Luigino Calzetta1, Paola Rogliani2, Francesco Facciolo3, Barbara Rinaldi4, Mario Cazzola5, Maria Gabriella Matera6. 1. Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy. Electronic address: luigino.calzetta@uniroma2.it. 2. Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy. Electronic address: paola.rogliani@uniroma2.it. 3. Regina Elena National Cancer Institute, Thoracic Surgery Unit, Rome, Italy. Electronic address: francesco.facciolo@ifo.gov.it. 4. Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy. Electronic address: barbara.rinaldi@unicampania.it. 5. Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy. Electronic address: mario.cazzola@uniroma2.it. 6. Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy. Electronic address: mariagabriella.matera@unicampania.it.
Abstract
AIMS: N-Acetylcysteine (NAC) reduces the risk of exacerbation of chronic obstructive pulmonary disease (COPD). Although NAC also has anti-inflammatory activity, the detailed mechanism leading to its protective role remains to be elucidated. We tested the impact of NAC against the effects of lipopolysaccharide (LPS) in an ex vivo model of COPD exacerbation, and investigated the role of neurokinin A (NKA) in this context. MAIN METHODS: Isolated airways from COPD patients were incubated overnight with LPS (100 ng/ml). NAC was tested at concentrations resembling the plasma levels elicited by oral administration of NAC at 200 mg/day (very low dose), 600 mg/day (low dose) and 1.200 mg/day (high dose). KEY FINDINGS: NAC at high concentrations normalized the peroxidase activity, H2O2, malondialdehyde (MDA), nitric oxide, glutathione (GSH), total antioxidant capacity (TAC), and interleukin 6 (IL-6) (overall change 34.32% ± 4.22%, P < 0.05 vs. LPS-treated). NAC at low concentrations modulated peroxidase activity, H2O2, MDA, GSH, TAC, and IL-6 (overall change 34.88% ± 7.39%, P < 0.05 vs. LPS-treated). NAC at very-low concentrations was effective on peroxidase activity, H2O2, GSH, and IL-6 (overall change 35.05 ± 7.71%, P < 0.05 vs. LPS-treated). Binary logistic regression analysis indicated that the modulatory effect of NAC on NKA levels was associated with a reduction of pro-oxidant factors and IL-6, and selectively blocking the NK2 receptor abolished such an association. SIGNIFICANCE: This study demonstrates that, along with its well-known antioxidant activity, the protective effect of NAC against the detrimental effect of LPS is due to the modulation of NKA and IL-6 levels.
AIMS: N-Acetylcysteine (NAC) reduces the risk of exacerbation of chronic obstructive pulmonary disease (COPD). Although NAC also has anti-inflammatory activity, the detailed mechanism leading to its protective role remains to be elucidated. We tested the impact of NAC against the effects of lipopolysaccharide (LPS) in an ex vivo model of COPD exacerbation, and investigated the role of neurokinin A (NKA) in this context. MAIN METHODS: Isolated airways from COPDpatients were incubated overnight with LPS (100 ng/ml). NAC was tested at concentrations resembling the plasma levels elicited by oral administration of NAC at 200 mg/day (very low dose), 600 mg/day (low dose) and 1.200 mg/day (high dose). KEY FINDINGS:NAC at high concentrations normalized the peroxidase activity, H2O2, malondialdehyde (MDA), nitric oxide, glutathione (GSH), total antioxidant capacity (TAC), and interleukin 6 (IL-6) (overall change 34.32% ± 4.22%, P < 0.05 vs. LPS-treated). NAC at low concentrations modulated peroxidase activity, H2O2, MDA, GSH, TAC, and IL-6 (overall change 34.88% ± 7.39%, P < 0.05 vs. LPS-treated). NAC at very-low concentrations was effective on peroxidase activity, H2O2, GSH, and IL-6 (overall change 35.05 ± 7.71%, P < 0.05 vs. LPS-treated). Binary logistic regression analysis indicated that the modulatory effect of NAC on NKA levels was associated with a reduction of pro-oxidant factors and IL-6, and selectively blocking the NK2 receptor abolished such an association. SIGNIFICANCE: This study demonstrates that, along with its well-known antioxidant activity, the protective effect of NAC against the detrimental effect of LPS is due to the modulation of NKA and IL-6 levels.