Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury.
Although activation of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) modulates the response to sepsis, the role of this pathway in the development of sepsis-induced acute lung injury (ALI) is not known. In this study, we addressed the contribution of alpha7 nAChR in mediating endotoxin- and live Escherichia coli-induced ALI in mice. Because we found that alpha7 nAChR(+) alveolar macrophages and neutrophils were present in bronchoalveolar lavage and injured lungs of mice, we tested whether acetylcholine released by lung vagal innervation stimulated these effector cells and thereby down-regulated proinflammatory chemokine/cytokine generation. Administration of alpha7 nAChR agonists reduced bronchoalveolar lavage MIP-2 production and transalveolar neutrophil migration and reduced mortality in E. coli pneumonia mice, whereas vagal denervation increased MIP-2 production and airway neutrophil accumulation and increased mortality. In addition, alpha7 nAChR(-/-) mice developed severe lung injury and had higher mortality compared with alpha7 nAChR(+/+) mice. The immunomodulatory cholinergic alpha7 nAChR pathway of alveolar macrophages and neutrophils blocked LPS- and E. coli-induced ALI by reducing chemokine production and transalveolar neutrophil migration, suggesting that activation of alpha7 nAChR may be a promising strategy for treatment of sepsis-induced ALI.
Su
Xiao
X
Center for Lung and Vascular Biology and Department of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USA. suxiao1@yahoo.com
Matthay
Michael A
MA
Malik
Asrar B
AB
D000109:Acetylcholine / Q000276:immunology; D055371:Acute Lung Injury / Q000276:immunology* / Q000382:microbiology; D000818:Animals; D019771:Axotomy; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology; D005434:Flow Cytometry; D006090:Gram-Negative Bacteria / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000276:immunology*; D018805:Sepsis / Q000276:immunology* / Q000382:microbiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014630:Vagus Nerve / Q000276:immunology / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D016207:Cytokines; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine