Vasoactive Intestinal Peptide Knockout (VIP KO) mouse model of sulfite-sensitive asthma: up-regulation of novel lung carbonyl reductase

Four male VIP KO mice and four wild-type age- and gender matched mice had lungs examined for whole genome microarray and a proteomics approach using mass spectrometry. The proteomics analysis revealed that a novel variant of anti-oxidant protein lung carbonyl reductase (car3) was uniquely and markedly elevated in the VIP KO mice. RT-PCR indicated that carbonic anhydrase 3, which is an anti-oxidant protein, was elevated in the VIP KO mice.These data support the concept that VIP influences the endogenous oxidant/antioxidant balance. One potential implication is that VIP and its analogues may be used to treat inflammatory diseases, including asthma.Asthma is an inflammatory airway disease with airway hyper-responsiveness to inhaled irritants such as methacholine and aeroallergens. Vasoactive Intestinal Peptide (VIP) is an endogenous anti-inflammatory peptide found in airway nerve terminals and mast cells, which also has potent airway smooth muscle relaxant properties [1]. We earlier reported that mice lacking VIP have the spontaneous asthma phenotype: 1) peribronchiolar airway inflammation with lymphocytes and eosinophils, and 2) airway hyper-responsiveness to inhaled methacholine. These Vasoactive Intestinal Peptide knockout mice (VIP KO) prepared by disruption by homologous recombination [2,3] have spontaneous airway inflammation, that is chronic, and airway hyper-responsiveness, that does-dependently increases with methacholine in the absence of allergic sensitization and challenge [1]. These features are consistent with the asthma phenotype. There is upregulation of pro-inflammatory and pro-remodeling genes [4]. Th1 and Th2 pro-inflammatory cytokines (IFN-γ, IL-5, IL-6) are upregulated in bronchoalveolar lavage fluid (BALF) spontaneously--without the need for antigenic sensitization and challenge [1].In human asthma, a phenotype with sulfite sensitivity, leads to airway inflammation and hyper-responsiveness to inhaled sulfites, and is associated with upregulation o