP_AQ-mEJl3hw0_tY_oeJI4fX7ZHbq8vJ8Jqtmjcwy2X-yCDTKZXhThR5aXkhjNA-zYzniU5za6x0meMiM4mTKUBnsINPPMAPeIU-1y5Jv5GPoQ7uB6Eey8lKCaF5njkhjXC58GWKbYP4wKh98qszyQw-Dqx46ODqp2bWGWWffG-tOlu0Gh4zADYK0d7P_449IJ9ajgiydQ7JpodlwR2RLfv8WDUPx9Hn4Dga3_wDndrmPg
linkProvider	ProQuest
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Treatment+of+sepsis-induced+acquired+protein+C+deficiency+reverses+Angiotensin-converting+enzyme-2+inhibition+and+decreases+pulmonary+inflammatory+response&rft.jtitle=The+Journal+of+pharmacology+and+experimental+therapeutics&rft.au=Richardson%2C+Mark+A&rft.au=Gupta%2C+Akanksha&rft.au=O%27Brien%2C+Lee+A&rft.au=Berg%2C+David+T&rft.date=2008-04-01&rft.issn=1521-0103&rft.eissn=1521-0103&rft.volume=325&rft.issue=1&rft.spage=17&rft_id=info:doi/10.1124%2Fjpet.107.130609&rft.externalDBID=NO_FULL_TEXT
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1521-0103&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1521-0103&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1521-0103&client=summon