Proinflammatory cytokines are involved in the development of lipopolysaccharide (LPS)-induced airway inflammation. Earlier we observed using IPT preparations that LPS (4 mg/kg, 18 h, i.p) increased the basal transepithelial potential difference (Vt), the hyperpolarizing response to methacholine (MCh), and the epithelium-derived relaxing factor (EpDRF)-mediated relaxation response to hyperosmolar solution, i.e., to Dmannitol (D-M). To identify the roles of cytokines in the LPS-induced changes, unmounted tracheas were incubated for 6 h with interleukin-lB (IL-1B 13, 10 ng/ml), interferon-y (IFN-y, 100 ng/ml) and tumor necrosis factor-a (TNF-a, 100 ng/ml) alone or in combination. IL-lB and lFN-y reduced MCh-induced contractile responses and potentiated D-M-induced relaxation responses. However, TNF-a incubation enhanced the MCh contractions but had no effect on relaxations to D-M. When the cytokines were incubated together (cytomix) they had no effect on the contractile responses, but potentiated the DM induced relaxations. MCh Vt concentration-response curves were biphasic. All the cytokines decreased the hyperpolarization responses at low MCh concentrations and increased the depolarization responses in higher concentrations. The individual cytokines had no effect on Vt responses to D-M. On the other hand, cytomix did not affect the Vt changes during MCh addition, but potentiated both the hyperpolarization and depolarization responses to D-M. The results indicate that incubation with cytokines affects airway smooth muscle reactivity to MCh and potentiates EpDRF-mediated relaxant responses to D-M. Thus, in the absence of inflammatory cells, the cytokines mimic the effect of LPS injection on D-M-induced relaxation, but do not recapitulate LPS' effects on Vt responses.
Proceedings of the American Thoracic Society. 2005 ATS International Conference, May 20-25, 2005, San Diego, California