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      Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

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          Abstract

          Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-α, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage.

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          Most cited references41

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          Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood.

          It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis.
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            Netting neutrophils in autoimmune small-vessel vasculitis.

            Small-vessel vasculitis (SVV) is a chronic autoinflammatory condition linked to antineutrophil cytoplasm autoantibodies (ANCAs). Here we show that chromatin fibers, so-called neutrophil extracellular traps (NETs), are released by ANCA-stimulated neutrophils and contain the targeted autoantigens proteinase-3 (PR3) and myeloperoxidase (MPO). Deposition of NETs in inflamed kidneys and circulating MPO-DNA complexes suggest that NET formation triggers vasculitis and promotes the autoimmune response against neutrophil components in individuals with SVV.
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              Pneumonia and respiratory failure from swine-origin influenza A (H1N1) in Mexico.

              In late March 2009, an outbreak of a respiratory illness later proved to be caused by novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. We describe the clinical and epidemiologic characteristics of persons hospitalized for pneumonia at the national tertiary hospital for respiratory illnesses in Mexico City who had laboratory-confirmed S-OIV infection, also known as swine flu. We used retrospective medical chart reviews to collect data on the hospitalized patients. S-OIV infection was confirmed in specimens with the use of a real-time reverse-transcriptase-polymerase-chain-reaction assay. From March 24 through April 24, 2009, a total of 18 cases of pneumonia and confirmed S-OIV infection were identified among 98 patients hospitalized for acute respiratory illness at the National Institute of Respiratory Diseases in Mexico City. More than half of the 18 case patients were between 13 and 47 years of age, and only 8 had preexisting medical conditions. For 16 of the 18 patients, this was the first hospitalization for their illness; the other 2 patients were referred from other hospitals. All patients had fever, cough, dyspnea or respiratory distress, increased serum lactate dehydrogenase levels, and bilateral patchy pneumonia. Other common findings were an increased creatine kinase level (in 62% of patients) and lymphopenia (in 61%). Twelve patients required mechanical ventilation, and seven died. Within 7 days after contact with the initial case patients, a mild or moderate influenza-like illness developed in 22 health care workers; they were treated with oseltamivir, and none were hospitalized. S-OIV infection can cause severe illness, the acute respiratory distress syndrome, and death in previously healthy persons who are young to middle-aged. None of the secondary infections among health care workers were severe. 2009 Massachusetts Medical Society
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                Author and article information

                Contributors
                Journal
                Am J Pathol
                The American Journal of Pathology
                American Society for Investigative Pathology
                0002-9440
                1525-2191
                July 2011
                : 179
                : 1
                : 199-210
                Affiliations
                [* ]Infectious Diseases Program, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Kent Ridge, Singapore
                []Department of Molecular Cell Biology, Faculty of Medicine, Vrije University of Amsterdam, Amsterdam, the Netherlands
                Author notes
                [* ]Address reprint requests to Vincent Chow, M.D., Ph.D., Infectious Diseases Program, Department of Microbiology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 5 Science Drive 2, Kent Ridge 117597, Singapore micctk@ 123456nus.edu.sg
                Article
                AJPA348
                10.1016/j.ajpath.2011.03.013
                3123873
                21703402
                a29421e0-2ffd-45cb-b9af-14b972c56a26
                © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
                History
                : 3 March 2011
                Categories
                Regular Article
                Immunopathology and Infectious Disease

                Pathology
                Pathology

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