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Deficiency in Neutrophil Elastase Does Not Impair Neutrophil Recruitment to Inflamed Sites

Departments of Medicine (Pulmonary Division) and Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence to: Abderrazzaq Belaaouaj, Ph.D., Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8052, St. Louis, MO 63110-1093. E-mail: Azzaq{at}im.wustl.edu

To reach the sites of inflammation, neutrophils traverse the endothelium, its underlying basement membrane, and other barriers depending on the localization of the insulting agent. Whether neutrophil elastase (NE) plays a role in neutrophil recruitment to inflamed sites is still debatable. By exploiting mice deficient in NE (NE^-/-), we sought to address this dilemma. We recruited neutrophils to the lungs or the peritoneum of wild-type (WT) or NE^-/- mice by intranasal or intraperitoneal challenge with Pseudomonas aeruginosa or its lipopolysaccharide. At designated times post-inoculation (0, 4, 24, and 48 h), groups of mice were killed to assess changes in leukocyte counts and inflammatory responses. NE^-/- and WT mice had normal circulating leukocyte numbers including neutrophils and changes in the hemograms in the setting of acute inflammation were indistinguishable. Analyses of lung tissues or fluids from the lungs and peritoneum found that regardless of the inflammatory model, the leukocyte counts including neutrophils and the inflammatory response were similar in NE^-/- and WT mice at all time points. In vitro, neutrophils isolated from the lungs or the peritoneum of NE^-/- and WT mice had comparable chemotactic and respiratory-burst functions and migrated normally through Matrigel in response to various stimuli. Interestingly, preincubation of human peripheral blood neutrophils with NE physiologic inhibitors did not alter the migration of the cells through Matrigel. In sum, our findings present the first in vivo description that the absence of NE does not impair neutrophil recruitment to inflamed sites and that NE is not required for basement membrane transmigration of neutrophils.

Abbreviations: ₁-antitrypsin, ₁-AT • bronchoalveolar lavage, BAL • Evans blue dye, EBD • extracellular matrix, ECM • Hanks' balanced salt solution, HBSS • intercellular adhesion molecule-1, ICAM-1 • interleukin, IL • inferior vena cava, IVC • lactate-dehydrogenase, LDH • lipopolysaccharide, LPS • matrix metalloprotease, MMP • myeloperoxidase, MPO • neutrophil elastase, NE • phosphate-buffered saline, PBS • peritoneal lavage, PL • secretory leukocyte protease inhibitor, SLPI • tumor necrosis factor, TNF • zymosan-activated serum, ZAS

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