desmosine and Bronchiolitis

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.

Topics: Animals; Apoptosis; Arginase; Bronchiolitis; Chitinases; Desmosine; Fibrosis; Hydroxyproline; Interleukin-13; Interleukin-4; Lung; Macrophages; Mice; Mice, Knockout; Oxidative Stress; Oxidoreductases; Pulmonary Emphysema; Shc Signaling Adaptor Proteins; Smoking; Src Homology 2 Domain-Containing, Transforming Protein 1; Transforming Growth Factor beta; Tumor Suppressor Protein p53

Pulmonary emphysema may be a disease in which some elastin in lung is lost. In order to evaluate lung elastin degradation, we developed an enzyme-linked immunosorbent assay for desmosine and measured urinary desmosine excretion and serum desmosine levels in healthy individuals and patients with pulmonary emphysema and other chronic pulmonary disorders. The measurement was performed by the inhibition technique of ELISA so that the samples had to be applied to CF11 cellulose mini-column for partial purification of desmosine. Total urinary excretion of desmosine was uniformly low in healthy individuals and patients with lung cancer, but urinary desmosine was elevated in some cases of pulmonary emphysema and diffuse panbronchiolitis. Using this ELISA method, more than 0.06 micrograms/ml serum desmosine concentration could be measured in 3 out of 25 healthy subjects who had never smoked (13.6%), 4/9 healthy current smokers (44.4%) and 19/26 patients with pulmonary emphysema (73.1%). Mean serum desmosine levels of meseared 19 cases of empysema were 0.182 micrograms/ml. It has been reported that approximately 15% of smokers develop pulmonary emphysema. The most important problem now is whether smokers with elevated urinary desmosine or with high serum desmosine will eventuality develop pulmonary emphysema.

Topics: Amino Acids; Bronchiolitis; Chronic Disease; Desmosine; Enzyme-Linked Immunosorbent Assay; Humans; Pulmonary Emphysema