title: Compartment- and cell-specific expression of coagulation and fibrinolysis factors in the murine lung undergoing inhalational versus intravenous endotoxin application.
abstract: Intraalveolar and intravascular fibrin formation are typical hallmarks of acute inflammatory lung diseases, and may foster subsequent fibroproliferative events. We investigated the regulation and cellular sources of key coagulation and fibrinolysis factors in lungs undergoing compartmentalized challenge with endotoxin (LPS). BALB/c mice received 15 ng LPS either by intravenous injection or by inhalation. Quantitative gene expression analysis (real-time RT-PCR) was performed for tissue factor (TF), TF pathway inhibitor (TFPI), tissue-type plasminogen activator (t-PA), urokinase-type-PA (u-PA), PA inhibitor-1 (PAI-1), and PAI-2 in peripheral white blood cells (PBC) as well as in alveolar macrophages (AM), type-II pneumocytes (ATII), endothelial cells (EC) and smooth muscle cells (SMC), all obtained by laser microdissection. Neither route of LPS administration caused substantial protein leakage or leukocyte recruitment into the alveolar space. Compartmentalized upregulation of procoagulant and downregulation of fibrinolytic activities was, however, observed in response to both modes of LPS challenge. Intraalveolar endotoxin, in particular, caused strong upregulation of TF ( approximately 20-fold increase in gene expression) and PAI-2 (225-fold increase) in microdissected AM, upregulation of PAI-1 in microdissected ATII (300-fold increase) and EC (180-fold increase), upregulation of t-PA in EC (40-fold), and downregulation of u-PA in vascular smooth muscle cells. TFPI was largely unchanged in all cell types, and PBC showed no major gene regulatory response to inhaled endotoxin. We conclude that the lung possesses a cell-specific alveolar coagulation and fibrinolysis system, being independent of the vascular coagulation cascade and responding readily with enhanced procoagulant and anti-fibrinolytic activities to LPS challenge.
authors.affiliation: Department of Internal Medicine, Faculty of Medicine, Justus-Liebig-University Giessen, Klinikstr. 36, 35392 Giessen, Germany.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
authors.forename: Tim
authors.initials: T
authors.lastname: Kuchenbuch
authors.forename: Ludger
authors.initials: L
authors.lastname: Fink
authors.forename: Rainer Maria
authors.initials: RM
authors.lastname: Bohle
authors.forename: Friedrich
authors.initials: F
authors.lastname: Grimminger
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001777:Blood Coagulation; D001779:Blood Coagulation Factors / Q000235:genetics*; D002451:Cell Compartmentation; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000494:pharmacology; D008168:Lung / Q000098:blood supply / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001779:Blood Coagulation Factors; D008070:Lipopolysaccharides