ABSTRACT
New evidence indicates that neural mechanisms can down-regulate acute inflammation. In these studies, we tested the potential role of the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) in a rodent model of acid-induced acute lung injury. We first determined that the alpha7 nAChR was expressed by alveolar macrophages and lung epithelial cells. Then, using an acid-induced acute lung injury mouse model, we found that nicotine, choline, and PNU-282,987 (a specific alpha7 nAChR agonist) decreased excess lung water and lung vascular permeability, and reduced protein concentration in the bronchoalveolar lavage (BAL). Deficiency of alpha7 nAChR resulted in a 2-fold increase in excess lung water and lung vascular permeability. The reduction of proinflammatory cytokines (macrophage inflammatory protein-2 and TNF-alpha) in the BAL with nicotine probably resulted from the suppression of NF-kappaB activation in alveolar macrophages. The beneficial effect of nicotine was also tested in rat model of acid-induced acute lung injury in which BAL protein and receptor for advanced glycation end products (RAGE), a marker of type I cell injury, were reduced by nicotine treatment. These results indicate that activation of alpha7 nAChR may provide a new therapeutic pathway for the treatment of acute lung injury.
Subject(s)
Hydrochloric Acid , Lung/drug effects , Lung/pathology , Receptors, Nicotinic/metabolism , Respiratory Distress Syndrome , Animals , Benzamides/metabolism , Bridged Bicyclo Compounds/metabolism , Capillary Permeability/drug effects , Cell Differentiation , Cells, Cultured , Choline/metabolism , Cytokines/metabolism , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Extravascular Lung Water/metabolism , Humans , Hydrochloric Acid/pharmacology , Hydrochloric Acid/toxicity , Lung/cytology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , NF-kappa B/metabolism , Neutrophils/cytology , Neutrophils/physiology , Nicotine/metabolism , Nicotine/pharmacology , Nicotinic Agonists/metabolism , Nicotinic Agonists/pharmacology , Rats , Receptors, Nicotinic/genetics , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology , alpha7 Nicotinic Acetylcholine ReceptorABSTRACT
RATIONALE: Receptor for advanced glycation end-products (RAGE) is one of the alveolar type I cell-associated proteins in the lung. OBJECTIVES: To test the hypothesis that RAGE is a marker of alveolar epithelial type I cell injury. METHODS: Rats were instilled intratracheally with 10 mg/kg lipopolysaccharide or hydrochloric acid. RAGE levels were measured in the bronchoalveolar lavage (BAL) and serum in the rats and in the pulmonary edema fluid and plasma from patients with acute lung injury (ALI; n = 22) and hydrostatic pulmonary edema (n = 11). MAIN RESULTS: In the rat lung injury studies, RAGE was released into the BAL and serum as a single soluble isoform sized approximately 48 kD. The elevated levels of RAGE in the BAL correlated well with the severity of experimentally induced lung injury. In the human studies, the RAGE level in the pulmonary edema fluid was significantly higher than the plasma level (p < 0.0001). The median edema fluid/plasma ratio of RAGE levels was 105 (interquartile range, 55-243). The RAGE levels in the pulmonary edema fluid from patients with ALI were higher than the levels from patients with hydrostatic pulmonary edema (p < 0.05), and the plasma RAGE level in patients with ALI were significantly higher than the healthy volunteers (p < 0.001) or patients with hydrostatic pulmonary edema (p < 0.05). CONCLUSION: RAGE is a marker of type I alveolar epithelial cell injury based on experimental studies in rats and in patients with ALI.
