Cellular origin of pro-coagulant and (anti)-fibrinolytic factors in bleomycin-injured lungs.
Excessive pro-coagulant and decreased fibrinolytic activities in the alveolar compartment have been repeatedly documented for inflammatory and fibrotic lung diseases. The current authors determined the contribution of different resident lung cells to the altered local production of coagulation- and fibrinolysis-system components in bleomycin-injured mouse lungs via cell-specific and quantitative assessment of mRNA levels of various pro-coagulant and (anti)-fibrinolytic factors. Laser-assisted microdissection technology was used to sample specific cell populations in combination with subsequent mRNA analysis by real-time quantitative reverse transcriptase-PCR. Additionally, western blot analysis, immunohistochemistry and activity assays were performed. Following bleomycin challenge, the strongest induction of tissue factor and plasminogen activator inhibitor (PAI)-1 mRNA expression was observed in alveolar macrophages (approximately 250- and 60-fold induction, respectively). These factors were also upregulated in alveolar type II cells, but to an approximately six-fold lesser extent. In contrast, PAI-2 expression was induced exclusively in alveolar macrophages. A slight increase of urokinase-type plasminogen activator (uPA) expression was also observed in alveolar macrophages (two-fold induction), but uPA activity was reduced due to a disproportionate increase of PAI production. Alveolar macrophages and, to a lesser extent, alveolar type II cells are the main sources of locally produced pro-coagulant and anti-fibrinolytic factors in bleomycin-injured lungs.
Wygrecka
M
M
Department of Biochemistry, Faculty of Medicine, University of Giessen Lung Center, Klinikstr. 36, 35392 Giessen, Germany.
Markart
P
P
Ruppert
C
C
Petri
K
K
Preissner
K T
KT
Seeger
W
W
Guenther
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid; D003029:Coagulants / Q000378:metabolism / Q000494:pharmacology*; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation; D008168:Lung / Q000187:drug effects* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D003029:Coagulants; D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D001761:Bleomycin; D013925:Thromboplastin