P38 mitogen-activated protein kinase inhibition attenuates intercellular adhesion molecule-1 up-regulation on human pulmonary microvascular endothelial cells

Background. Increased expresion of pulmonary endothelial intercellular dhesion 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 cell 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 phophorylation inhibitor 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. Western blotting was used to show p38 MAPK activity after stimulation with lipopolysaccharide (LPS) 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 p38 MAPKs contributes to LPS and TNF-alpha stimulated ICAM-1 surface expression on HMVECs. Thus p38 MAPKs appear integral to both neutrophil and endothelial cell pro-inflammatory signaling and may be a potential therapeutic target in the treatment of ARDS.