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Acute Lung Injury (ALI) This Information Is Current As of September 28, 2021 Improved Survival and Reduced Vascular Permeability by Eliminating or Blocking 12/15-Lipoxygenase in Mouse Models of Acute Lung Injury (ALI) This information is current as of September 28, 2021. Alexander Zarbock, Matthew R. DiStasi, Emily Smith, John M. Sanders, Gerhard Kronke, Brian L. Harry, Sibylle von Vietinghoff, Konrad Buscher, Jerry L. Nadler and Klaus Ley J Immunol 2009; 183:4715-4722; Prepublished online 14 September 2009; Downloaded from doi: 10.4049/jimmunol.0802592 http://www.jimmunol.org/content/183/7/4715 http://www.jimmunol.org/ References This article cites 59 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/183/7/4715.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Improved Survival and Reduced Vascular Permeability by Eliminating or Blocking 12/15-Lipoxygenase in Mouse Models of Acute Lung Injury (ALI)1 Alexander Zarbock,2*‡§ Matthew R. DiStasi,§ Emily Smith,* John M. Sanders,* Gerhard Kronke,* Brian L. Harry,* Sibylle von Vietinghoff,§ Konrad Buscher,§ Jerry L. Nadler,*† and Klaus Ley*§ Acute lung injury (ALI) is a prevalent disease associated with high mortality. 12/15-lipoxygenase (12/15-LO) is an enzyme pro- ducing 12-hydroxyeicosatetraenoic acid (HETE) and 15-HETE from arachidonic acid. To test whether 12/15-LO is involved in increasing vascular permeability in the lung, we investigated the role of 12/15-LO in murine models of LPS-induced pulmonary inflammation and clinically relevant acid-induced ALI. The vascular permeability increase upon LPS inhalation was abolished in Downloaded from Alox15؊/؊ mice lacking 12/15-LO and in wild-type mice after pharmacological blockade of 12/15-LO. Alox15؊/؊ mice also showed improved gas exchange, reduced permeability increase, and prolonged survival in the acid-induced ALI model. Bone marrow chimeras and reconstitution experiments revealed that 12-HETE produced by hematopoietic cells regulates vascular permeability through a CXCR2-dependent mechanism. Our findings suggest that 12/15-LO-derived 12-HETE is a key mediator of vascular permeability in acute lung injury. The Journal of Immunology, 2009, 183: 4715–4722. http://www.jimmunol.org/ cute lung injury (ALI)3 is a common disease with an in- nant barrier to prevent movement of molecules across the blood cidence of 79 per 100,000 person-years in the United States vessel wall (5, 8). Under physiological conditions, vascular per- A (1). Despite improved treatment, this disease is associated meability is tightly regulated. In response to different inflammatory with a high mortality of up to 38%. The 3.6 million hospital days per stimuli, the increase of endothelial permeability is regulated by year associated with ALI have a large impact on the health system (1). several receptors, including the chemokine receptor CXCR2, the ALI has intrapulmonary causes such as pneumonia and aspiration of adenosine receptor A2B, and the thromboxane A2 receptor (7, 9, gastric content, and extrapulmonary causes such as sepsis and massive 10). Sphingosine 1-phosphate, a biologically active lipid, also reg- transfusion. In ALI, the alveolar capillary and epithelial membranes ulates endothelial cell activation and vascular permeability by by guest on September 28, 2021 are damaged by infiltration of polymorphonuclear neutrophils and binding to several G protein-coupled receptors (11, 12). monocytes, leading to leakage of protein-rich edema fluid into the In addition to chemokines, lipid mediators play a role in pul- alveolar space, formation of hyaline membranes, and impaired gas monary inflammation (13–15). Lipoxygenases incorporate oxygen exchange (2). Currently available treatments are only marginally ef- into unsaturated fatty acids and are named according to the posi- fective (3). tion of the carbon double bonds they oxidize (16). Humans and Tissue injury of many etiologies changes vascular barrier func- rabbits express 15-lipoxygenase (15-LO) (17, 18), whereas pigs, tion and consequently leads to fluid loss, edema, and organ dys- rats, and mice express “leukocyte-type” 12-LO (19) with some function (4–7). The vascular endothelium presents the predomi- 15-LO activity. Mouse leukocyte 12/15-LO is highly related to 15-LO in humans and probably represents the mouse ortholog of human 15-LO (20, 21). 12/15-LO catalysis of arachidonic acid *Robert M. Berne Cardiovascular Research Center and †Internal Medicine, Univer- sity of Virginia, Charlottesville, VA 22908; ‡Department of Anesthesiology and In- yields short-lived peroxidized products, which are reduced or en- tensive Care Medicine, University of Mu¨nster, Mu¨nster, Germany; and §La Jolla zymatically converted to 12-hydroxyeicosatetraenoic acid (12- Institute for Allergy and Immunology, La Jolla, CA 92037 HETE), lipoxins, hepoxilins, and others (22). 12/15-LO mRNA Received for publication August 6, 2008. Accepted for publication August 3, 2009. expression is highest in monocytes and macrophages (23), and The costs of publication of this article were defrayed in part by the payment of page some is found in endothelial cells (24) and other cells. 12-HETE is charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. a proinflammatory chemoattractant for neutrophils (25), regulates 1 This study was supported by Else Kro¨ner-Fresenius-Stiftung (Grant A69/07 to endothelial cell cytoskeleton rearrangement (26), induces cytokine A.Z.), by the German Research Foundation (ZA428/2-1 to A.Z., VI508/1-1 to production (27) and expression of adhesion molecules on endo- S.v.V.), by National Institutes of Health Grant P01 HL 73361 to Joel Linden thelial cells (28), and is involved in chronic inflammatory pro- (project 2 to K.L.), and by National Institutes of Health Grant P01 HL 55798 to Ϫ/Ϫ J.N. (project 4 to K.L.). cesses (23). Alox15 mice were found to be protected from the 2 Address correspondence and reprint requests to Dr. Alexander Zarbock, Depart- development of allergic sensitization and airway inflammation ment of Anesthesiology and Critical Care Medicine, University of Muenster, Al- (29). However, leukotrienes and other lipoxygenases, such as the bert-Schweitzer Strasse 33, 48149 Muenster, Germany. E-mail address: zarbock@ uni-muenster.de 5-LO, are also involved in modulating inflammation. Elimination of 5-LO preserves gas exchange and increases survival in a ven- 3 Abbreviations used in this paper: ALI, acute lung injury; BAL, bronchoalveolar ␣ lavage; CDC, cinnamyl-3,4-dihydroxy- -cyanocinnamate; FiO2, fraction of inspira- tilator-induced lung injury model (30). tory oxygen; HETE, hydroxyeicosatetraenoic acid; LO, lipoxygenase; PaO2, partial The present study was designed to investigate the role of 12/ pressure of arterial oxygen; WT, wild type. 15-LO and 12-HETE on vascular permeability in murine models Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 of LPS-induced pulmonary inflammation and acid-induced lung www.jimmunol.org/cgi/doi/10.4049/jimmunol.0802592 4716 12/15-LIPOXYGENASE IN ACUTE LUNG INJURY injury. To investigate the main source of 12/15-LO relevant to vascular permeability, chimeric mice were generated by bone mar- row transplantation that expressed 12/15-LO in hematopoietic cells, nonhematopoietic cells, both, or neither. To address the mechanism by which 12/15-LO products influence vascular per- meability in ALI, we tested the interaction between 12-HETE and the CXCL1-CXCR2 axis of inflammatory chemokine signaling. Materials and Methods Animals We used 8- to 12-wk-old C57BL/6 mice (The Jackson Laboratory) and Alox15-deficient mice (31) backcrossed to C57BL/6 for at least 10 gener- ations (UVA colony) (32). Furthermore, Cxcr2Ϫ/Ϫ mice (The Jackson Lab- oratory) on the BALB/c background and BALB/c controls were used. Mice were housed in a barrier facility under specific pathogen-free conditions. The Animal Care and Use Committee of the University of Virginia (Char- lottesville) approved all animal experiments. Murine model of LPS-induced pulmonary inflammation and acid-induced ALI Downloaded from LPS from Salmonella enteritidis (500 ␮g/ml; Sigma-Aldrich) was nebu- lized to induce pulmonary inflammation as previously described (33). Briefly, mice were exposed to 30 min of aerosolized LPS or saline aerosol as a control. In some experiments 12/15-LO activity was pharmacologically inhibited by cinnamyl-3,4-dihydroxy-␣-cyanocinnamate (CDC; BIOMOL Interna- tional). Mice were injected 1 h (8 mg/kg, i.p.) before induction of the http://www.jimmunol.org/ pulmonary inflammation. Acid-induced ALI was induced by injection of 2 ␮l/g HCl (pH 1.5) intratracheally, followed by a bolus of air (30 ␮l/g) as previously described (7). Following a tracheotomy, mice were ventilated with a respirator (Mini- Vent, type 845; Hugo Sachs Elektronik) for 2 h (tidal volume, 10 ␮l/g; respiration rate, 140/min; fraction of inspiratory oxygen (FiO2), 0.21). Control animals received saline instead of HCl in the same manner. Pulmonary microvascular permeability We determined pulmonary microvascular permeability in wild-type (WT), by guest on September 28, 2021 Alox15Ϫ/Ϫ, and chimeric mice using the Evans blue dye extravasation tech- nique as described previously (10).
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  • CAF Secreted Mir-522 Suppresses Ferroptosis and Promotes Acquired Chemo-Resistance in Gastric Cancer
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