Localization of leukaemia inhibitory factor to airway epithelium and its amplification of contractile responses to tachykinins

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Abstract
1. In neural tissue, leukaemia inhibitory factor (LIF) is an important trophic cytokine. In this investigation, we determined if LIF was present in human and guinea-pig airways and examined the role of this cytokine in modulating airway responses to endogenous and exogenous tachykinins as well as muscarinic receptor and beta-adrenoceptor stimulation. 2. The presence of LIF in both human and guinea-pig airways was determined by immunohistochemistry. Guinea-pig tracheal explants were incubated in CRML-1066 media containing LIF (0.5, 5 or 50 ng ml-1) for periods of 3, 6, 24 and 48 h. Tracheal rings were then transferred to organ baths for measurement of isometric force in response to carbachol, capsaicin, the neurokinin1 (NK1) receptor agonist [Sar9,Met(O2)11]-substance P (SP), the NK2 receptor agonist neurokinin A (NKA) and isoprenaline. 3. LIF immunoreactivity was observed primarily in basally situated cells in the airway epithelium of both large and small airways. Less intense immunoreactivity was observed in vascular endothelium and glandular epithelium. 4. Treatment with LIF (0.5 ng ml-1) for 3 and 6 h significantly increased contractile responses to capsaicin by 42% and 43%, respectively, compared to time controls, whereas higher concentrations of LIF (5 and 50 ng ml-1) enhanced capsaicin-induced contractions only after 6 h. After 24 h, responses to capsaicin were not significantly different from 0 h control. Contractile responses to capsaicin following exposure to LIF at any concentration for 24 h were not significantly different from relative time control values. 5. Responses to [Sar9,Met(O2)11]-SP, carbachol and isoprenaline were not influenced by time in culture or by exposure to LIF for up to 48 h. Contractile responses induced by NKA were not influenced by 3 or 6 h exposure to LIF, but at 24 and 48 h the mean maximum contractile responses to NKA were significantly increased by 33% and 35%, respectively, compared to control. 6. These results demonstrate that LIF is present in guinea-pig and human airway epithelium, and modulates airway responses to tachykinins. In the acute setting LIF augments the capsaicin-induced release of endogenous tachykinins, whilst in the longer term (> 24 h), LIF increases airway smooth muscle responses to tachykinins via an NK2 receptor selective mechanism. We conclude that LIF may be an important effector molecule in the response of airways to injury or inflammation.