jaw and Bronchial-Hyperreactivity

Ozone is a potent oxidant and causes airway hyperresponsiveness and neutrophilia. To determine the role of p38 mitogen-activated protein kinase (MAPK) activation, we studied the effect of a p38alpha inhibitor SD-282 (Scios Inc, Fremont, CA USA) on ozone-induced airway hyperresponsiveness and neutrophilia. Balb/c mice received SD-282 (30 or 90 mg/kg i.p) or vehicle 1 h before exposure to either ozone (3 ppm, 3 h) or air. Three hours after exposure, lungs were analysed for cytokine levels and bronchoalveolar lavage was performed. Another set of mice were dosed 6 h after exposure and 1 h before assessing airway hyperresponsiveness. SD-282 (90 mg/kg) significantly inhibited ozone-induced airway hyperresponsiveness (-LogPC(150): SD-282: -1.73+/-0.14 vs. vehicle: -0.99+/-0.15, P<0.05). Bronchoalveolar lavage neutrophil numbers were time-dependently increased in vehicle-dosed, ozone-exposed mice, greatest at 20-24 h after exposure. SD-282 (30 and 90 mg/kg) significantly inhibited ozone induced neutrophil numbers at 3 h and 20-24 h after ozone SD-282 significantly inhibited ozone-induced increases in phosphorylated p38 MAPK expression, and in cyclooxygenase-2 (COX-2), interleukin-6 (IL-6) and IL-1beta but not MIP-1alpha gene expression. We conclude that p38 MAPK is involved in ozone-induced airway hyperresponsiveness and lung neutrophilia. Inhibition of p38 MAPK with small molecule kinase inhibitors may be a means of reducing ozone-induced inflammation and airway hyperresponsiveness.

Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cytokines; Dose-Response Relationship, Drug; Gene Expression Regulation; Indoles; Inflammation; Lung; Male; Mice; Mice, Inbred BALB C; Neutrophils; Oxidants, Photochemical; Ozone; p38 Mitogen-Activated Protein Kinases; Time Factors

p38 mitogen-activated protein kinase (MAPK) plays an important role in the activation of inflammatory cells and in the proliferation of airway structural cells. We investigated the role of p38 MAPK by using a selective inhibitor of p38 alpha and beta isoforms, SD282, in a chronic model of 15 ovalbumin exposures in sensitised mice using two doses (30 and 90 mg/kg). Allergen exposure induced bronchial hyperresponsiveness to methacholine as measured by the concentration of methacholine needed to increase pulmonary resistance by 200% (PC200), eosinophilia in bronchoalveolar lavage fluid and increase in airway smooth muscle area and goblet cell hyperplasia. In addition, p38 MAPK activity as measured by phosphorylated p38 expression on Western blots was increased after allergen challenge, which was suppressed by SD282 at both doses. SD282 inhibited bronchial hyperresponsiveness, but had no effect on eosinophils in bronchoalveolar lavage fluid. It also reduced airway smooth muscle and goblet cell hyperplasia, but had no effect on serum immunoglobulin E. p38 MAPK is involved in the pathogenesis of bronchial hyperresponsiveness but not in eosinophilic inflammation or the allergic response; however, remodelling features such as airway smooth muscle or goblet cell hyperplasia are regulated through p38 MAPK. Furthermore, bronchial hyperresponsiveness induced by chronic allergen exposure may be related to the development of airway wall remodelling.

Topics: Alcian Blue; Animals; Bronchi; Bronchial Hyperreactivity; Enzyme Activation; Immunoglobulin E; Indoles; Male; Mice; Mice, Inbred BALB C; Myocytes, Smooth Muscle; p38 Mitogen-Activated Protein Kinases; Respiratory System; Schiff Bases