| 15743925 |
Phagoo SB, Reddi K, Silvallana BJ, Leeb-Lundberg LM, Warburton D: Infection-induced kinin B1 receptors in human pulmonary fibroblasts: role of intact pathogens and p38 mitogen-activated protein kinase-dependent signaling. J Pharmacol Exp Ther. 2005 Jun;313(3):1231-8. Epub 2005 Mar 2.
Kinin B (1) receptors (B (1) R) are involved in many pathophysiological processes, and its expression is up-regulated in inflammatory pulmonary disease. Although bacteria can generate kinin peptides, the molecular signaling mechanisms regulating B (1) R during infection by intact pathogens is unknown. The serious opportunistic clinical isolate Burkholderia cenocepacia (B. cen.) belongs to the important B. cepacia complex (Bcc) of gram-negative pathogens that rapidly causes fatal pulmonary disease in hospitalized and immunocompromised patients and those with cystic fibrosis. We demonstrate here that B. cen. infection induced a rapid increase in B (1) R mRNA (1 h) proceeded by an increase in B (1) R protein expression (2 h), without affecting B (2) receptor expression in human pulmonary fibroblasts. The B (1) R response was dose-dependent and maximal by 6 to 8 h (3- to 4-fold increase), however, brief B. cen. infection could sustain B (1) R up-regulation. In contrast, nonclinical Bcc phytopathogens were much less B (1) R inducive. The protein synthesis inhibitor cycloheximide and transcriptional inhibitor actinomycin D abrogated the B (1) response to B. cen. indicating de novo B (1) R synthesis. B. cen. activated p38 mitogen-activated protein kinase (MAPK), and blocking p38 MAPK with the specific inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) 1H-imidazole (SB 203580) dramatically reduced B. cen.-induced B (1) R. Furthermore, B. cen. regulation of B (1) R was diminished by the anti-inflammatory glucocorticoid dexamethasone. In conclusion, this study is the first demonstration that infection with intact pulmonary pathogens like B. cen. positively modulates the selective expression of B (1) R. Thus, providing evidence that B (1) R regulation may be an important and novel mechanism in the inflammatory cascade in response to chronic pulmonary infection and disease. |
2(0,0,0,2) |