title: Activated protein C attenuates leukocyte elastase-induced lung injury in mice.
abstract: Leukocyte elastase (LE), a neutrophil serine protease, is known to cause alveolar wall destruction and alveolar hemorrhage in the lung, but recent evidence suggests that it may also produce a significant inflammatory response. The purpose of the current study was to (1) examine the relationship between LE-induced lung injury and specific markers of inflammation and cytokine/chemokine, and to (2) determine the potential of activated protein C (APC), a potent immunomodulator, to block the inflammatory response to LE. We treated the C57BL/6 mice with LE (10 U/kg, i.t.) and assessed the lung inflammation over 72 h. Total cells, total protein, and neutrophils were increased and peaked at 16 h in bronchial alveolar lavage fluid. Macrophages were also increased and peaked at 24 h. Administration of LE up-regulated the synthesis of proinflammatory cytokines, IL-1beta and IL-6, chemokines, keratinocyte-derived chemokine, and macrophage inflammatory protein 2 in bronchial alveolar lavage fluid, and their peaks were at 6 h. Furthermore, the mice were treated with APC at 0.2, 2.0, and 10 mg/kg (i.v.) after instillation of LE. Therapeutic treatment of APC at 2.0 and 10 mg/kg significantly attenuated the increases in all these parameters. Lung histology revealed that, in addition to inflammation, alveolar hemorrhage and alveolar wall destruction induced by LE were also attenuated by APC. Finally, the expression of tissue plasminogen activator and plasminogen activator inhibitor in whole lung of mice exposed to LE, detected by means of reverse-transcriptase-polymerase chain reaction, were not influenced by the treatment with APC. These data demonstrate that intratracheal administration of LE to mice causes a transient inflammatory response, and APC can play a protective role against LE-induced lung injury.
authors.affiliation: First Department of Internal Medicine, Showa University, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Tanaka
authors.forename: Kenji
authors.initials: K
authors.lastname: Minoguchi
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Chen
authors.forename: Naruhito
authors.initials: N
authors.lastname: Oda
authors.forename: Takuya
authors.initials: T
authors.lastname: Yokoe
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Mayumi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Shin
authors.initials: S
authors.lastname: Ohta
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Adachi
mesh_terms: D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D005342:Fibrinolysis; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology / Q000627:therapeutic use*; D007442:Intubation, Intratracheal; D019272:Leukocyte Elastase / Q000633:toxicity*; D008171:Lung Diseases / Q000139:chemically induced* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000502:physiology; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000473:pathology; D011486:Protein C / Q000378:metabolism* / Q000502:physiology / Q000627:therapeutic use*; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D011486:Protein C; D019272:Leukocyte Elastase