VBP15, a Glucocorticoid Analogue, Is Effective at Reducing Allergic Lung Inflammation in Mice

Abstract

Asthma is a chronic inflammatory condition of the lower respiratory tract associated with airway hyperreactivity and mucus obstruction in which a majority of cases are due to an allergic response to environmental allergens. Glucocorticoids such as prednisone have been standard treatment for many inflammatory diseases for the past 60 years. However, despite their effectiveness, long-term treatment is often limited by adverse side effects believed to be caused by glucocorticoid receptor-mediated gene transcription. This has led to the pursuit of compounds that retain the anti-inflammatory properties yet lack the adverse side effects associated with traditional glucocorticoids. We have developed a novel series of steroidal analogues (VBP compounds) that have been previously shown to maintain anti-inflammatory properties such as NFκB-inhibition without inducing glucocorticoid receptor-mediated gene transcription. This study was undertaken to determine the effectiveness of the lead compound, VBP15, in a mouse model of allergic lung inflammation. We show that VBP15 is as effective as the traditional glucocorticoid, prednisolone, at reducing three major hallmarks of lung inflammation—NFκB activity, leukocyte degranulation, and pro-inflammatory cytokine release from human bronchial epithelial cells obtained from patients with asthma. Moreover, we found that VBP15 is capable of reducing inflammation of the lung in vivo to an extent similar to that of prednisone. We found that prednisolone–but not VBP15 shortens the tibia in mice upon a 5 week treatment regimen suggesting effective dissociation of side effects from efficacy. These findings suggest that VBP15 may represent a potent and safer alternative to traditional glucocorticoids in the treatment of asthma and other inflammatory diseases.

VBP15, a novel dissociative steroid compound, reduces NFκB-induced expression of inflammatory cytokines in vitro and symptoms of murine trinitrobenzene sulfonic acid-induced colitis

“…We have previously shown that chronic VBP15 treatment does not affect bone growth in vivo [20,21]. Thus, we determined whether or not extended VBP15 treatment could result in reduced body length by treating young outbred wild type mice (12 days of age) daily for 5 weeks.…”

“…VBP15 is an anti-inflammatory compound that has been shown to be an effective inhibitor of NFjB activity both in vitro and in vivo [19][20][21][22] but does not induce the GREmediated transcription (genomic transactivation property) believed to be responsible for many of the detrimental metabolic side effects of glucocorticoids [19,21]. In the current study, VBP15 inhibited the production of pro-inflammatory cytokines IL-6 and IL-8, as well as chemokine, CCL5, in TNFa-stimulated human intestinal epithelial cells.…”

“…Having previously shown that VBP15 reduces NFjB activity in vitro in muscle cells, lung cells, splenocytes, and macrophages [19][20][21][22], we sought to determine if VBP15 could reduce the expression of pro-inflammatory NFjBregulated cytokines in human intestinal epithelial cells. We treated intestinal epithelial cells for 24 h with VBP15 (10 lM), prednisolone (10 lM), or vehicle control (DMSO) and subsequently stimulated them with TNFa for an additional 24 h. Focusing on three cytokines (CCL5, IL-6 and IL-8) that are important in the pathogenesis of IBD, we found that VBP15 treatment significantly reduced the expression of all three by at least 68 %, and to a similar degree to that observed with prednisolone (Fig.…”

“…1). VBP15 has demonstrated strong anti-inflammatory activity in vivo across multiple murine models of disease, while resulting in a reduced glucocorticoid-associated side effect profile [20][21][22]. The purpose of this study was to assess the effect of VBP15 on disease symptoms in the TNBS-induced mouse model of colitis and further characterize VBP15's in vivo effects on growth during chronic treatment in juvenile mice.…”

VBP15, a Novel Anti-Inflammatory, is Effective at Reducing the Severity of Murine Experimental Autoimmune Encephalomyelitis

“…VBP15 shows strong anti-inflammatory activities with potent inhibition of NFjB activity both in vitro and in vivo Damsker et al 2013;Heier et al 2013). Side effect profiles of VBP15 are also reduced, through selective loss of the GRE-mediated transactivation properties of glucocorticoids Heier et al 2013).…”