Increased lungkine and chitinase levels in allergic airway inflammation: a proteomics approach.

Asthma is a chronic inflammatory disease characterized by pulmonary eosinophilia and airway hyperresponsiveness. Mechanisms underlying the pathogenesis of asthma are still not fully understood. The present study investigated alterations in global protein expression in bronchoalveolar lavage fluid in allergic airway inflammation using a proteomics approach. BALB/c mice sensitized and challenged with ovalbumin developed airway eosinophilia, mucus hypersecretion, elevation of immunoglobulin E, and airway hyperresponsiveness. Lavage fluid proteins from normal and asthmatic mice were resolved by two-dimensional gel electrophoresis, and identified by peptide mass fingerprinting matrix-assisted laser desorption/ionization-time of flight mass spectrometry. A total of 28 protein spots were significantly altered. Several of these proteins were undetectable or at very low levels in normal mice but were significantly increased in airway inflammation. These include lungkine, a recently described chemokine, a family of chitinases including Ym1, Ym2, and acidic mammalian chitinase, gob-5, a protein that mediates mucus secretion, and surfactant protein-D, a C-type lectin capable of modulating inflammatory responses. Overall, proteomics is a powerful tool in unraveling protein expression changes in allergic airway inflammation. The proteins identified in this study may be associated with the pathogenesis of allergic airway inflammation and may also be found useful as surrogate biomarkers for asthma.

Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model.

Mitogen-activated protein kinase (MAPK) signaling cascade plays a pivotal role in the activation of inflammatory cells. Recent findings revealed that the activity of p42/44 MAPK (also known as extracellular signal-regulated kinase (ERK)) in the lungs was significantly higher in asthmatic mice than in normal controls. We hypothesized that inhibition of ERK activity may have anti-inflammatory effects in allergic asthma. BALB/c mice were sensitized with OVA and, upon OVA aerosol challenge, developed airway eosinophilia, mucus hypersecretion, elevation in cytokine and chemokine levels, up-regulation of VCAM-1 expression, and airway hyperresponsiveness. Intraperitoneal administration of U0126, a specific MAPK/ERK kinase inhibitor, significantly (p < 0.05) inhibited OVA-induced increases in total cell counts, eosinophil counts, and IL-4, IL-5, IL-13, and eotaxin levels recovered in bronchoalveolar lavage fluid in a dose-dependent manner. U0126 also substantially (p < 0.05) reduced the serum levels of total IgE and OVA-specific IgE and IgG1. Histological studies show that U0126 dramatically inhibited OVA-induced lung tissue eosinophilia, airway mucus production, and expression of VCAM-1 in lung tissues. In addition, U0126 significantly (p < 0.05) suppressed OVA-induced airway hyperresponsiveness to inhaled methacholine in a dose-dependent manner. Western blot analysis of whole lung lysates shows that U0126 markedly attenuated OVA-induced tyrosine phosphorylation of ERK1/2. Taken together, our findings implicate that inhibition of ERK signaling pathway may have therapeutic potential for the treatment of allergic airway inflammation.