Modulatory effects of the cholinergic system and nicotinic receptors on a murine model of acute lung injury induced by LPS

Abstract

Acute lung injury (ALI) is characterized by sudden onset, polymorphonuclear cells recruitment and release of pro-inflammatory mediators, which can induce changes in cytokines. The reduction of vesicular transport of acetylcholine (VAChT), which is associated to reduction on the release of ACh, the main mediator of cholinergic anti-inflammatory system, modulates pulmonary inflammation. Nicotinic receptors, particularly ±7 nicotinic receptor, is involved in the control of pulmonary inflammation in acute lung injury model. Aim: The aim of the present study is to elucidate the role of nicotinic receptors with a focus on: a. To investigate the expression and the function of these receptors on lung from mice with acute lung injury induced by LPS model. b. To investigates how cholinergic deficiency which induces lung inflammation modulates these receptors. Additional aim to be performed in the return to Brazil: c. test new allosteric drugs of these receptors in animals with acute lung injury, depending on the results obtained in this study to be performed abroad. Considering that the use of allosteric nicotinic receptors has a great clinical potential this proposal has great relevance for patients who develop ARDS. Methods: Lungs will be collected from VAChT male mice (70% reduction in VAChT) following induction of acute lung injury with intratracheal LPS instillation with or without concurrent treatment with nicotinic ligands in Brazil and sent to Prof Hamouda by mail. Then, there, the membrane fraction will be isolated from these lungs and radioligand binding assays, protein chemistry, and biophysical methods will be used evaluation the expression and function of several subtypes of nicotinic receptors. A data analysis will be performed through the SigmaStat program. (AU)