• Daniela Vecchio, Beatrice Arezzini, Alessandra Pecorelli, Giuseppe Valacchi, Piero A Martorana, and Concetta Gardi.
• Dept. of Physiopathology and Experimental Medicine, Univ. of Siena, Italy.
• Am. J. Physiol. Lung Cell Mol. Physiol. 2010 May 1; 298 (5): L704-13.

AbstractCigarette smoke (CS) is a main risk factor in chronic obstructive pulmonary disease (COPD), but only 20% of smokers develop COPD, suggesting genetic predisposition. Animal studies have shown that C57BL/6J mice are sensitive to CS and develop emphysema, whereas Institute of Cancer Research (ICR) mice are not. To investigate the potential factors responsible for the different susceptibility of ICR and C57BL/6J mice to CS, we evaluated in alveolar macrophages (AMs) isolated from these strains of mice the possible mechanisms involved in the inflammatory and oxidative responses induced by CS. Lactate dehydrogenase (LDH) release revealed that C57BL/6J AMs were more susceptible to CS extract (CSE) toxicity than ICR. Differences were observed in inflammatory and oxidative response after CSE exposure. Proinflammatory cytokines and matrix metalloproteinases (MMPs) were increased in C57BL/6J but not ICR AMs. Control C57BL/6J AMs showed a higher baseline production of reactive oxygen species (ROS) and H(2)O(2) with lower baseline levels of GSH, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase (GPX2). This was associated with reduced histone deacetylase-2 (HDAC2) expression, activation of NF-κB, and higher basal levels of TNF-α and IL-6. CSE induced a decrease in HDAC2 protein levels in both C57BL/6J and ICR AMs; however, the level of HDAC2 was significantly lower in C57BL/6 than in ICR AMs. Furthermore, CSE enhanced NF-κB-dependent cytokine release only in C57BL/6J AMs. We suggest that an imbalance in oxidative stress decreases HDAC2 levels and facilitates NF-κB binding, resulting in a proinflammatory response in C57BL/6J but not in ICR AMs. These results could contribute in understanding the different susceptibility to CS of these strains of mice.

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