Omalizumab decreases exacerbation frequency, oral intake of corticosteroids and peripheral blood eosinophils in atopic patients with uncontrolled asthma.

Omalizumab is a humanized monoclonal anti-IgE antibody approved in 2005 by the European Medicine Agency (EMA) for the treatment of severe persistent allergic asthma, which remains inadequately controlled despite optimal therapy with high doses of inhaled corticosteroids and long-acting ß2-adrenergic agonists. Within this context, the present observational study refers to 16 patients currently treated with omalizumab at the Respiratory Unit of "Magna Græcia" University Hospital located in Catanzaro, Italy, whose anti- IgE therapy was started in the period included between March 2007 and February 2010, thus lasting at least 10 months. After 40 weeks of add-on treatment with omalizumab, very relevant decreases were detected, in comparison with pre-treatment mean (± standard deviation) values, in monthly exacerbation numbers (from 1.1 ± 0.6 to 0.2 ± 0.4; p < 0.01) and oral corticosteroid consumption (from 22.6 ± 5.0 to 1.2 ± 2.9 mg/day of prednisone; p < 0.01). These changes were associated with stable improvements in lung function, expressed as increases of both FEV1 (from 53.6 ± 14.6% to 77.0 ± 14.9% of predicted values; p < 0.01) and FEV1/FVC ratio (from 56.3 ± 9.5% to 65.8 ± 9.2%; p < 0.01). Moreover, in 5 patients who persistently had increased numbers of eosinophils (mean ± SD: 15.9 ± 8.0% of total WBC count; absolute number: 1,588.0 ± 956.9/µl) despite a long-lasting therapy with inhaled and systemic corticosteroids, the peripheral counts of these cells decreased down to near normal levels (mean ± SD: 6.3 ± 2.3% of total WBC count; absolute number: 462.0 ± 262.3/µl) after 16 weeks of treatment with omalizumab. Therefore, this descriptive evaluation confirms the efficacy of add-on omalizumab therapy in selected patients with exacerbation-prone, chronic allergic uncontrolled asthma, requiring a continuous intake of oral corticosteroids.

Effects of budesonide on P38 MAPK activation, apoptosis and IL-8 secretion, induced by TNF-alpha and Haemophilus influenzae in human bronchial epithelial cells.

Non-typeable Haemophilus influenzae (NTHi) is one of the most frequently involved pathogens in bacterial exacerbations of chronic obstructive pulmonary disease (COPD). In the airways, the main tissue target of NTHi is bronchial epithelium, where this pathogen can further amplify the inflammatory and structural changes induced by proinflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha). Therefore, the aim of this study is to investigate, in primary cultures of human bronchial epithelial cells, the effects of NTHi on signal transduction pathways, apoptotic events and chemokine production activated by TNF-alpha. Moreover, we also evaluated the effects exerted on such cellular and molecular phenomena by a corticosteroid drug. p38 mitogen-activated protein kinase (MAPK) phosphorylation was analyzed by Western blotting, using an anti-phospho-p38 MAPK monoclonal antibody. Apoptosis was assayed by active caspase-3 expression. Interleukin-8 (IL-8/CXCL8) was detected in cell-free culture supernatants by ELISA. TNF-alpha induced a significant increase in p38 MAPK phosphorylation. NTHi was able to potentiate the stimulatory actions of TNF-alpha on caspase-3 expression and, to a lesser extent, on IL-8 secretion. These effects were significantly (P less than 0.01) inhibited by a pharmacological pre-treatment with budesonide. These results suggest that TNF-alpha is able to stimulate, via activation of p38 MAPK signalling pathway, IL-8 release and airway epithelial cell apoptosis; the latter effect can be markedly potentiated by NTHi. Furthermore, budesonide can be very effective in preventing, through inhibition of p38 MAPK phosphorylation, both structural and proinflammatory changes elicited in bronchial epithelium by TNF-alpha and NTHi.

Effects of statins and farnesyl transferase inhibitors on ERK phosphorylation, apoptosis and cell viability in non-small lung cancer cells.

OBJECTIVE: 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can affect post-translational processes, thus being responsible for decreased farnesylation and geranylgeranylation of intracellular small G proteins such as Ras, Rho and Rac, essential for cell survival and proliferation. In this regard, recent in vitro and in vivo studies suggest a possible role for both statins and farnesyl transferase inhibitors in the treatment of malignancies. Within such a context, the aim of our study was to investigate effects of either simvastatin (at concentrations of 1, 15, and 30 µm) or the farnesyl transferase inhibitor R115777 (at concentrations of 0.1, 1, and 10 µm), on two cultures of human non-small lung cancer cells, adenocarcinoma (GLC-82) and squamous (CALU-1) cell lines. In particular, we evaluated actions of these two drugs on phosphorylation of the ERK1/2 group of mitogen-activated protein kinases and on apoptosis, plus on cell numbers and morphology. MATERIALS AND METHODS: Western blotting was used to detect ERK phosphorylation, and to assess apoptosis by evaluating caspase-3 activation; apoptosis was also further assessed by terminal deoxynucleotidyl-mediated dUTP nick end labelling (TUNEL) assay. Cell counting was performed after trypan blue staining. RESULTS AND CONCLUSION: In both GLC-82 and CALU-1 cell lines, simvastatin and R115777 significantly reduced ERK phosphorylation; this effect, which reached the greatest intensity after 36 h treatment, was paralleled by a concomitant induction of apoptosis, documented by significant increase in both caspase-3 activation and TUNEL-positive cells, associated with a reduction in cell numbers. Our results thus suggest that simvastatin and R115777 may exert, in susceptible lung cancer cell phenotypes, a pro-apoptotic and anti-proliferative activity, which appears to be mediated by inhibition of the Ras/Raf/MEK/ERK signalling cascade.