Nicotinic acetylcholine receptor agonist reduces acute lung injury after renal ischemia-reperfusion injury by acting on splenic macrophages in mice.

Acute kidney injury (AKI) contributes to development of acute lung injury (ALI) via proinflammatory responses. We hypothesized that activation of a nicotinic acetylcholine receptor (nAChR), which exerts cholinergic anti-inflammatory effects on macrophages, could reduce ALI after AKI. We aimed to determine: 1) whether nAChR agonists could reduce ALI after AKI and 2) which macrophages in the lung or spleen contribute to the improvement of ALI by nAChR agonists. We induced AKI in C57BL/6 male mice by unilateral ischemia-reperfusion injury (IRI) with contralateral nephrectomy and administered nAChR agonists in three experimental settings: 1) splenectomy, 2) splenic macrophage deletion via intravenous administration of clodronate liposomes, and 3) alveolar macrophage deletion via intratracheal administration of clodronate liposomes. Treatment with GTS-21, anα7nAChR selective agonist, significantly reduced the levels of circulating IL-6, a key proinflammatory cytokine and lung CXCL1 and CXCL2 and neutrophil infiltration and Evans blue dye vascular leakage increased after renal IRI. In splenectomized mice, GTS-21 did not reduce circulating IL-6 and lung CXCL1 and CXCL2levels and neutrophil infiltration, and Evans blue dye vascular leakage increased after renal IRI. In mice depleted of splenic macrophages, GTS-21 treatment did not reduce lung neutrophil infiltration, and Evans blue dye vascular leakage increased after renal IRI. In mice depleted of alveolar macrophages, GTS-21 treatment significantly reduced lung neutrophil infiltration, and Evans blue dye vascular leakage increased after renal IRI. Our findings show that nAChR agonist reduces circulating IL-6 levels and acute lung injury after renal IRI by acting on splenic macrophages.