Secretory leukocyte protease inhibitor plays an important role in the regulation of allergic asthma in mice.

Secretory leukocyte protease inhibitor (SLPI) is an anti-inflammatory protein that is observed at high levels in asthma patients. Resiquimod, a TLR7/8 ligand, is protective against acute and chronic asthma, and it increases SLPI expression of macrophages in vitro. However, the protective role played by SLPI and the interactions between the SLPI and resiquimod pathways in the immune response occurring in allergic asthma have not been fully elucidated. To evaluate the role of SLPI in the development of asthma phenotypes and the effect of resiquimod treatment on SLPI, we assessed airway resistance and inflammatory parameters in the lungs of OVA-induced asthmatic SLPI transgenic and knockout mice and in mice treated with resiquimod. Compared with wild-type mice, allergic SLPI transgenic mice showed a decrease in lung resistance (p < 0.001), airway eosinophilia (p < 0.001), goblet cell hyperplasia (p < 0.001), and plasma IgE levels (p < 0.001). Allergic SLPI knockout mice displayed phenotype changes significantly more severe compared with wild-type mice. These phenotypes included lung resistance (p < 0.001), airway eosinophilia (p < 0.001), goblet cell hyperplasia (p < 0.001), cytokine levels in the lungs (p < 0.05), and plasma IgE levels (p < 0.001). Treatment of asthmatic transgenic mice with resiquimod increased the expression of SLPI and decreased inflammation in the lungs; resiquimod treatment was still effective in asthmatic SLPI knockout mice. Taken together, our study showed that the expression of SLPI protects against allergic asthma phenotypes, and treatment by resiquimod is independent of SLPI expression, displayed through the use of transgenic and knockout SLPI mice.

Modulation of the allergic asthma transcriptome following resiquimod treatment.

Resiquimod is a compound belonging to the imidazoquinoline family of compounds known to signal through Toll-like receptor 7. Resiquimod treatment has been demonstrated to inhibit the development of allergen induced asthma in experimental models. The aim of the present study was to elucidate the molecular processes that were altered following resiquimod treatment and allergen challenge in a mouse model of allergic asthma. Employing microarray analysis, we have characterized the "asthmatic" transcriptome of the lungs of A/J and C57BL/6 mice and determined that it includes genes involved in the control of cell cycle progression, the complement and coagulation cascades, and chemokine signaling. Our results demonstrated that resiquimod treatment resulted in the normalization of the expression of genes involved with airway remodeling, and generally, chemokine signaling. Resiquimod treatment also altered the expression of cell adhesion molecules, and molecules involved in natural killer (NK) cell-mediated cytotoxicity. Furthermore, we have demonstrated that systemic resiquimod administration resulted in the recruitment of NK cells to the lungs and livers of the mice, although no causal relationship between NK cell recruitment and treatment efficacy was found. Overall, our findings identified several genes, important in the development of asthma pathology, that were normalized following resiquimod treatment, thus improving our understanding of the molecular consequences of resiquimod treatment in the lung milieu. The recruitment of NK cells to the lungs may also have application in the treatment of virally induced asthma exacerbations.

Fenretinide prevents the development of osteoporosis in Cftr-KO mice.

BACKGROUND: The most recently described phenotype associated with Cystic Fibrosis (CF) is reduced bone mineral density which results in osteopenia and osteoporosis. The etiology of the early onset of osteoporosis in CF patients has remained to be established. It has been suggested that inadequate nutritional absorption of essential fatty acids may play a role in the altered bone metabolism. In this study, we characterized the protective effect of fenretinide [N-(4-hydroxyphenyl) retinamide], a vitamin A derivative, on the early onset of osteoporosis in cystic fibrosis transmembrane conductance regulator knockout (Cftr-KO) mice. METHODS: Using micro-computed-tomography we examined the effect of fenretinide on the bone composition and architecture in a Cftr-KO mouse model which was then confirmed with histological analyses. Plasma fatty acids were quantified using thin layer chromatography-ELISA method. RESULTS: Twice-weekly treatments with fenretinide, over four weeks dramatically increased trabecular bone volume compared to controls. This increase in bone volume was also related to an increased concentration of ceramide in the plasma resulting in the down regulation of phospholipid-bound AA in Cftr-KO mice. CONCLUSIONS: To our knowledge, this is the first time that fenretinide's protective effect against osteoporosis has been demonstrated. The results of this study strongly suggest that fenretinide has potential to be used as a prophylaxis by preventing the early onset of osteoporosis.