Abstract
The adaptor protein p66Shc regulates intracellular oxidant levels through the modulation of a forkhead-related transcription factor (FOXO3a). The genetic ablation of p66Shc (p66Shc–/–) renders mice resistant to oxidative stress and p53-dependent apoptosis. We investigated whether p66Shc ablation in mice modifies lung cellular and molecular responses to cigarette smoke (CS) exposure. No differences between wild type (WT) and p66Shc–/– mice were observed in terms of inflammation and oxidant burden after acute CS exposure; however,p66Shc ablation modifies specific features of chronic inflammation induced by repeated exposure to CS. Unlike WT mice, p66Shc–/– mice did not develop emphysema, showing protection toward oxidative damage to DNA and apoptosis as revealed by a trivial 8-hydroxyguanosine staining and faint TUNEL and caspase-3 positivity on alveolar epithelial cells. Unexpectedly, CS exposure in p66Shc–/– mice resulted in respiratory bronchiolitis with fibrosis in surrounded alveoli. Respiratory bronchiolitis was characterized by peribronchiolar infiltrates of lymphocytes and histiocytes, accumulation of ageing pigmented macrophages within and around bronchioles, and peribronchiolar fibrosis. The blockage of apoptosis interferes with the macrophage “clearance” from alveolar spaces, favouring the accumulation of aging macrophages into alveoli and the progressive accumulation of iron pigment in long-lived senescent cells. The presence of areas of interstitial and alveolar fibrosis in peripheral parenchyma often accompanied the bronchiolar changes. Macrophages from smoking p66Shc–/– mice elaborate M2 cytokines (i.e., IL-4 and IL-13) and enzymes (i.e., chitinase and arginase I), which can promote TGF-beta expression, collagen deposition, and fibrosis in the surrounding areas. We demonstrate here that resistance to oxidative stress and p53-dependent apoptosis can modify tissue responses to CS caused by chronic inflammation without influencing early inflammatory response to CS exposure.
Highlights
Cigarette smoke (CS) is considered to be the main causative factor of chronic obstructive pulmonary disease (COPD) in man [1, 2, 3]
No differences were found in BAL cell profile and inflammatory mediators between wild type (WT) and p66Shc−/− mice in response to acute CS exposure
The data of this study suggest P66Shc ablation in mouse genome affords protection towards CS induced pulmonary emphysema
Summary
Cigarette smoke (CS) is considered to be the main causative factor of chronic obstructive pulmonary disease (COPD) in man [1, 2, 3]. Accumulating evidence suggests that the adaptor protein p66Shc, recently involved in lung development [10], regulates intracellular oxidant levels in mammalian cells through the regulation of a forkhead related transcription factor (FKHRL1, called FOXO3a)[11,12,13,14,15]. Recent studies suggest that FOXO3a is involved in the transactivation of a number of antioxidant enzymes and stress-related gene products [12] and that FOXO3 deficiency leads to increased susceptibility to CS resulting in development of COPD [16]. The ablation of p66Shc from mouse genome by gene targeting (p66Shc−/−) renders mice resistant to oxidative stress in vivo upon treatment with paraquat [12, 15] and amazingly increases 70th percentile survival in respect to other strains without influencing the life span [17]. It is observed that p66Shc−/− cells have enhanced resistance to apoptosis since p66Shc acts as a downstream target of the tumour suppressor p53 and regulates p53-dependent apoptosis [15]
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