Abstract
Platelets, cellular mediators of thrombosis, are activated during sepsis and are increasingly recognized as mediators of the immune response. Platelet activation is significantly increased in sepsis patients compared to ICU control patients. Despite this correlation, the role of activated platelets in contributing to sepsis pathophysiology remains unclear. We previously demonstrated NOD-like receptor protein 3 inflammasome (NLRP3) inflammasome activation in sepsis-induced platelets from cecal-ligation puncture (CLP) rats. Activated platelets were associated with increased pulmonary edema and glomerular injury in CLP vs. SHAM controls. In this study, we investigated whether inhibition of platelet activation would attenuate NLRP3 activation and renal and pulmonary injury in response to CLP. CLP was performed in male and female Sprague Dawley (SD) rats (n = 10/group) to induce abdominal sepsis and SHAM rats served as controls. A subset of CLP animals was treated with Clopidogrel (10 mg/kg/day, CLP + CLOP) to inhibit platelet activation. At 72 h post-CLP, platelet activation and NLRP3 inflammasome assembly were evaluated, IL-1β and IL-18 were measured in plasma, and tissues, renal and pulmonary pathology, and renal function were assessed. Activated platelets were 7.8 ± 3.6% in Sham, 22 ± 6% in CLP and significantly decreased to 14.5 ± 0.6% in CLP + CLOP (n = 8–10/group, p < 0.05). NLRP3 inflammasome assembly was inhibited in platelets of CLP + CLOP animals vs. CLP. Significant increases in plasma and kidney IL-1β and IL-18 in response to CLP were decreased with Clopidogrel treatment. Renal injury, but not lung histology or renal function was improved in CLP + CLOP vs. CLP. These data provide evidence that activated platelets may contribute to sepsis-induced renal injury, possibly via NLRP3 activation in platelets. Platelets may be a therapeutic target to decrease renal injury in septic patients.
Highlights
Sepsis is a life-threatening dysregulated host inflammatory response to an infectious agent [1] and one of the leading causes of death in the world
There is a need for the identification of novel therapy that may modulate inflammatory response and decrease mortality
Platelets have been postulated to have a role in immunomodulation
Summary
Sepsis is a life-threatening dysregulated host inflammatory response to an infectious agent [1] and one of the leading causes of death in the world. Increasing number of organs involved in sepsis is associated with increased mortality [6]. Thrombocytopenia is frequently seen in sepsis an thought to occur due to platelet activation and consumption; its role in the ease process remains unclear. Thrombocytopenia is associated with developmen (multi-organ failure) MOF and increased 90 day mortality [10,11,12,13,14]. MTherdomiabtoecdytcolpeeanviaaigsefreaqnudenatlcytisveeantiionnseopsfisILan-1dBis athnodugIhLt-18 and beetno oimccuprlidcuaetetodpilnatethleet apcatitvhaotigonenanesdiscoonfsuinmfplatimonm; haotwoervyedr, istseraosle ipnrtohceedsisseassleikperoa- sthma Parckeisns sreomna’sin[s1u6n]c, lienarf.laTmhrommabtoocryytobpoenwiaeilsdasissoecaisateed[1w7i]thadnedvesleoppmsiesn[t1o8f](.mIunlhti-iobrigtiaonn of NL iinnfjulfocaarofmiynltuhtm[rre1iebi9a)nu–sMflto2eaO3mmto]F.emmaWaanutsdeolstriiehyn-omacrrrvegebseaaplnsypoeindrhnseja9euv0srtioyodbusaieseyseptlnhmysirsoosd.ruhetAgaomlhwiptoaoynnct[ets1intvt0otra–iaat1bilt4oeem]n.dpeoPctrflhhoatathateneetlicesNNttmsiOLvmbDReya-Paylwi3gkbhaeieinicrnaehfnlscapetimplnsattetomeeprglerasptaisrslsoomptmieanairnyedt uiscaecdtiov in p3liantflealmetms ainsomrees(pNoLnRsPe3)t.oNcLeRcPa3l ilsigaactyitoonso-lpicuimncmtuunree s(iCgnLaPlin) garnedcepistoarswshoiccihalteeaddswtoith mul gancaisnpjausrey-1 imnerdeiastpeodnclseeavtaogepaonlydmacitcivroatbioianlosf eILp-s1iBs ainndaIL7-128hanCdLhPas rbaetenmimodpleicl.atIend the pre stuidnyt,hwe peahthyopgeontheseissiozfeidnfltahmamt batloorcykdinisgeapselaptreolceetssaecstilivkaetaiostnhmwait[h15C], lPoaprkidinosognr’esl[(1C6]L, OP) w deciarnseflsaeamsmebmlNyatLhoaRrsyPbb3eoewinnesfllhadomiwsemnastaeos[bo1em7]pearonatdecctstieivvpaestiasiog[an1i8,n]s.rteIsnnehapilsbiiastniiondnduopcfueNdlmLoRrogPna3anirniynfljauinmryjmu[r1ay9so–2imn3e].respon polWyme hiacvroe bpiraelvisoeupsslyisd.emonstrated that NLRP3 inflammasome is activated in platelets in response to cecal ligation-puncture (CLP) and is associated with multi-organ injury in. NLoRfPN3LaRndP3apaonpdtoaspiso-pastososicsia-atesdsoscpiaetcekd-liskpeepckro-ltiekine (pAroSCte)inus(iAngSCim) umsuinngociymtomchuenmocisyttroy.ch* epm
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