Role of MAP kinase activation in interleukin-8 production by human BEAS-2B bronchial epithelial cells submitted to cyclic stretch.
Overstretching the airways during positive pressure mechanical ventilation or attacks of acute severe asthma is associated with important biologic responses. Interleukin (IL)-8-dependent neutrophil recruitment seems to play a critical role in the process of mechanical stress-induced airway inflammation. Herein, we show that human bronchial epithelial BEAS-2B cells submitted to cyclic stretch in vitro produce IL-8, at both the mRNA and protein levels. This cellular stress "turns on" activator protein (AP)-1 and cyclic AMP (cAMP)-responding elements. The mitogen-activated protein (MAP) kinases (MAPK) p44/42, SAPK/JNK, and p38 were all rapidly activated (phosphorylated) after the initiation of the cyclic strain (5-10 min). The blockade of p38 with the pharmacologic inhibitor SB203580 abrogated IL-8 production by cell stretching, and an inhibitor of the p44/42 pathway, PD98059, partially inhibited the IL-8 response. A nonspecific tyrosine kinase inhibitor, genistein, also blocked the stretch-induced IL-8 production. This suggests that MAPK, and p38 in particular, are proximal and key intracellular signaling molecules mediating cell activation in response to cyclic stretch, a mechanical strain similar to that applied to lung epithelial cells during mechanical ventilation. Pharmacologic inhibition of the p38 pathway holds promise as a new therapeutic avenue in ventilated patients.
Oudin
Séverine
S
Division of Medical Intensive Care, Department of Internal Medicine, University of Geneva, Switzerland.
Pugin
Jérôme
J
D001980:Bronchi / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D013314:Stress, Mechanical
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016209:Interleukin-8; D011725:Pyridines; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one