This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150× against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.
Macrophage infiltration is common to both emphysema and atherosclerosis, and cigarette smoke down-regulates the macrophage cholesterol efflux transporter ATP binding cassette (ABC)A1. This decreased cholesterol efflux results in lipid-laden macrophages. We hypothesize that cigarette smoke adversely affects cholesterol transport via an ABCA1-dependent mechanism in macrophages, enhancing TLR4/myeloid differentiation primary response gene 88 (Myd88) signaling and resulting in matrix metalloproteinase (MMP) up-regulation and exacerbation of pulmonary inflammation. ABCA1 is significantly down-regulated in the lung upon smoke exposure conditions. Macrophages exposed to cigarette smoke in vivo and in vitro exhibit impaired cholesterol efflux correlating with significantly decreased ABCA1 expression, up-regulation of the TLR4/Myd88 pathway, and downstream MMP-9 and MMP-13 expression. Treatment with liver X receptor (LXR) agonist restores ABCA1 expression after short-term smoke exposure and attenuates the inflammatory response; after long-term smoke exposure, there is also attenuated physiologic and morphologic changes of emphysema. In vitro, treatment with LXR agonist decreases macrophage inflammatory activation in wild-type but not ABCA1 knockout mice, suggesting an ABCA1-dependent mechanism of action. These studies demonstrate an important association between cigarette smoke exposure and cholesterol-mediated pathways in the macrophage inflammatory response. Modulation of these pathways through manipulation of ABCA1 activity effectively blocks cigarette smoke-induced inflammation and provides a potential novel therapeutic approach for the treatment of chronic obstructive pulmonary disease.-Sonett, J., Goldklang, M., Sklepkiewicz, P., Gerber, A., Trischler, J., Zelonina, T., Westerterp, M., Lemaître, V., Okada, V., D'Armiento, J. A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure.
Developmentally expressed genes are believed to play a central role in tissue repair after injury; however, in lung disease their role has not been established. This study demonstrates that SFRP1, an inhibitor of Wnt signaling normally expressed during lung embryogenesis, is induced in the lungs of emphysema patients and in two murine models of the disease. SFRP1 was found to be essential for alveolar formation as Sfrp1 ؊/؊ mice exhibited aberrant Wnt signaling, mesenchymal proliferation, and impaired alveoli formation. In contrast , SFRP1 activated ERK and up-regulated MMP1 and MMP9 without altering TIMP1 production when expressed in human lung epithelial cells. These findings demonstrate that SFRP1 promotes normal alveolar formation in lung development, although its expression in the adult up-regulates proteins that can cause tissue destruction. Thus, SFRP1 induction during tissue injury is unlikely to contribute to the repair response but rather is a participatory factor in the pathogenesis of emphysema and tissue destruction. (Am J Pathol
Background The Wnt/β-catenin signaling pathway plays a central role during cardiac development and has been implicated in cardiac remodeling and aging. However, the role of Wnt modulators in this process is unknown. In the present study, we examined the role of the Wnt signaling inhibitor sFRP-1 in aged wildtype and sFRP-1 deficient mice. Methods and Results sFRP-1 gene deletion mice were grossly normal with no difference in mortality but developed abnormal cardiac structure and dysfunction with progressive age. Ventricular dilation and hypertrophy in addition to deterioration of cardiac function and massive cardiac fibrosis, all features present in dilated cardiomyopathy was observed in the aged sFRP-1 KO mice when aged. Loss of sFRP-1 led to increased expression of Wnt ligands (Wnt1, 3, 7b, 16) and Wnt target genes (Wisp1, Lef1) in aged hearts, which correlated with increased protein levels of β-Catenin. Cardiac fibroblasts lacking endogenous sFRP-1 showed increased αSMA expression, higher cell proliferation rates and increased collagen production consistent with the cardiac phenotype exhibited in aged sFRP-1 KO mice. The clinical relevance of these findings was supported by the demonstration of decreased sFRP-1 gene expression and increased Wisp-1 levels in the left ventricles of patients with ischemic dilated cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). Conclusions This study identifies a novel role for sFRP-1 in age-related cardiac deterioration and fibrosis. Further exploration of this pathway will identify downstream molecules important in these processes and also suggest the potential use of Wnt signaling agents as therapeutic targets for age-related cardiovascular disorders in humans.
Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure–activity relationships within the series of 1-(3-amino-1H-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.e., AMCase and CHIT1) inhibitors with very good pharmacokinetic properties. Among them, compound 30 was shown to reduce the total number of cells in bronchoalveolar lavage fluid of mice challenged with house dust mite extract after oral administration (50 mg/kg, qd). In addition, affinity toward the hERG potassium channel of compound 30 was significantly reduced when compared to the earlier reported chitinase inhibitors.
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