title: Inhaled activated protein C attenuates lung injury induced by aerosolized endotoxin in mice.
abstract: The serine protease activated protein C (APC) possesses prominent anticoagulant and anti-inflammatory actions. In this study, we investigated the effect of inhaled recombinant human (rh) APC in a murine lung injury model. Animals inhaled 10 mg of Pseudomonas lipopolysaccharide (LPS) in 3 mL normal saline (NS); 30 min prior to LPS, mice were pretreated with inhaled rhAPC (4 mg/3 mL NS; APC+LPS group) or NS (LPS group). A control animal group inhaled vehicle (NS) twice. 24 h later, total cells and cell-types, protein content, and the cytokines tumor necrosis factor-alpha, interleukin (IL)-6, macrophage inflammatory protein-1alpha, and mouse keratinocyte-derived chemokine (a homolog of human IL-8) were estimated in bronchoalveolar lavage fluid (BALF). Lung pathology given as total histology score (THS), wet/dry lung weight ratios, and lung vascular cell adhesion molecule (VCAM)-1 expression were additionally assessed. rhAPC inhalation attenuated the aerosolized LPS-induced increases of: total cells, neutrophils and macrophages in BALF, lung tissue VCAM-1 protein levels, and THS. Total protein levels and cytokines in BALF, and wet/dry weight ratios were increased in the LPS group, but rhAPC pretreatment did not significantly alter the LPS-induced responses. In conclusion, in this murine septic model of lung injury, inhaled rhAPC appears to attenuate lung inflammation, without reversing the observed increases in lung permeability and BALF cytokines. This effect may be associated with leukocyte trafficking modifications, related, at least in part, to VCAM-1 reduction.
authors.affiliation: 1st Department of Critical Care Medicine--Pulmonary Services, Evangelismos Hospital, University of Athens Medical School, Athens, Greece. akotanid@med.uoa.gr
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kotanidou
authors.forename: Heleni
authors.initials: H
authors.lastname: Loutrari
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadomichelakis
authors.forename: Constantinos
authors.initials: C
authors.lastname: Glynos
authors.forename: Christina
authors.initials: C
authors.lastname: Magkou
authors.forename: Apostolos
authors.initials: A
authors.lastname: Armaganidis
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.forename: Charis
authors.initials: C
authors.lastname: Roussos
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Orfanos
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D004195:Disease Models, Animal; D004731:Endotoxins; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008171:Lung Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011486:Protein C / Q000008:administration & dosage* / Q000235:genetics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000336:Aerosols; D004731:Endotoxins; D011486:Protein C; D011994:Recombinant Proteins