Article

High Dose but not Low Dose Mainstream Cigarette Smoke Suppresses Allergic Airway Inflammation by Inhibiting T Cell Function

Department of Medicine, Univ. of Rochester, Rochester, NY 14642, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.04). 07/2008; 295(3):L412-21. DOI: 10.1152/ajplung.00392.2007
Source: PubMed

ABSTRACT Epidemiological studies have identified childhood exposure to environmental tobacco smoke as a significant risk factor for the onset and exacerbation of asthma, but studies of smoking in adults are less conclusive, and mainstream cigarette smoke (MCS) has been reported to both enhance and attenuate allergic airway inflammation in animal models. We sensitized mice to ovalbumin (OVA) and exposed them to MCS in a well-characterized exposure system. Exposure to MCS (600 mg/m(3) total suspended particulates, TSP) for 1 h/day suppresses the allergic airway response, with reductions in eosinophilia, tissue inflammation, goblet cell metaplasia, IL-4 and IL-5 in bronchoalveolar lavage (BAL) fluid, and OVA-specific antibodies. Suppression is associated with a loss of antigen-specific proliferation and cytokine production by T cells. However, exposure to a lower dose of MCS (77 mg/m(3) TSP) had no effect on the number of BAL eosinophils or OVA-specific antibodies. This is the first report to demonstrate, using identical smoking methodologies, that MCS inhibits immune responses in a dose-dependent manner and may explain the observation that, although smoking provokes a systemic inflammatory response, it also inhibits T cell-mediated responses involved in a number of diseases.

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    ABSTRACT: Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano-3,12-dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA) on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p≤0.01), inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p≤0.001), and excess production of the pro-fibrotic cytokine TGFβ by 50%. CDDO-Me also inhibited α-smooth muscle actin and fibronectin mRNA by 50% (p≤0.05). On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and αSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation) and by systemic autoimmune diseases.
    PLoS ONE 05/2013; 8(5):e63798. DOI:10.1371/journal.pone.0063798 · 3.23 Impact Factor
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    • "Total protein in BALF was determined by the bicinchoninic acid (BCA) colorimetric assay (Thermo Scientific, Rockford, IL). The right lung was homogenized in RIPA buffer as described [32], and lung proteins were analyzed for expression of COX-2 (Clone CX229, Cayman Chemical, Ann Arbor, MI), Arg-1 (H-52; Santa Cruz Biotechnologies, Santa Cruz, CA) and total actin (CP01; Calbiochem, San Diego) by Western blotting. In some experiments, the lungs were inflated and fixed with 10% neutral buffered formalin without undergoing lavage. "
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    PLoS ONE 03/2013; 8(3):e58258. DOI:10.1371/journal.pone.0058258 · 3.23 Impact Factor
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    • "It is possible that the subjects were not heavy smokers to cause any changes to the lymphocytes proliferation activity. Studied by Thatcher et al.[40] showed that at the higher dose of mainstream cigarette smoke (MSC) exposure (600 mg/m3 total suspended particulates (TSP) suppresses the antigen-specific proliferation and cytokine production by T-cell than low dose of MSC (77 mg/m3 TSP). "
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