P38 MITOGEN-ACTIVATED PROTEIN-KINASE INHIBITION ATTENUATES INTERCELLULAR-ADHESION MOLECULE-1 UP-REGULATION ON HUMAN PULMONARY MICROVASCULARENDOTHELIAL-CELLS

Background. Increased expresion of pulmonary endothelial intercellular dhesion molecule-1 (ICAM-1) is obligatory to neutrophil adherence cul minating in adult respiratory distress syndrome (ARDS). The p38 mitoge n-activated protein kinases (MAPKs) have been established as crucial i n leukocyte proinflammatory signaling, but their role in the endotheli al cell remains ill defined. We hypothesized that p38 MAPK activity is integral to ICAM-1 up-regulation on pulmonary endothelium. Methods. H uman pulmonary microvascular endothelial cells (HMVECs) were grown to confluence and pretreated with either the tyrosine phophorylation inhi bitor herbimycin A (1 mu mol/L) or the p38 MAPK inhibitor SB203580 (10 (-7) to 10(-5) mol/L) for 6 hours. ICAM-1 expression was quantified by flow cytometry Data are expressed as mean fluorescence intensity. Wes tern blotting was used to show p38 MAPK activity after stimulation wit h lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha). Results. Tyrosine phosphorylation inhibition with herbimycin A attenu ated 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) stim ulated expression of ICAM-1 on HMVECs. Both LPS and TNF-alpha induced activation of p38 in HMVECs. Conclusions. Signaling through p38 MAPKs contributes to LPS and TNF-alpha stimulated ICAM-1 surface expression on HMVECs. Thus p38 MAPKs appear integral to both neutrophil and endot helial cell pro-inflammatory signaling and may be a potential therapeu tic target in the treatment of ARDS.