Requisite role of the cholinergic alpha7 nicotinic acetylcholine receptor pathway in suppressing Gram-negative sepsis-induced acute lung inflammatory injury.

Abstract

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.

• Authors: Xiao Su, Michael A Matthay, Asrar B Malik
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 184 Issue 1 Pg. 401-10 (Jan 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 19949071 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Chrna7 protein, mouse
• Cytokines
• Nicotinic Agonists
• Receptors, Nicotinic
• alpha7 Nicotinic Acetylcholine Receptor
• Acetylcholine

Topics

• Acetylcholine (immunology)
• Acute Lung Injury (immunology, microbiology)
• Animals
• Axotomy
• Blotting, Western
• Bronchoalveolar Lavage
• Cytokines (biosynthesis, immunology)
• Enzyme-Linked Immunosorbent Assay
• Escherichia coli (immunology)
• Escherichia coli Infections (immunology)
• Flow Cytometry
• Gram-Negative Bacteria (immunology)
• Macrophage Activation (drug effects, immunology)
• Macrophages, Alveolar (drug effects, immunology)
• Mice
• Mice, Mutant Strains
• Neutrophils (drug effects, immunology)
• Nicotinic Agonists (pharmacology)
• Receptors, Nicotinic (immunology)
• Sepsis (immunology, microbiology)
• Signal Transduction (drug effects, immunology)
• Vagus Nerve (immunology, metabolism)
• alpha7 Nicotinic Acetylcholine Receptor