Abstract
BackgroundRetinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. RXRs play key roles not only as homodimers but also as heterodimeric partners, e.g., for retinoic acid receptors, vitamin D receptors, and peroxisome proliferator-activated receptors. The NR family may also play important roles in the development of emphysema. However, the role of RXRs in the pathogenesis of emphysema is not well defined.MethodsWe developed a novel RXR partial agonist (NEt-4IB) and investigated its effect and mechanism compared to a full agonist (bexarotene) in a murine model of emphysema. For emphysema induction, BALB/c mice received intraperitoneal cigarette smoke extract (CSE) or intratracheal porcine pancreas elastase (PPE). Treatment with RXR agonists was initiated before or after emphysema induction.ResultsTreatment with NEt-4IB significantly suppressed the increase in static lung compliance and emphysematous changes in CSE-induced emphysema and PPE-induced established and progressive emphysema. NEt-4IB significantly suppressed PPE-induced neutrophilic airway inflammation and the levels of keratinocyte chemoattractant (KC), C-X-C motif ligand5 (CXCL5), interferon (IFN)-γ and IL-17. NEt-4IB also improved the matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) imbalance and the reduced anti-oxidant activity in bronchoalveolar lavage (BAL) fluid. NEt-4IB suppressed PPE-induced vascular endothelial growth factor (VEGF) expression in the airway. Treatment with NEt-4IB and bexarotene significantly suppressed the increase in static lung compliance and emphysematous changes. However, adverse effects of RXR agonists, including hypertriglyceridemia and hepatomegaly, were observed in bexarotene-treated mice but not in NEt-4IB-treated mice.ConclusionThese data suggest that RXRs play crucial roles in emphysema and airway inflammation, and novel partial RXR agonists could be potential therapeutic strategies for the treatment of PPE- and CSE-induced emphysema.
Highlights
Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative
The optimal dosage of the novel RXR partial agonist NEt-4IB in a murine model We assessed the dose-related effects of the novel RXR partial agonist NEt-4IB in a murine model of emphysema to determine the optimal dosage of NEt-4IB in an emphysema model. These results suggested that the optimal concentration of NEt-4IB in our murine emphysema model was 0.015%; this concentration has therapeutic efficacy without inducing adverse effects and is consistent with our recent study in a murine model of asthma [20]
Treatment with 0.015% NEt-4IB significantly suppressed the increases in Mean linear intercept (Lm) and destructive index (DI) values compared to the increases in cigarette smoke extract (CSE)/vehicle mice (Fig. 1b)
Summary
Retinoid X receptors (RXRs) are members of the nuclear receptor (NR) superfamily that mediate signalling by 9-cis retinoic acid, a vitamin A derivative. Retinoid X receptors (RXRs) are NRs that control gene transcription in a manner dependent on ligand binding [5] and act as homodimers or heterodimers with PPARs, LXRs, and other NRs [6,7,8]. These data suggest that RXRs may be potential targets for the prevention and management of COPD. We previously reported that a new RXR full agonist, NEt-TMN, has the potential to reduce adverse effects while retaining desired activities [13]. RXR full agonists including NEt-TMN and bexarotene induce various adverse events, such as weight gain, hepatomegaly, and blood triglyceride elevation, when used to treat underlying diseases [13]
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