bms345541 and Asthma

Nuclear factor-kappaB (NFkappaB) is an inducible transcription factor that plays a central role in the regulation of many immune and inflammatory responses. While NFkappaB is required for cell survival and immunity, abnormal expression and/or activation of NFkappaB leads to the development of many pathological states, especially those involved in chronic and acute inflammation. Many different signal transduction pathways, originating from a wide variety of cellular stresses and stimuli, converge on a single target; the NFkappaB/IkappaB complex and its activating kinase (inhibitor of kappaB kinase, IKK). Here, we review some of the major NFkappaB activating pathways, their role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD), and their potential as targets in the treatment of asthma and COPD.

Topics: Anti-Inflammatory Agents; Asthma; Heterocyclic Compounds, 3-Ring; Humans; I-kappa B Kinase; Imidazoles; NF-kappa B; Protein Serine-Threonine Kinases; Pulmonary Disease, Chronic Obstructive; Pyridines; Quinoxalines

The present study aimed to investigate the possible effects and regulatory mechanism of the inhibitor of nuclear factor‑κB kinase complex β subunit (IKKβ) inhibitor BMS‑345541 on airway inflammation, airway remodeling and epithelial‑mesenchymal transition (EMT) in an ovalbumin (OVA) exposure asthma model in mice. The asthma mouse model was generated by sensitization and challenge with OVA. BMS‑345541/dimethyl sulfoxide (DMSO) was administered perorally dairy in two therapeutic groups throughout the entire OVA challenge process. At 24 h following the last challenge, airway hyperresponsiveness (AHR) and airway inflammation were examined, and serum, bronchoalveolar lavage fluid (BALF) and lung samples were collected. Lung tissue was stained and assessed for pathological changes. The total number and classification of inflammatory cells in the BALF were examined. Levels of transforming growth factor β1 (TGFβ1) in the serum and BALF were measured using an enzyme‑linked immunosorbent assay. The differential expression of EMT regulators E‑cadherin and vimentin was detected by immunohistochemical staining, reverse transcription‑quantitative polymerase chain reaction analysis and western blot analysis. The results showed that OVA successfully induced allergic asthma. The asthmatic mice had AHR, airway inflammation, airway remodeling, a high expression of TGFβ1, and evidence of EMT. Following BMS‑345541 treatment, there was significant inhibition of pathophysiological signs, including increased pulmonary eosinophilia infiltration, mucus hypersecretion and AHR. Treatment with BMS‑345541 significantly reduced levels of TGFβ1. In addition, BMS‑345541 notably downregulated the expression of vimentin and increased the expression of E‑cadherin. These data suggested that the increased secretion of TGFβ1 induced by asthmatic inflammation can lead to EMT, and the IKKβ inhibitor BMS‑345541 may alter airway remodeling by preventing EMT in an OVA asthma model. Therefore, IKKβ inhibitors require investigation as potential asthma therapies.

Topics: Airway Remodeling; Animals; Asthma; Epithelial-Mesenchymal Transition; Female; Imidazoles; Inflammation; Mice; Mice, Inbred BALB C; Quinoxalines

Eosinophils play a central role in asthma. The present study was performed to investigate the effect of tumour necrosis factor-α (TNF-α) on longevity of isolated human eosinophils. In contrast to Fas, TNF-α inhibited eosinophil apoptosis as evidenced by a combination of flow cytometry, DNA fragmentation assay and morphological analyses. The effect of TNF-α on eosinophil apoptosis was reversed by a TNF-α neutralising antibody. The anti-apoptotic effect of TNF-α was not due to autocrine release of known survival-prolonging cytokines interleukins 3 and 5 or granulocyte-macrophage-colony-stimulating factor as their neutralisation did not affect the effect of TNF-α. The anti-apoptotic signal was mediated mainly by the TNF-receptor 1. TNF-α induced phosphorylation and degradation of IκB and an increase in NF-κB DNA-binding activity. The survival-prolonging effect of TNF-α was reversed by inhibitors of NF-κB pyrrolidinedithiocarbamate and gliotoxin and by an inhibitor of IκB kinase, BMS-345541. TNF-α induced also an increase in AP-1 DNA-binding activity and the antiapoptotic effect of TNF-α was potentiated by inhibitors of AP-1, SR 11302 and tanshinone IIA and by an inhibitor of c-jun-N-terminal kinase, SP600125, which is an upstream kinase activating AP-1. Our results thus suggest that TNF-α delays human eosinophil apoptosis via TNF-receptor 1 and the resulting changes in longevity depend on yin-yang balance between activation of NF-κB and AP-1.

Topics: Antibodies; Apoptosis; Asthma; Cell Survival; Eosinophils; fas Receptor; Gene Expression Regulation; Gliotoxin; Humans; I-kappa B Kinase; Imidazoles; NF-kappa B; Phosphorylation; Primary Cell Culture; Protein Binding; Pyrrolidines; Quinoxalines; Receptors, Tumor Necrosis Factor, Type I; Retinoids; Signal Transduction; Thiocarbamates; Transcription Factor AP-1; Tumor Necrosis Factor-alpha