title: Smoking p66Shc knocked out mice develop respiratory bronchiolitis with fibrosis but not emphysema.
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.
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Benedetta
authors: B
authors: Lunghi
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Giovanna
authors: G
authors: De Cunto
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Eleonora
authors: E
authors: Cavarra
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Silvia
authors: S
authors: Fineschi
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Barbara
authors: B
authors: Bartalesi
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Giuseppe
authors: G
authors: Lungarella
authors: Department of Life Sciences, Section of Experimental Pathology, University of Siena, Siena, Italy.
authors: Monica
authors: M
authors: Lucattelli
mesh_terms: D000818:Animals; D017209:Apoptosis; D001119:Arginase / Q000378:metabolism; D001988:Bronchiolitis / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D002688:Chitinases / Q000378:metabolism; D003895:Desmosine / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics*; D006909:Hydroxyproline / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000378:metabolism; D011656:Pulmonary Emphysema / Q000473:pathology; D055765:Shc Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018793:Interleukin-13; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D003895:Desmosine; D015847:Interleukin-4; D010088:Oxidoreductases; D002688:Chitinases; C544448:Arg1 protein, mouse; D001119:Arginase; D006909:Hydroxyproline