title: Inhibition of neutrophil elastase contributes to attenuation of lipopolysaccharide-induced acute lung injury during neutropenia recovery in mice.
abstract: OBJECTIVE
  Patients in whom neutropenia recovery is complicated by pneumonia have an increased risk of acute lung injury (ALI) and detrimental outcomes. The aim of the present study was to investigate whether inhibition of neutrophil elastase (NE) is effective in lipopolysaccharide (LPS)-induced ALI during neutropenia recovery in a murine model, and whether it upregulates the activation of the MerTK signaling pathway.
  
  
  METHODS
  Cyclophosphamide was given to mice to induce neutropenia. Seven days later, they were administered LPS by intratracheal instillation. Sivelestat, a neutrophil elastase inhibitor, was given by intraperitoneal injection once daily starting on day 0 and continuing until mice were sacrificed on day 5 (preventive group). Alternatively, sivelestat was given after, instead of before, LPS administration on day 2 (therapeutic group).
  
  
  RESULTS
  Sivelestat attenuated the lung edema and histopathological changes associated with LPS-induced lung injury. The accumulation of neutrophils and the concentrations of TNF-α, IL-6, and MPO in bronchoalveolar lavage (BAL) fluids were inhibited effectively by sivelestat. The expression of ICAM-1 and NF-κB p65 was also reduced after sivelestat administration. The protein and gene expression of MerTK tended to increase with sivelestat treatment.
  
  
  CONCLUSIONS
  Sivelestat significantly attenuated LPS-induced ALI during recovery from neutropenia, and this effect was associated with MerTK induction. These findings suggest that NE inhibition could be a promising means of alleviating lung inflammation without increasing susceptibility to infection in ALI/ARDS during neutropenia recovery.
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea.
authors.forename: Jong Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea.
authors.forename: Chang Dong
authors.initials: CD
authors.lastname: Yeo
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea.
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Lee
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea.
authors.forename: Chin Kook
authors.initials: CK
authors.lastname: Rhee
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea.
authors.forename: In Kyoung
authors.initials: IK
authors.lastname: Kim
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Dong Gun
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea.
authors.forename: Sang Haak
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, School of Medicine, The Catholic University of Korea, Uijeongbu St. Mary's Hospital, 65-1 Geumo-dong, Uijeongbu, Seoul, Gyunggi-do, Republic of Korea. medkjw@catholic.ac.kr.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009503:Neutropenia / Q000188:drug therapy; D009504:Neutrophils / Q000378:metabolism*; D011654:Pulmonary Edema / Q000209:etiology; D013449:Sulfonamides / Q000494:pharmacology*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D013449:Sulfonamides; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine
keywords: Acute lung injury; Mer tyrosine kinase; Neutropenia recovery; Neutrophil elastase inhibition