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Neutrophil DNA Contributes to the Antielastase Barrier during Acute Lung Inflammation

Unité de Défense Innée et Inflammation, INSERM E336, Institut Pasteur, Paris, France; Rayne Laboratory, Centre of Inflammation Research, Edinburgh University Medical School, Edinburgh, Scotland, United Kingdom; and Unité Inserm U408, Faculté de Médecine Xavier Bichat, Paris, France

Address correspondence to: Dr. Michel Chignard, Défense Innée et Inflammation, INSERM E336, Institut Pasteur, 25 rue du Dr. Roux, 75015 Paris, France. E-mail: chignard{at}pasteur.fr

During acute lung inflammation, the airspaces are invaded by circulating neutrophils. These may then injure tissues through the release of elastase. Different natural specific inhibitors such as 1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin are nonetheless able to counteract the enzymatic activity of elastase. The present study was undertaken to assess the role of these different inhibitors in the intrinsic antielastase barrier during lipopolysaccharide-induced lung inflammation in mice. Upon intranasal administration of lipopolysaccharide to mice, the antielastase activity recovered from bronchoalveolar lavage fluids (BALF) increases progressively up to 48 h (7-fold) and returns to the basal level within 72 h. By contrast, when the same experiments are performed with neutropenic mice (pretreatment with an antigranulocyte antibody, or vinblastine), the increase is almost totally absent. Ultrafiltration of BALF through 100 kD cutoff membranes shows that the activity remains in the retentate, thus ruling out a role for native 1-proteinase inhibitor, secretory leukocyte proteinase inhibitor, and elafin. Gel filtration and fraction analysis show that the material eluted with a M_r of 600 kD. Agarose gel electrophoresis and ethidium bromide staining reveal that the activity corresponds to the presence a large amount of DNA. Interestingly, DNase treatment of the active fraction suppresses the antielastase activity. Analysis of BALF from patients with acute lung inflammation shows the presence of DNA with antielastase activity. We therefore concluded that during acute lung inflammation, the recruitment of neutrophils in the airspaces accounts for the increased presence of DNA, which in turn contributes to the antielastase barrier.

Abbreviations: 1-protease inhibitor, 1-PI • acute respiratory distress syndrome, ARDS • bronchoalveolar lavage fluid(s), BALF • bovine serum albumin, BSA • enhanced chemiluminescence, ECL • lipopolysaccharide, LPS • monoclonal antibody, mAb • phosphate-buffered saline, PBS • secretory leukocyte proteinase inhibitor, SLPI

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