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Abstract
(1) Background: The lung cholinergic pathway is important for controlling pulmonary inflammation in acute lung injury, a condition that is characterized by a sudden onset and intense inflammation. This study investigated changes in the expression levels of nicotinic and muscarinic acetylcholine receptors (nAChR and mAChR) in the lung during acute lung injury. (2) Methods: acute lung injury (ALI) was induced in wild-type and cholinergic-deficient (VAChT-KDHOM) mice using intratracheal lipopolysaccharide (LPS) instillation with or without concurrent treatment with nicotinic ligands. Bronchoalveolar lavage fluid was collected to evaluate markers of inflammation, and then the lung was removed and processed for isolation of membrane fraction and determination of acetylcholine receptors level using radioligand binding assays. (3) Results: LPS-induced increase in lung inflammatory markers (e.g., neutrophils and IL-1β) was significantly higher in VAChT-KDHOM than wild-type mice. In contrast, LPS treatment resulted in a significant increase in lung’s α7 nicotinic receptor level in wild-type, but not in VAChT-KDHOM mice. However, treatment with PNU 282987, a selective α7 nicotinic receptor agonist, restored VAChT-KDHOM mice’s ability to increase α7 nicotinic receptor levels in response to LPS-induced acute lung injury and reduced lung inflammation. LPS also increased muscarinic receptors level in VAChT-KDHOM mice, and PNU 282987 treatment reduced this response. (4) Conclusions: Our data indicate that the anti-inflammatory effects of the lung cholinergic system involve an increase in the level of α7 nicotinic receptors. Pharmacological agents that increase the expression or the function of lung α7 nicotinic receptors have potential clinical uses for treating acute lung injury.
Highlights
Acute respiratory distress syndrome (ARDS) is defined as a diffuse and acute lung inflammatory, and characterized by the presence of alveolar edema with reduced pulmonary complacency and a reduction in the relationship between partial oxygen pressure and an oxygen inspired fraction [1]
We previously showed that animals with acute lung injury (ALI) treated with nicotinic acetylcholine receptors (nAChRs) agonist PNU 282987 significantly reduced lung inflammatory responses due to a change in the macrophages profile from M1 to M2-like [16]
It is relevant to highlight that we evaluated α7 nAChR, α4 nAChR, and muscarinic acetylcholine receptors (mAChRs), and none of the components are altered in the mutant mice [17,49] and, the effects observed in the lungs of animals with cholinergic deficiency are attributed to the reduction in vesicular acetylcholine transporter (VAChT), which is associated to a long-term reduction in cholinergic tone in response to an inflammatory insult
Summary
Acute respiratory distress syndrome (ARDS) is defined as a diffuse and acute lung inflammatory, and characterized by the presence of alveolar edema with reduced pulmonary complacency and a reduction in the relationship between partial oxygen pressure and an oxygen inspired fraction [1]. Animals with deletion of the α7 nAChR gene exhibit increased LPS-induced TNF-α release, and this response was not reversed upon vagal stimulation, suggesting a vital role of this receptor in controlling the anti-inflammatory response [13]. The use of α7nAChR agonists reduced inflammatory cells and the pulmonary release cytokines in acute lung injury (ALI) models [12,14,15]. We previously showed that animals with ALI treated with nAChR agonist PNU 282987 significantly reduced lung inflammatory responses due to a change in the macrophages profile from M1 to M2-like [16]
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