Compartment- and cell-specific expression of coagulation and fibrinolysis factors in the murine lung undergoing inhalational versus intravenous endotoxin application

Summary

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 15ng 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 (∼ 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.

Keywords

Inflammation - endotoxin - coagulation and fibrinolysis - gene expression

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