Murine Left Pulmonary Hilar Clamp Model of Lung Ischemia Reperfusion Injury

Ischemia reperfusion injury (IRI) during lung transplantation is a major risk factor for post-transplant complications, including primary graft ...

Intravital Two-Photon Microscopy of the Transplanted Mouse Lung

Complications after lung transplantation are largely related to the host immune system responding to the graft. Such immune responses are regulated by ...

Washington University, St. Louis

Washington University in St. Louis

&#xD3D0; &#xB04A;&#xC784;&#xC5C6;&#xC774; &#xC545;&#xC758; &#xC7A0;&#xC7AC;&#xC801;&#xC73C;&#xB85C; &#xC720;&#xD574;&#xD55C; &#xD56D; &#xC6D0;&#xC5D0; &#xB178;&#xCD9C; &#xB41C;,&#xC774; &#xC624;&#xB974;&#xAC04;&#xC5D0; &#xD0C0;&#xACE0; &#xB09C; &#xBC0F; &#xC801;&#xC751;&#xD615; &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC758; &#xCCA0;&#xC800; &#xD55C; &#xC774;&#xD574;&#xC758; &#xBCF8;&#xC9C8;&#xC785;&#xB2C8;&#xB2E4;. &#xC790;&#xAE30; &#xACF5;&#xBA85; &#xC601;&#xC0C1;, &#xC591;&#xC804;&#xC790; &#xBC29;&#xCD9C; &#xB2E8;&#xCE35; &#xCD2C;&#xC601; &#xB4F1;&#xACFC; confocal &#xD604;&#xBBF8;&#xACBD; &#xC774;&#xBBF8;&#xC9D5; modalities &#xB2E4;&#xC591; &#xD55C; &#xBD84;&#xC790; &#xD504;&#xB85C;&#xC138;&#xC2A4;&#xC640; &#xD3D0; &#xD734;&#xB300; &#xC804;&#xD654; &#xC751;&#xB2F5;&#xC5D0; &#xB300; &#xD55C; &#xC6B0;&#xB9AC;&#xC758; &#xC9C0;&#xC2DD;&#xC744; &#xD655;&#xC7A5; &#xD588;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB450; &#xAD11;&#xC790; &#xD604;&#xBBF8;&#xACBD; &#xC2E4;&#xC2DC;&#xAC04;&#xC5D0;&#xC11C; &#xC138;&#xD3EC; &#xC0C1;&#xD638; &#xC791;&#xC6A9;&#xC744; &#xAD00;&#xCC30; &#xD558;&#xAE30; &#xC704;&#xD574; &#xAC15;&#xB825;&#xD55C; &#xB3C4;&#xAD6C;&#xB85C; &#xC9C4;&#xD654; &#xD558; &#xACE0; &#xD604;&#xC800; &#xD558; &#xAC8C; &#xBA74;&#xC5ED; &#xCCB4;&#xACC4;&#xC5D0; &#xB300; &#xD55C; &#xC6B0;&#xB9AC;&#xC758; &#xC774;&#xD574;&#xB97C; &#xD655;&#xC7A5; &#xD588;&#xB2E4;. &#xCD5C;&#xADFC;, &#xB450; &#xAD11;&#xC790; &#xD604;&#xBBF8;&#xACBD; &#xB610;&#xD55C; murine &#xD3D0;&#xC758; &#xC774;&#xBBF8;&#xC9C0;&#xB97C; &#xD65C;&#xC6A9; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xD3D0;&#xC5D0; &#xBA74;&#xC5ED; &#xBC18;&#xC751;&#xC744; &#xB2E4;&#xB978; &#xBE44; &#xB9BC;&#xD504; &#xC870;&#xC9C1;&#xC5D0;&#xC11C; &#xADF8;&#xC640; &#xB2E4;,&#xC774; &#xAE30;&#xC220;&#xC744; &#xAD11;&#xBC94;&#xC704; &#xD55C; &#xD3D0; &#xC9C8;&#xD658;&#xC758; &#xAE30;&#xCD08;&#xAC00; &#xB418;&#xB294; &#xC0DD;&#xBB3C;&#xD559;&#xC758; &#xC6B0;&#xB9AC;&#xC758; &#xC9C0;&#xC2DD;&#xC744; &#xC0AC;&#xC804;&#xC5D0; &#xC704;&#xB300;&#xD55C; &#xC57D;&#xC18D;&#xC744; &#xBCF4;&#xC720; &#xD558;&#xACE0;&#xC788;&#xB2E4;.

&#xB450; &#xAD11;&#xC790; &#xD604;&#xBBF8;&#xACBD; &#xD3D0; &#xC5F0;&#xAD6C;&#xC5D0;.

&#x5982;&#x80BA;&#x65F6;&#x4E0D;&#x65AD;&#x66B4;&#x9732;&#x7ED9;&#x6F5C;&#x5728;&#x6709;&#x6BD2;&#x65E0;&#x6BD2;&#x65E0;&#x5BB3;&#x6297;&#x539F;&#xFF0C;&#x900F;&#x5F7B;&#x5730;&#x4E86;&#x89E3;&#x8FD9;&#x4E00;&#x673A;&#x6784;&#x4E2D;&#x56FA;&#x6709;&#x7684;&#x3001; &#x81EA;&#x9002;&#x5E94;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x662F;&#x81F3;&#x5173;&#x91CD;&#x8981;&#x7684;&#x3002;&#x78C1;&#x5171;&#x632F;&#x6210;&#x50CF;&#x3001; &#x6B63;&#x7535;&#x5B50;&#x53D1;&#x5C04;&#x65AD;&#x5C42;&#x626B;&#x63CF;&#x7B49;&#x5171;&#x805A;&#x7126;&#x663E;&#x5FAE;&#x955C;&#x6210;&#x50CF;&#x65B9;&#x5F0F;&#x6269;&#x5927;&#x4E86;&#x6211;&#x4EEC;&#x5BF9;&#x5404;&#x79CD;&#x5206;&#x5B50;&#x8FC7;&#x7A0B;&#x548C;&#x80BA;&#x4E2D;&#x7684;&#x7EC6;&#x80DE;&#x53CD;&#x5E94;&#x77E5;&#x8BC6;&#x3002;&#x53CC;&#x5149;&#x5B50;&#x663E;&#x5FAE;&#x955C;&#x5DF2;&#x6F14;&#x53D8;&#x6210;&#x5F3A;&#x5927;&#x7684;&#x5DE5;&#x5177;&#xFF0C;&#x4EE5;&#x89C2;&#x5BDF;&#x7EC6;&#x80DE;&#x4E2D;&#x5B9E;&#x65F6;&#x4EA4;&#x4E92;&#x548C;&#x663E;&#x8457;&#x6269;&#x5927;&#x4E86;&#x6211;&#x4EEC;&#x7684;&#x514D;&#x75AB;&#x7CFB;&#x7EDF;&#x7684;&#x7406;&#x89E3;&#x3002;&#x6700;&#x8FD1;&#xFF0C;&#x8FD8;&#x5229;&#x7528;&#x53CC;&#x5149;&#x5B50;&#x663E;&#x5FAE;&#x955C;&#x56FE;&#x50CF;&#x5C0F;&#x9F20;&#x7684;&#x80BA;&#x3002;&#x5982;&#x80BA;&#x5185;&#x7684;&#x514D;&#x75AB;&#x53CD;&#x5E94;&#x4E0D;&#x540C;&#x4E8E;&#x5176;&#x4ED6;&#x975E;&#x6DCB;&#x5DF4;&#x7EC4;&#x7EC7;&#x4E2D;&#xFF0C;&#x8FD9;&#x79CD;&#x6280;&#x672F;&#x5E26;&#x6765;&#x4E86;&#x5DE8;&#x5927;&#x7684;&#x5E0C;&#x671B;&#xFF0C;&#x63A8;&#x52A8;&#x6211;&#x4EEC;&#x5BF9;&#x751F;&#x7269;&#x5B66;&#x7684;&#x57FA;&#x7840;&#x5E7F;&#x6CDB;&#x7684;&#x80BA;&#x75BE;&#x75C5;&#x7684;&#x77E5;&#x8BC6;&#x3002;

&#x53CC;&#x5149;&#x5B50;&#x663E;&#x5FAE;&#x955C;&#x5728;&#x80BA;&#x7814;&#x7A76;&#x4E2D;&#x3002;

As the lung is constantly exposed to both innocuous and potentially noxious antigens, a thorough understanding of both innate and adaptive immune responses in this organ is of the essence. Imaging modalities such as magnetic resonance imaging, positron emission tomography, and confocal microscopy have expanded our knowledge about various molecular processes and cellular responses in the lung. Two-photon microscopy has evolved into a powerful tool to observe cellular interactions in real time and has markedly expanded our understanding of the immune system. Recently, two-photon microscopy has also been utilized to image the murine lung. As immune responses in the lung differ from those in other non-lymphoid tissues, this technique holds great promise to advance our knowledge of the biology that underlies a wide spectrum of pulmonary diseases.

Two-photon microscopy in pulmonary research.

Comme le poumon est constamment expos&#xE9;e &#xE0; des antig&#xE8;nes &#xE0; la fois anodins et potentiellement nocive, une connaissance approfondie des deux inn&#xE9;es et adaptatives des r&#xE9;ponses immunitaires dans cet organe est de l&#x26;#39;essence. Modalit&#xE9;s d&#x26;#39;imagerie telles que l&#x26;#39;imagerie par r&#xE9;sonance magn&#xE9;tique, tomographie par &#xE9;mission de positons et la microscopie confocale ont &#xE9;largi nos connaissances sur les diff&#xE9;rents processus mol&#xE9;culaires et les r&#xE9;ponses cellulaires dans le poumon. Microscopie &#xE0; deux photons a &#xE9;volu&#xE9; pour devenir un outil puissant pour observer les interactions cellulaires en temps r&#xE9;el et a nettement &#xE9;largi notre compr&#xE9;hension du syst&#xE8;me immunitaire. R&#xE9;cemment, microscopie &#xE0; deux photons a &#xE9;galement &#xE9;t&#xE9; utilis&#xE9;e pour l&#x26;#39;image du poumon murin. Les r&#xE9;ponses immunitaires dans les poumons diff&#xE8;rent de ceux dans d&#x26;#39;autres tissus non lympho&#xEF;des, cette technique est tr&#xE8;s prometteuse pour faire avancer notre connaissance de la biologie qui sous-tend un large spectre de maladies pulmonaires.

Microscopie &#xE0; deux photons dans la recherche pulmonaire

Wie die Lunge st&auml;ndig sowohl harmlose als auch potenziell sch&auml;dliche Antigene ausgesetzt ist, ist ein gr&uuml;ndliches Verst&auml;ndnis sowohl angeborene und adaptive Immunantworten in dieses Organ von entscheidender Bedeutung. Bildgebung Modalit&auml;ten wie Magnetresonanztomographie, Positronen-Emissions-Tomographie und konfokale Mikroskopie haben unser Wissen &uuml;ber die verschiedenen molekularen Prozesse und zellul&auml;re Reaktionen in der Lunge erweitert. Zwei-Photonen-Mikroskopie entwickelte sich zu einem m&auml;chtigen Werkzeug, zellul&auml;re Interaktionen in Echtzeit zu beobachten und hat unser Verst&auml;ndnis des Immunsystems deutlich erweitert. Zwei-Photonen-Mikroskopie ist in letzter Zeit auch verwandt worden, um das murine Lung Bild. Wie Immunantworten der Lunge von denen in anderen nicht-lymphatischen Geweben unterscheiden, vielversprechend diese Technik sehr, unser Wissen &uuml;ber die Biologie zu f&ouml;rdern, die ein breites Spektrum von Lungenerkrankungen zugrunde liegt.

Zwei-Photonen-Mikroskopie in der pulmonalen Forschung.

Come il polmone &egrave; costantemente esposti agli antigeni innocui e potenzialmente nocivi, una conoscenza approfondita della risposta immunitaria innata e adattiva in questo organo &egrave; dell&#39;essenza. Le modalit&agrave; di imaging come la risonanza magnetica, tomografia ad emissione di positroni e microscopia confocale hanno ampliato la nostra conoscenza sui vari processi molecolari e cellulari risposte nel polmone. Microscopia del due-fotone si &egrave; evoluto in un potente strumento per osservare le interazioni cellulari in tempo reale e ha notevolmente ampliato la nostra comprensione del sistema immunitario. Recentemente, microscopia del due-fotone &egrave; stata utilizzata anche per il polmone murino di immagine. Come risposta immunitaria nel polmone differiscono da quelli in altri tessuti non linfoidi, questa tecnica molto promettente per far progredire la nostra conoscenza della biologia che sottende un ampio spettro di malattie polmonari.

Microscopia del due-fotone nella ricerca polmonare.

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&#x80BA;&#x7814;&#x7A76;&#x306B;&#x304A;&#x3051;&#x308B;&#x4E8C;&#x5149;&#x5B50;&#x9855;&#x5FAE;&#x93E1;

A medida que el pulm&#xF3;n est&#xE1; constantemente expuesto a los ant&#xED;genos, tanto inocuas y nocivas potencialmente, un profundo conocimiento tanto de las respuestas inmune innata y adaptativa en este &#xF3;rgano es de la esencia. Modalidades de imagen como la resonancia magn&#xE9;tica, tomograf&#xED;a por emisi&#xF3;n de positrones, y la microscop&#xED;a confocal se han ampliado nuestros conocimientos sobre los diversos procesos moleculares y las respuestas celulares en el pulm&#xF3;n. Microscopio de dos fotones se ha convertido en una poderosa herramienta para observar las interacciones celulares en tiempo real y se ha ampliado notablemente nuestra comprensi&#xF3;n del sistema inmunitario. Recientemente, dos fotones de microscop&#xED;a tambi&#xE9;n ha sido utilizada para la imagen del pulm&#xF3;n murino. Como las respuestas inmunes en el pulm&#xF3;n difieren de las de otros tejidos no linfoides, esta t&#xE9;cnica es muy prometedora para hacer avanzar nuestro conocimiento de la biolog&#xED;a que subyace en un amplio espectro de enfermedades pulmonares.

Dos fotones de Microscop&#xED;a de Investigaci&#xF3;n Pulmonar

&#x6D3B;&#x5316;&#x7684; T &#x6DCB;&#x5DF4;&#x7EC6;&#x80DE;&#x5728;&#x80BA;&#x79FB;&#x690D;&#x6392;&#x65A5;&#x53CD;&#x5E94;&#x8FC7;&#x7A0B;&#x5177;&#x6709;&#x4E30;&#x5BCC;&#x7684;&#x6C14;&#x9053;&#x3002;&#x5B83;&#x57FA;&#x4E8E;&#x547C;&#x5438;&#x9053;&#x75C5;&#x6BD2;&#x7684;&#x7814;&#x7A76;&#xFF0C;&#x662F;&#x62DB;&#x8058;&#x7684;&#x5F53;&#x524D;&#x7684;&#x8303;&#x5F0F;&#xFF0C;T &#x7EC6;&#x80DE;&#x4E0D;&#x80FD;&#x5206;&#x88C2;&#x4E2D;&#x6C14;&#x9053;&#xFF0C;&#x800C;&#x4E14;&#x4ED6;&#x4EEC;&#x79EF;&#x7D2F;&#x5728;&#x7BA1;&#x8154;&#x4E2D;&#x7684;&#x547C;&#x5438;&#x9053;&#x75BE;&#x75C5;&#x662F;&#x62DB;&#x8058;&#x7684;&#x4E13;&#x5C5E;&#x7684;&#x4ECE;&#x5176;&#x4ED6;&#x7AD9;&#x70B9;&#xFF0C;&#x5982;&#x7EB5;&#x9694;&#x6DCB;&#x5DF4;&#x7ED3;&#x7ED3;&#x679C;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x663E;&#x793A; CD8(+) T &#x7EC6;&#x80DE;&#x7684;&#x6FC0;&#x6D3B;&#x548C;&#x589E;&#x6B96;&#x53EF;&#x4EE5;&#x53D1;&#x751F;&#x5728;&#x6C14;&#x7BA1;&#x80BA;&#x79FB;&#x690D;&#x672F;&#x540E;&#x3002;&#x6211;&#x4EEC;&#x8FD8;&#x8868;&#x660E;&#x8BE5;&#x6C14;&#x9053;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x8868;&#x793A;&#x4E3B;&#x8981;&#x7EC4;&#x7EC7;&#x76F8;&#x5BB9;&#x6027;&#x7C7B;&#x6211;&#x4E3B;&#x8981;&#x662F;&#x5728;&#x5FC3;&#x5C16;&#x4E0A;&#x4E24;&#x8005;&#x4F53;&#x5916;&#x7684;&#x8868;&#x9762;&#x5E76;&#x5728;&#x4F53;&#x5185;&#x53CA;&#x4FEE; CD8(+) T &#x7EC6;&#x80DE;&#x53CD;&#x5E94;&#x4E24;&#x6781;&#x5316;&#x7684;&#x65B9;&#x5F0F;&#xFF0C;&#x6709;&#x5229;&#x4E8E;&#x9C81;&#x7C73;&#x90A3;&#x6FC0;&#x6D3B;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x6570;&#x636E;&#x6807;&#x8BC6;&#x552F;&#x4E00;&#x7684;&#x7AD9;&#x70B9;&#x4E3A;&#x80BA;&#x79FB;&#x690D;&#x540E;&#x7684; CD8(+) T &#x7EC6;&#x80DE;&#x6FC0;&#x6D3B;&#x548C;&#x5EFA;&#x8BAE;&#x51CF;&#x8F7B;&#x8FD9;&#x4E9B;&#x53CD;&#x5E94;&#x53EF;&#x80FD;&#x63D0;&#x4F9B;&#x4E34;&#x5E8A;&#x76F8;&#x5173;&#x7684;&#x76EE;&#x6807;&#x3002;

&#x6C14;&#x9053;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x4E24;&#x6781;&#x5206;&#x5316;&#x7684;&#x6297;&#x539F;&#x4ECB;&#x7ECD;&#x6709;&#x52A9;&#x4E8E;&#x76F4;&#x63A5; CD8 + T &#x7EC6;&#x80DE;&#x6D3B;&#x5316;&#x7684;&#x6C14;&#x9053;&#x3002;

Activated T lymphocytes are abundant in the airway during lung allograft rejection. Based on respiratory viral studies, it is the current paradigm that T cells cannot divide in the airway, and that their accumulation in the lumen of the respiratory tract is the exclusive result of recruitment from other sites, such as mediastinal lymph nodes. Here, we show that CD8(+) T cell activation and proliferation can occur in the airway after orthotopic lung transplantation. We also demonstrate that airway epithelium expresses major histocompatibility class I predominantly on the apical surface, both in vitro and in vivo, and initiates CD8(+) T cell responses in a polarized fashion, favoring luminal activation. Our data identify a unique site for CD8(+) T cell activation after lung transplantation, and suggest that attenuating these responses may provide a clinically relevant target.

Polarized alloantigen presentation by airway epithelial cells contributes to direct CD8+ T cell activation in the airway.

Lymphocytes T activ&#xE9;s sont abondants dans les voies respiratoires lors de rejet d&#x26;#39;allogreffe du poumon. Bas&#xE9; sur des &#xE9;tudes respiratoires virales, il est le paradigme actuel que les cellules T ne peuvent pas se diviser dans les voies respiratoires, et que leur accumulation dans la lumi&#xE8;re de l&#x26;#39;appareil respiratoire est le r&#xE9;sultat exclusif de recrutement &#xE0; partir d&#x26;#39;autres sites, tels que les ganglions lymphatiques m&#xE9;diastinaux. Ici, nous montrons que CD8 (+) l&#x26;#39;activation des cellules T et la prolif&#xE9;ration peut se produire dans les voies respiratoires apr&#xE8;s une transplantation pulmonaire orthotopique. Nous d&#xE9;montrons &#xE9;galement que l&#x26;#39;&#xE9;pith&#xE9;lium respiratoire exprime la classe majeur d&#x26;#39;histocompatibilit&#xE9; I principalement sur la surface apicale, &#xE0; la fois in vitro et in vivo, et initie CD8 (+) les r&#xE9;ponses des cellules T dans un mode polaris&#xE9;, en favorisant l&#x26;#39;activation luminale. Nos donn&#xE9;es d&#x26;#39;identifier un site unique pour les CD8 (+) l&#x26;#39;activation des lymphocytes T apr&#xE8;s une transplantation pulmonaire, et sugg&#xE8;rent que ces r&#xE9;ponses peuvent att&#xE9;nuer fournir une cible cliniquement pertinente.

Pr&#xE9;sentation alloantig&#xE8;ne polaris&#xE9;e par les cellules &#xE9;pith&#xE9;liales des voies a&#xE9;riennes contribue &#xE0; Direct CD8 + activation des lymphocytes T dans les voies respiratoires

Aktivierte T-Lymphozyten sind reichlich in die Atemwege w&auml;hrend der Lunge Allograft Ablehnung. Auf der Grundlage der Atemwege viraler Studies ist es das aktuelle Paradigma, die T-Zellen k&ouml;nnen nicht teilen, in die Atemwege, und ihre Ansammlung in das Lumen der Atemwege ist das exklusive Ergebnis der Rekrutierung von anderen Websites, z. B. Mediastinum Lymphknoten. Hier zeigen wir, dass CD8(+) T Zelle Aktivierung und Vermehrung in die Atemwege nach Lungentransplantation Orthotopic auftreten k&ouml;nnen. Wir zeigen auch, dass Airway-Epithel dr&uuml;ckt major Histocompatibility Klasse ich &uuml;berwiegend auf die apikale Oberfl&auml;che, sowohl in-vitro und in Vivo und initiiert CD8(+) T Zelle Antworten in eine polarisierte Mode, Beg&uuml;nstigung luminalen Aktivierung. Unsere Daten identifizieren eine einzigartige Website f&uuml;r CD8(+) T-ZELLAKTIVIERUNG nach Lungentransplantation und schlagen Sie diese Antworten abgeschw&auml;cht k&ouml;nnte ein klinisch relevante Ziel darstellen.

Polarisierte Alloantigen-Pr&auml;sentation von Epithelzellen der Atemwege tr&auml;gt zur direkten CD8 + T-ZELLAKTIVIERUNG in die Atemwege.

Linfociti T attivati sono abbondanti nelle vie aeree durante il rifiuto del allograft del polmone. Sulla base di studi virali respiratorie &egrave; il paradigma corrente che le cellule T non possono dividere nelle vie aeree, e che loro accumulo nel lume delle vie respiratorie &egrave; il risultato esclusivo di reclutamento da altri siti, come ad esempio i linfonodi mediastinici. Mostriamo qui, proliferazione e attivazione delle cellule T cellule pu&ograve; verificarsi nelle vie aeree dopo trapianto ortotopico del polmone. Abbiamo anche dimostrare che epitelio respiratorio esprime classe di istocompatibilit&agrave; prevalentemente sull&#39;apicale superficie, sia in vitro e in vivo e iniziati cellule T cell responses in modo polarizzato, favorendo l&#39;attivazione del lume. I nostri dati individuare un unico sito per l&#39;attivazione delle cellule T cellule dopo trapianto di polmone e suggeriscono che attenuare queste risposte pu&ograve; fornire un bersaglio clinicamente rilevante.

Presentazione alloantigen polarizzata dalle cellule epiteliali delle vie aeree contribuisce all&#39;attivazione delle cellule T CD8 + diretta nelle vie aeree.

&#x6D3B;&#x6027;&#x5316;T&#x30EA;&#x30F3;&#x30D1;&#x7403;&#x304C;&#x80BA;&#x306E;&#x540C;&#x7A2E;&#x79FB;&#x690D;&#x7247;&#x62D2;&#x7D76;&#x53CD;&#x5FDC;&#x6642;&#x306E;&#x6C17;&#x9053;&#x306B;&#x8C4A;&#x5BCC;&#x306B;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x547C;&#x5438;&#x5668;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x7814;&#x7A76;&#x306B;&#x57FA;&#x3065;&#x3044;&#x3066;&#x3001;&#x305D;&#x308C;&#x304C;T&#x7D30;&#x80DE;&#x304C;&#x6C17;&#x9053;&#x306B;&#x5206;&#x5272;&#x3059;&#x308B;&#x3053;&#x3068;&#x306F;&#x3067;&#x304D;&#x307E;&#x305B;&#x3093;&#x73FE;&#x5728;&#x306E;&#x30D1;&#x30E9;&#x30C0;&#x30A4;&#x30E0;&#x3067;&#x3042;&#x308A;&#x3001;&#x6C17;&#x9053;&#x306E;&#x5185;&#x8154;&#x3067;&#x306E;&#x84C4;&#x7A4D;&#x306F;&#x3001;&#x3053;&#x306E;&#x3088;&#x3046;&#x306A;&#x7E26;&#x9694;&#x30EA;&#x30F3;&#x30D1;&#x7BC0;&#x306A;&#x3069;&#x4ED6;&#x306E;&#x30B5;&#x30A4;&#x30C8;&#x304B;&#x3089;&#x306E;&#x52DF;&#x96C6;&#x306E;&#x6392;&#x4ED6;&#x7684;&#x306A;&#x7D50;&#x679C;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;CD8&#xFF08;+&#xFF09;T&#x7D30;&#x80DE;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;&#x5897;&#x6B96;&#x304C;&#x540C;&#x6240;&#x6027;&#x80BA;&#x79FB;&#x690D;&#x5F8C;&#x306E;&#x6C17;&#x9053;&#x306B;&#x767A;&#x751F;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306F;&#x307E;&#x305F;&#x3001;&#x6C17;&#x9053;&#x4E0A;&#x76AE;&#x306E;&#x7BA1;&#x8154;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x652F;&#x6301;&#x3059;&#x308B;&#x3001;&#x504F;&#x5149;&#x65B9;&#x5F0F;&#x3067;&#x306E;T&#x7D30;&#x80DE;&#x5FDC;&#x7B54;&#x3092;in vitro&#x304A;&#x3088;&#x3073;in vivo&#x306E;&#x4E21;&#x65B9;&#x3067;&#x3001;&#x9802;&#x7AEF;&#x90E8;&#x8868;&#x9762;&#x306B;&#x306F;&#x4E3B;&#x306B;&#x4E3B;&#x8981;&#x7D44;&#x7E54;&#x9069;&#x5408;&#x6027;&#x30AF;&#x30E9;&#x30B9;I&#x3092;&#x767A;&#x73FE;&#x3057;&#x3001;CD8&#xFF08;+&#xFF09;&#x3092;&#x958B;&#x59CB;&#x3057;&#x307E;&#x3059;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;CD8&#xFF08;+&#xFF09;&#x80BA;&#x79FB;&#x690D;&#x5F8C;&#x306E;T&#x7D30;&#x80DE;&#x6D3B;&#x6027;&#x5316;&#x306E;&#x305F;&#x3081;&#x306E;&#x30E6;&#x30CB;&#x30FC;&#x30AF;&#x306A;&#x30B5;&#x30A4;&#x30C8;&#x3092;&#x8B58;&#x5225;&#x3057;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x5FDC;&#x7B54;&#x3092;&#x6E1B;&#x8870;&#x3055;&#x305B;&#x308B;&#x3053;&#x3068;&#x306F;&#x81E8;&#x5E8A;&#x7684;&#x306B;&#x95A2;&#x9023;&#x3059;&#x308B;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x6C17;&#x9053;&#x4E0A;&#x76AE;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x504F;&#x30A2;&#x30ED;&#x6297;&#x539F;&#x63D0;&#x793A;&#x306F;&#x3001;&#x6C17;&#x9053;&#x306B;&#x304A;&#x3051;&#x308B;CD8 + T&#x7D30;&#x80DE;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3092;&#x76F4;&#x63A5;&#x306B;&#x8CA2;&#x732E;&#x3059;&#x308B;

&#xD65C;&#xC131;&#xD654; &#xB41C; T &#xC138;&#xD3EC;&#xB294; &#xD3D0; allograft &#xAC70;&#xBD80; &#xD558;&#xB294; &#xB3D9;&#xC548; &#xAE30;&#xB3C4;&#xC5D0; &#xD48D;&#xBD80;. &#xD638;&#xD761;&#xAE30; &#xBC14;&#xC774;&#xB7EC;&#xC2A4; &#xC5F0;&#xAD6C;&#xB97C; &#xBC14;&#xD0D5;&#xC73C;&#xB85C;, &#xADF8;&#xAC83;&#xC740; T &#xC138;&#xD3EC;&#xB294; &#xAE30;&#xB3C4;&#xC5D0;&#xC11C; &#xB098;&#xB20C; &#xC218; &#xC5C6;&#xC2B5;&#xB2C8;&#xB2E4; &#xADF8;&#xB9AC;&#xACE0; &#xD638;&#xD761;&#xAE30;&#xC758; &#xB8E8;&#xBA58;&#xC5D0; &#xC788;&#xB294; &#xADF8;&#xB4E4;&#xC758; &#xCD95;&#xC801;&#xC740; mediastinal &#xB9BC;&#xD504;&#xC808; &#xB4F1; &#xB2E4;&#xB978; &#xC0AC;&#xC774;&#xD2B8;&#xC5D0;&#xC11C; &#xBAA8;&#xC9D1;&#xC758; &#xB3C5;&#xC810;&#xC801;&#xC778; &#xACB0;&#xACFC; &#xD604;&#xC7AC; &#xD328;&#xB7EC;&#xB2E4;&#xC784; &#xC774;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC; CD8(+) T &#xC138;&#xD3EC; &#xD65C;&#xC131;&#xD654;&#xC640; &#xD655;&#xC0B0; &#xAE30;&#xB3C4;&#xC5D0;&#xC11C; orthotopic &#xD3D0; &#xC774;&#xC2DD; &#xD6C4; &#xBC1C;&#xC0DD;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xB294; &#xB610;&#xD55C; &#xADF8; &#xAE30;&#xB3C4; &#xC0C1;&#xD53C; &#xD45C;&#xD604; &#xC911;&#xC694; &#xD55C; &#xC870;&#xC9C1; &#xC801;&#xD569;&#xC131; &#xD074;&#xB798;&#xC2A4; &#xB098;&#xB294; &#xD600;&#xB05D;&#xC5D0; &#xC8FC;&#xB85C; &#xD45C;&#xBA74;, &#xBAA8;&#xB450; &#xCCB4; &#xC678; &#xBC0F; vivo &#xBC0F; &#xCD08;&#xAE30;&#xD654; CD8(+) T &#xC140; &#xD3B8;&#xAD11; &#xBC29;&#xC2DD;&#xC5D0;&#xC11C; &#xC751;&#xB2F5; luminal &#xD65C;&#xC131;&#xD654;&#xB97C; &#xC560; &#xC6A9; &#xD558; &#xACE0; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xB370;&#xC774;&#xD130; &#xD3D0; &#xC774;&#xC2DD; &#xD6C4; CD8(+) T &#xC138;&#xD3EC; &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xB300; &#xD55C; &#xACE0;&#xC720;&#xC758; &#xC0AC;&#xC774;&#xD2B8;&#xB97C; &#xC2DD;&#xBCC4; &#xD558; &#xACE0; &#xC774;&#xB7EC;&#xD55C; &#xC751;&#xB2F5; &#xAC10;&#xC1E0; &#xC784;&#xC0C1; &#xAD00;&#xB828; &#xB300;&#xC0C1;&#xC744; &#xC81C;&#xACF5;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xAC83;&#xC774; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xAE30;&#xB3C4; &#xC0C1;&#xD53C; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xD3B8;&#xAD11;&#xB41C; alloantigen &#xD504;&#xB808; &#xC820; &#xD14C;&#xC774; &#xC158; &#xAE30;&#xB3C4;&#xC5D0; &#xC9C1;&#xC811; CD8 + T &#xC138;&#xD3EC; &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xAE30;&#xC5EC; &#xD55C;&#xB2E4;.

Los linfocitos T activados son abundantes en las v&#xED;as respiratorias durante el rechazo del injerto pulmonar. Con base en los estudios de las v&#xED;as respiratorias virales, es el paradigma actual que las c&#xE9;lulas T no se puede dividir en las v&#xED;as respiratorias, y que su acumulaci&#xF3;n en el lumen del tracto respiratorio es el resultado exclusivo de la contrataci&#xF3;n de otros sitios, como los ganglios linf&#xE1;ticos del mediastino. Aqu&#xED;, mostramos que la activaci&#xF3;n de c&#xE9;lulas CD8 (+) de las c&#xE9;lulas T y la proliferaci&#xF3;n puede ocurrir en la v&#xED;a a&#xE9;rea despu&#xE9;s de un trasplante de pulm&#xF3;n ortot&#xF3;pico. Tambi&#xE9;n demuestran que las v&#xED;as respiratorias epitelio expresa clase principal de histocompatibilidad I predominantemente en la superficie apical, tanto in vitro como in vivo, e inicia CD8 (+) respuestas de c&#xE9;lulas T de una manera polarizada, favoreciendo la activaci&#xF3;n luminal. Nuestros datos identificar un sitio &#xFA;nico para CD8 (+) la activaci&#xF3;n de c&#xE9;lulas T despu&#xE9;s del trasplante pulmonar, y sugieren que la atenuaci&#xF3;n de estas respuestas puede proporcionar un objetivo cl&#xED;nicamente relevante.

Presentaci&#xF3;n aloant&#xED;geno polarizada por las c&#xE9;lulas epiteliales respiratorias contribuye a la activaci&#xF3;n directa CD8 + de c&#xE9;lulas T en las v&#xED;as respiratorias

Early immune responses are important in shaping long-term outcomes of human lung transplants. To examine the role of early immune responses in lung rejection and acceptance, we developed a method to retransplant mouse lungs. Retransplantation into T-cell-deficient hosts showed that for lungs and hearts alloimmune responses occurring within 72 h of transplantation are reversible. In contrast to hearts, a 72-h period of immunosuppression with costimulation blockade in primary allogeneic recipients suffices to prevent rejection of lungs upon retransplantation into untreated allogeneic hosts. Long-term lung acceptance is associated with induction of bronchus-associated lymphoid tissue, where Foxp3(+) cells accumulate and recipient T cells interact with CD11c(+) dendritic cells. Acceptance of retransplanted lung allografts is abrogated by treatment of immunosuppressed primary recipients with anti-CD25 antibodies. Thus, events contributing to lung transplant acceptance are established early in the graft and induction of bronchus-associated lymphoid tissue can be associated with an immune quiescent state.

Lung transplant acceptance is facilitated by early events in the graft and is associated with lymphoid neogenesis.

Two-photon intravital microscopy has substantially broadened our understanding of tissue- and organ-specific differences in the regulation of inflammatory responses. However, little is known about the dynamic regulation of leukocyte recruitment into inflamed heart tissue, largely due to technical difficulties inherent in imaging moving tissue. Here, we report a method for imaging beating murine hearts using intravital 2-photon microscopy. Using this method, we visualized neutrophil trafficking at baseline and during inflammation. Ischemia reperfusion injury induced by transplantation or transient coronary artery ligation led to recruitment of neutrophils to the heart, their extravasation from coronary veins, and infiltration of the myocardium where they formed large clusters. Grafting hearts containing mutant ICAM-1, a ligand important for neutrophil recruitment, reduced the crawling velocities of neutrophils within vessels, and markedly inhibited their extravasation. Similar impairment was seen with the inhibition of Mac-1, a receptor for ICAM-1. Blockade of LFA-1, another ICAM-1 receptor, prevented neutrophil adherence to endothelium and extravasation in heart grafts. As inflammatory responses in the heart are of great relevance to public health, this imaging approach holds promise for studying cardiac-specific mechanisms of leukocyte recruitment and identifying novel therapeutic targets for treating heart disease.

Intravital 2-photon imaging of leukocyte trafficking in beating heart.

The mechanisms that link bacterial infection to solid organ rejection remain unclear. In this study, we show that following the establishment of lung allograft acceptance in mice, Pseudomonas aeruginosa airway infection induces a G-CSF-dependent neutrophilia that stimulates acute rejection. Graft-infiltrating neutrophils sharply upregulate the B7 molecules CD80 and CD86, but they do not express CD40 or MHC class II in response to P. aeruginosa infection. Neutrophil B7 promotes naive CD4(+) T cell activation and intragraft IL-2(+), IFN-γ(+), and IL-17(+) T lymphocyte accumulation. Intravital two-photon microscopy reveals direct interactions between neutrophils and CD4(+) T cells within pulmonary allografts. Importantly, lung rejection in P. aeruginosa-infected recipients is triggered by CD80/86 on neutrophils and can be prevented by B7 blockade without affecting clearance of this pathogen. These data show that neutrophils enhance T cell activation through B7 trans-costimulation and suggest that inhibiting neutrophil-mediated alloimmunity can be accomplished without compromising bacterial immune surveillance.

Cutting edge: Pseudomonas aeruginosa abolishes established lung transplant tolerance by stimulating B7 expression on neutrophils.

Lung transplantation is a life saving treatment for end stage pulmonary diseases. The development and refinement of this therapy required the utilization of various animal models, without which this procedure would not have become a clinical reality. Canine models were critical in the initial breakthroughs in surgical technique and immunosuppressive regimens, which directly led to the first successful human lung transplantation. Orthotopic lung transplant models in the rat provided a platform for more detailed investigation of immune responses to pulmonary grafts. Investigation of chronic rejection of lungs has significantly been advanced through the use of mouse tracheal transplant experiments. And finally, the advent of orthotopic, vascularized lung transplantation in the mouse opened the door to the use of genetic and molecular tools that are necessary for the rigorous mechanistic study of alloimmune and non-alloimmune factors contributing to lung graft failure. Taken together, animal models will continue to be a cornerstone in the advancement of clinical success in lung transplantation.

Experimental models of lung transplantation.

Microsurgical cuff techniques for orthotopic vascularized murine lung transplantation have allowed for the design of studies that examine mechanisms contributing to the high failure rate of pulmonary grafts. Here, we provide a detailed technical description of orthotopic lung retransplantation in mice, which we have thus far performed in 144 animals. The total time of the retransplantation procedure is approximately 55 minutes, 20 minutes for donor harvest and 35 minutes for the implantation, with a success rate exceeding 95%. The mouse lung retransplantation model represents a novel and powerful tool to examine how cells that reside in or infiltrate pulmonary grafts shape immune responses. 

Surgical technique for lung retransplantation in the mouse.

Tertiary lymphoid organs are aggregates of immune and stromal cells including high endothelial venules and lymphatic vessels that resemble secondary lymphoid organs and can be induced at nonlymphoid sites during inflammation. The function of lymphatic vessels within tertiary lymphoid organs remains poorly understood. During lung transplant tolerance, Foxp3+ cells accumulate in tertiary lymphoid organs that are induced within the pulmonary grafts and are critical for the local downregulation of alloimmune responses. Here, we showed that tolerant lung allografts could induce and maintain tolerance of heterotopic donor-matched hearts through pathways that were dependent on the continued presence of the transplanted lung. Using lung retransplantation, we showed that Foxp3+ cells egressed from tolerant lung allografts via lymphatics and were recruited into donor-matched heart allografts. Indeed, survival of the heart allografts was dependent on lymphatic drainage from the tolerant lung allograft to the periphery. Thus, our work indicates that cellular trafficking from tertiary lymphoid organs regulates immune responses in the periphery. We propose that these findings have important implications for a variety of disease processes that are associated with the induction of tertiary lymphoid organs.

Lymphatic drainage from bronchus-associated lymphoid tissue in tolerant lung allografts promotes peripheral tolerance.

Patient-reported outcomes are critical for delivering high-quality surgical care, yet they are seldom collected in routine clinical practice. The objective of this quality improvement study was to improve routine patient-reported outcomes collection in a thoracic surgery clinic.

Routine Collection of Patient-Reported Outcomes in Thoracic Surgery: A Quality Improvement Study.

Dissemination and implementation (D&I) science is the practice of taking evidence-based interventions and sustainably incorporating them into routine clinical practice. As a relatively young field, D&I techniques are underutilized in cardiothoracic surgery. This review offers an overview of D&I science from the context of the cardiothoracic surgeon. First, we provide a general introduction to D&I science and basic terminology that is used in the field. Second, to illustrate D&I techniques in a real-world example, we discuss a case study for implementing lung protective management strategies for lung donor optimization nationally. Finally, we discuss challenges to successful implementation that are unique to cardiothoracic surgery and give several examples of evidence-based interventions that have been poorly implemented into surgical practice. We also provide examples of successful D&I interventions-including deimplementation strategies-from other surgical subspecialties. We hope that this review offers additional tools for cardiothoracic surgeons to explore when introducing evidence-based interventions into routine practice.

Dissemination and Implementation Science in Cardiothoracic Surgery: A Review and Case Study.

Ischemia reperfusion injury represents a common pathological condition that is triggered by the release of endogenous ligands. While neutrophils are known to play a critical role in its pathogenesis, the tissue-specific spatiotemporal regulation of ischemia-reperfusion injury is not understood. Here, using oxidative lipidomics and intravital imaging of transplanted mouse lungs that are subjected to severe ischemia reperfusion injury, we discovered that necroptosis, a nonapoptotic form of cell death, triggers the recruitment of neutrophils. During the initial stages of inflammation, neutrophils traffic predominantly to subpleural vessels, where their aggregation is directed by chemoattractants produced by nonclassical monocytes that are spatially restricted in this vascular compartment. Subsequent neutrophilic disruption of capillaries resulting in vascular leakage is associated with impaired graft function. We found that TLR4 signaling in vascular endothelial cells and downstream NADPH oxidase 4 expression mediate the arrest of neutrophils, a step upstream of their extravasation. Neutrophil extracellular traps formed in injured lungs and their disruption with DNase prevented vascular leakage and ameliorated primary graft dysfunction. Thus, we have uncovered mechanisms that regulate the initial recruitment of neutrophils to injured lungs, which result in selective damage to subpleural pulmonary vessels and primary graft dysfunction. Our findings could lead to the development of new therapeutics that protect lungs from ischemia reperfusion injury.

Necroptosis triggers spatially restricted neutrophil-mediated vascular damage during lung ischemia reperfusion injury.

Multiple stakeholders have advocated for minimum volume standards for complex surgical procedures. The Leapfrog Group recommends that patients with non-small cell lung cancer (NSCLC) receive surgical resection at hospitals that perform at least 40 lung resections annually. However, the cost-effectiveness of this paradigm is unknown.

Ruben G. Nava

Division of Cardiothoracic Surgery

Washington University, St. Louis

Murine Left Pulmonary Hilar Clamp Model of Lung Ischemia Reperfusion Injury

Intravital Two-Photon Microscopy of the Transplanted Mouse Lung

Ruben G. Nava

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Division of Cardiothoracic Surgery

Washington University, St. Louis

Murine Left Pulmonary Hilar Clamp Model of Lung Ischemia Reperfusion Injury

Intravital Two-Photon Microscopy of the Transplanted Mouse Lung

Division of Cardiothoracic Surgery