Bleomycin induces IL-8 and ICAM-1 expression in microvascular pulmonary endothelial cells.
To investigate the pathomechanisms of bleomycin-induced early inflammation of lung parenchyma which is known to result in pulmonary fibrosis, we examined the in vitro effect of bleomycin (BLM) on primary human pulmonary microvascular endothelial cells (HMVEC-L). After incubation of microvascular endothelial cells with BLM we detected an induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) by immunoblotting. Further, after BLM-exposure an increased concentration of interleukin-8 (IL-8) in culture supernatant and an increased expression of intercellular adhesion molecule-1 (ICAM-1, CD54) on the cell surface have been observed. Real-time PCR revealed up-regulated mRNA expression levels of both, IL-8 and ICAM-1 after treatment with BLM. Finally, pre-treatment with a selective p38 MAPK-inhibitor, SB 203580, potently reduced the BLM-induced up-regulation of IL-8 expression but did not show any effect on expression of ICAM-1. These results demonstrate that BLM induces the expression of pro-inflammatory molecules in the pulmonary microvascular endothelium, which thereby may actively contribute to the development of early inflammation and later fibrosis of the lung. Furthermore, investigating the effect of an inhibitor of p38 MAPK the data indicate the involvement of p38 MAPK-dependent as well as p38 MAPK-independent mechanisms in the effects of BLM on the pulmonary microvasculature.
Fichtner
Falk
F
Institute of Anatomy, Medical Faculty Carl Gustav Carus, University of Technology Dresden, Germany.
Koslowski
Roland
R
Augstein
Antje
A
Hempel
Ute
U
Röhlecke
Cora
C
Kasper
Michael
M
D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001761:Bleomycin / Q000633:toxicity*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000098:blood supply; D008833:Microcirculation; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D004791:Enzyme Inhibitors; D007093:Imidazoles; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D001761:Bleomycin; D018799:Intercellular Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580