Expression of functional NK1 receptors in human alveolar macrophages: superoxide anion production, cytokine release and involvement of NF‐κB pathway

• Published in: British journal of pharmacology 2005-06, Vol.145 (3), p.385-396
• Main Authors: Bardelli, Claudio, Gunella, Gabriele, Varsaldi, Federica, Balbo, Pietro, Del Boca, Elisa, Bernardone, Ilaria Seren, Amoruso, Angela, Brunelleschi, Sandra
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; cytokine release; human alveolar macrophages; Medical sciences; NF‐κB activation; NK1 receptor; Pharmacology. Drug treatments; respiratory burst; Substance P; TNF‐α; IL‐1β; IL‐10
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0706198

1 Substance P (SP) is deeply involved in lung pathophysiology and plays a key role in the modulation of inflammatory‐immune processes. We previously demonstrated that SP activates guinea‐pig alveolar macrophages (AMs) and human monocytes, but a careful examination of its effects on human AMs is still scarce. 2 This study was undertaken to establish the role of SP in human AM isolated from healthy smokers and non‐smokers, by evaluating the presence of tachykinin NK1 receptors (NK‐1R) and SP's ability to induce superoxide anion (O2−) production and cytokine release, as well as activation of the nuclear factor‐κB (NF‐κB) pathway. 3 By Western blot analysis and immunofluorescence, we demonstrate that authentic NK‐1R are present on human AMs, a three‐fold enhanced expression being observed in healthy smokers. These NK‐1R are functional, as SP and NK1 agonists dose‐dependently induce O2− production and cytokine release. In AMs from healthy smokers, SP evokes an enhanced respiratory burst and a significantly increased release of tumor necrosis factor‐α as compared to healthy non‐smokers, but has inconsistent effects on IL‐10 release. The NK1 selective antagonist CP 96,345 ((2S,3S)‐cis‐2‐diphenylmethyl‐N[(2‐methoxyphenyl)‐methyl]‐1‐azabicyclo‐octan‐3‐amine)) competitively antagonized SP‐induced effects. 4 SP activates the transcription factor NF‐κB, a three‐fold increased nuclear translocation being observed in AMs from healthy smokers. This effect is receptor‐mediated, as it is reproduced by the NK1 selective agonist [Sar9Met(O2)11]SP and reverted by CP 96,345. 5 These results clearly indicate that human AMs possess functional NK‐1R on their surface, which are upregulated in healthy smokers, providing new insights on the mechanisms involved in tobacco smoke toxicity. British Journal of Pharmacology (2005) 145, 385–396. doi:10.1038/sj.bjp.0706198