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Pro-apoptotic role of NF-kappaB pathway inhibition in lipopolysaccharide-stimulated polymorphonuclear neutrophils.

OBJECTIVE
To investigate the role of nuclear factor kappa B (NF-kappaB) pathway inhibition in lipopolysaccharide (LPS)-stimulated apoptosis of polymorphonuclear neutrophils (PMNs).


METHODS
Rats with acute lung injury induced by LPS intratracheal instillation and cultured human venous PMNs were studied. Pyrrolidine dithiocarbamate (PDTC) and gliotoxin were used as NF-kappaB inhibitors. Additionally, to explore the role of extracellularly regulated protein kinase as an upstream signal in NF-kappaB pathway on regulating LPS-stimulated PMN apoptosis, PD098059, the specific inhibitor of extracellularly regulated protein kinase, was also applied. The lung injury was determined by protein content and PMN numbers in bronchoalveolar lavage fluid. PMN apoptosis was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) end labeling and DNA fragmentation. IkappaBalpha degradation was analyzed by Western blot. NF-kappaB DNA binding activity was detected by an electrophoretic mobility shift assay.


RESULTS
(1) The increase of protein content and PMN numbers in bronchoalveolar lavage fluid induced by LPS (100 micro g per rat) intratracheal instillation were alleviated by PDTC (50, 100, or 200 mg/kg, i.p.) in a dose-dependent manner. (2) PMNs apoptosis in vivo or in vitro was delayed by LPS, and accelerated by PDTC, gliotoxin or PD098059 pretreatment. (3) IkappaBalpha degradation and increased NF-kappaB DNA binding activity mediated by LPS were inhibited by PDTC, gliotoxin or PD098059 pretreatment.


CONCLUSION
Inhibition of either NF-kappaB itself or the upstream signals in NF-kappaB pathway such as extracellularly regulated protein kinases has therapeutic effect on LPS-induced acute lung injury, in which the dysregulation of PMN apoptosis plays an important role.