Thiopental (TP) along with being an intravenous anaesthetic is frequently used in high doses to treat increased intracranial hypertension. Long-term treatments result in its accumulation in the lungs and an increased incidence of nosocomial infections. Since TP has been shown to modulate TNF-induced inflammatory pathways in lymphocytes, we hypothesised that TP may modulate pro-inflammatory events in human pulmonary epithelial cells. We investigated the potential influence of TP on MAPK and NF-κB signal transduction pathways in the absence and presence of TNF. TP at 1 mg/ml concentrations produced a 10-fold increase in p38 activation as assessed by Western blotting using monoclonal antibodies specific for double phosphorylated, thereby activated form of p38. This increase in p38 MAPK phosphorylation was evident as early as 10 minutes (4.5-fold), peaked at 60 minutes (11.3-fold) with return towards baseline (3.6-fold) in 2 hours. This response was specific for p38, since there was no evidence for activation of NF-κB pathway by TP as judged from Western blot analysis of steady-state IκB levels. TNF activated both p38 (2.4–11.4-fold increases) and depleted IκB (64–35% of control) in a concentration dependent manner (0.1–10 ng/ml). Interestingly, in the presence of TP, TNF did not produce a further increase in p38 activation. In addition, TP tended to attenuate TNF-induced NF-κB activation. These data suggest that high dose TP has the capacity to specifically alter p38MAPK activation and to modulate TNF signalling in epithelial cells, which might have implications to immunological responses in the lung.
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