Effects of distension on airway inflammation and venular P-selectin expression.
We previously have shown in mice and rats, enhanced leukocyte recruitment to airway postcapillary venules after excessive distention imposed by the application of positive end-expiratory pressure. Because P-selectin was shown to be essential for this outcome, we sought to establish an in vitro endothelial cell model and determine the mechanisms whereby mechanical distension alters adhesion molecule expression. P-selectin surface expression on mouse jugular vein endothelial cells exposed to cyclic stretch (5 or 20% elongation for 5 min; Flexercell) were compared with static cells. The larger, pathophysiological regimen of cyclic stretch showed a 54% increase in P-selectin expression after stretch compared with static cells. This response was attenuated but confirmed in tracheal venular endothelium (29% increase). We questioned whether these changes were dependent on increases in intracellular Ca(2+) through voltage-gated Ca(2+) channels. The stretch-induced increase in P-selectin expression was substantially decreased by pretreatment with the T-type Ca(2+) channel inhibitor mibefradil (76% inhibition). Furthermore, when the Ca(v)3.1 T-type Ca(2+) channel expression was decreased in both endothelial cell subtypes with specific small-interfering RNA, the distension-induced expression of P-selectin decreased to levels less than that observed in static cells. We conclude that P-selectin expression on systemic venular endothelial cells contributes to a proinflammatory phenotype after mechanical stretch and can be selectively modulated by voltage-gated calcium channel inhibition.
Moldobaeva
Aigul
A
Johns Hopkins Asthma and Allergy Center, Division of Pulmonary and Critical Care Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA.
Jenkins
John
J
Wagner
Elizabeth
E
D000818:Animals; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008853:Microscopy; D019007:P-Selectin / Q000378:metabolism*; D011014:Pneumonia / Q000378:metabolism*; D011175:Positive-Pressure Respiration; D011667:Pulmonary Veins / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical; D014700:Verapamil / Q000494:pharmacology
D020747:Calcium Channels, T-Type; D019007:P-Selectin; D012333:RNA, Messenger; D020748:Mibefradil; D014700:Verapamil