p38 mitogen-activated protein kinase inhibition attenuates intercellular adhesion molecule-1 up-regulation on human pulmonary microvascular endothelial cells.
BACKGROUND
Increased expression of pulmonary endothelial intercellular adhesion molecule-1 (ICAM-1) is obligatory to neutrophil adherence culminating in adult respiratory distress syndrome (ARDS). The p38 mitogen-activated protein kinases (MAPKs) have been established as crucial in leukocyte proinflammatory signaling, but their role in the endothelial cells remains ill defined. We hypothesized that p38 MAPK activity is integral to ICAM-1 up-regulation on pulmonary endothelium.


METHODS
Human pulmonary microvascular endothelial cells (HMVECs) were grown to confluence and pretreated with either the tyrosine phosphorylation inhibitor herbimycin A (1 mumol/L or the p38 MAPK inhibitor SB 203580 (10(-7) to 10(-5) mol /L) for 6 hours. ICAM-1 expression was quantified by flow cytometry. Data expressed as mean fluorescence intensity. Western blotting was used to show p38 MAPK activity after stimulation with lipopolysaccharide (LOS) or tumor necrosis factor-alpha (TNF-alpha).


RESULTS
Tyrosine phosphorylation inhibition with herbimycin A attenuated both LPS and TNF-alpha stimulated ICAM-1 up-regulation. Similarly, specific inhibition of p38 MAPK attenuated both LPS (10(-6) to 10(-5) mol/L SB203580) and TNF-alpha (10(-7) to 10(-5) mol/L SB203580) stimulated expression of ICAM-1 on HMVECs. Both LPS and TNF-alpha induced activation of p38 in HMVECs.


CONCLUSIONS
Signaling through p 38 MAPKs contributes to LP and TNF-alpha stimulated ICAM-1 surface expression on HMVECs. Thus p38 MAPKs appear integral to both neutrophil and endothelial cell proinflammatory signaling and may be a potential therapeutic target in the treatment of ARDS.
Department of Surgery, Denver Health Medical Center, CO 80204, USA.
D Y
DY
Tamura
E E
EE
Moore
J L
JL
Johnson
G
G
Zallen
J
J
Aiboshi
C C
CC
Silliman
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002196:Capillaries / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000098:blood supply; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D014443:Tyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580