The most trusted hypothesis to explain how α2-adrenergic agonists may preserve pulmonary functions in
critically ill patients is that they directly act on macrophages by interfering with an autocrine/paracrine
adrenergic system that controls
cytokine release through locally synthetized
noradrenaline and α1- and α2-adrenoreceptors. We tested this hypothesis in primary cultures of resident macrophages from human lung (HLMs). HLMs were isolated by centrifugation on
percoll gradients from macroscopically healthy human lung tissue obtained from four different patients at the time of lung resection for
cancer. HLMs from these patients showed a significant expression of α2A, α2B and α2C adrenoreceptors both at the
mRNA and at the
protein level. To evaluate whether α2 adrenoreceptors controlled
cytokine release from HMLs, we measured
IL-6,
IL-8 and TNF-α concentrations in the culture medium in basal conditions and after preincubation with several α2-adrenergic agonists or antagonists. Neither the pretreatment with the α2-adrenergic agonists
clonidine,
medetomidine or dexdemetomidine or with the α2-adrenergic antagonist
yohimbine caused significant changes in the response of any of these
cytokines to LPS. These results show that, different from what reported in rodents,
clonidine and dexdemetomidine do not directly suppress
cytokine release from human pulmonary macrophages. This suggests that alternative mechanisms such as effects on immune cells activation or the modulation of autonomic neurotransmission could be responsible for the beneficial effects of these drugs on lung function in critical patients.