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      Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury

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          Summary

          Multiple lung pathogens such as chemical agents, H5N1 avian flu, or SARS cause high lethality due to acute respiratory distress syndrome. Here we report that Toll-like receptor 4 (TLR4) mutant mice display natural resistance to acid-induced acute lung injury (ALI). We show that TLR4-TRIF-TRAF6 signaling is a key disease pathway that controls the severity of ALI. The oxidized phospholipid (OxPL) OxPAPC was identified to induce lung injury and cytokine production by lung macrophages via TLR4-TRIF. We observed OxPL production in the lungs of humans and animals infected with SARS, Anthrax, or H5N1. Pulmonary challenge with an inactivated H5N1 avian influenza virus rapidly induces ALI and OxPL formation in mice. Loss of TLR4 or TRIF expression protects mice from H5N1-induced ALI. Moreover, deletion of ncf1, which controls ROS production, improves the severity of H5N1-mediated ALI. Our data identify oxidative stress and innate immunity as key lung injury pathways that control the severity of ALI.

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          Most cited references32

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          Conditional gene targeting in macrophages and granulocytes using LysMcre mice.

          Conditional mutagenesis in mice has recently been made possible through the combination of gene targeting techniques and site-directed mutagenesis, using the bacteriophage P1-derived Cre/loxP recombination system. The versatility of this approach depends on the availability of mouse mutants in which the recombinase Cre is expressed in the appropriate cell lineages or tissues. Here we report the generation of mice that express Cre in myeloid cells due to targeted insertion of the cre cDNA into their endogenous M lysozyme locus. In double mutant mice harboring both the LysMcre allele and one of two different loxP-flanked target genes tested, a deletion efficiency of 83-98% was determined in mature macrophages and near 100% in granulocytes. Partial deletion (16%) could be detected in CD11c+ splenic dendritic cells which are closely related to the monocyte/macrophage lineage. In contrast, no significant deletion was observed in tail DNA or purified T and B cells. Taken together, LysMcre mice allow for both specific and highly efficient Cre-mediated deletion of loxP-flanked target genes in myeloid cells.
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            Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function.

            MyD88, originally isolated as a myeloid differentiation primary response gene, is shown to act as an adaptor in interleukin-1 (IL-1) signaling by interacting with both the IL-1 receptor complex and IL-1 receptor-associated kinase (IRAK). Mice generated by gene targeting to lack MyD88 have defects in T cell proliferation as well as induction of acute phase proteins and cytokines in response to IL-1. Increases in interferon-gamma production and natural killer cell activity in response to IL-18 are abrogated. In vivo Th1 response is also impaired. Furthermore, IL-18-induced activation of NF-kappaB and c-Jun N-terminal kinase (JNK) is blocked in MyD88-/- Th1-developing cells. Taken together, these results demonstrate that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor.
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              Avian influenza A (H5N1) infection in humans.

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                Author and article information

                Contributors
                Journal
                Cell
                Cell
                Cell
                Elsevier Inc.
                0092-8674
                1097-4172
                17 April 2008
                18 April 2008
                17 April 2008
                : 133
                : 2
                : 235-249
                Affiliations
                [1 ]IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Dr. Bohrgasse 3, A-1030 Vienna, Austria
                [2 ]Medical Research Institute, Tokyo Medical and Dental University, Kandasurugadai 2-3-10, Chiyoda-ku, Tokyo 101-0062, Japan
                [3 ]CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences and Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
                [4 ]European Molecular Biology Laboratory (EMBL), Mouse Biology Unit, Via Ramarini 32, Monterotondo-Scalo, Rome 00016, Italy
                [5 ]Institute for Genetics, University of Cologne, Zülpicher Str. 47, D-50674 Cologne, Germany
                [6 ]Lawson Health Research Institute, Departments of Medicine and Physiology and Pharmacology, The University of Western Ontario, London Ontario, N6A 4V2, Canada
                [7 ]Department of Pathology, University of Hong Kong, SAR
                [8 ]Department of Microbiology, University of Hong Kong, SAR
                [9 ]National Key Laboratory of Medical Molecular Biology, School of Basic Medicine Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100005, China
                [10 ]Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH-8952 Zürich-Schlieren, Switzerland
                [11 ]US Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD 21701, USA
                [12 ]Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto M5B 1W8, Canada
                [13 ]Department of Critical Care, St. Michael's Hospital, University of Toronto, Toronto M5B 1W8, Canada
                [14 ]Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
                [15 ]Medical Inflammation Research, MBB, Karolinska Institutet, Stockholm, Sweden and Medical Inflammation Research BMC I11 Lund, Sweden
                Author notes
                []Corresponding author josef.penninger@ 123456imba.oeaw.ac.at
                [∗∗ ]Corresponding author imai@ 123456med.akita-u.ac.jp
                [16]

                Present address: The Global COE program, Akita University School of Medicine, Akita 010-8543, Japan.

                Article
                S0092-8674(08)00340-1
                10.1016/j.cell.2008.02.043
                7112336
                18423196
                5ec28353-286b-493e-b353-98745ef46a29
                Copyright © 2008 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 25 April 2007
                : 10 December 2007
                : 29 February 2008
                Categories
                Article

                Cell biology
                cellimmuno,humdisease
                Cell biology
                cellimmuno, humdisease

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