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.
RationalePulmonary arterial hypertension (PAH) is a rare progressive pulmonary vascular disorder associated with vascular remodeling and right heart failure. Vascular remodeling involves numerous signaling cascades governing pulmonary arterial smooth muscle cell (PASMC) proliferation, migration and differentiation. Glycogen synthase kinase 3beta (GSK3ß) is a serine/threonine kinase and can act as a downstream regulatory switch for numerous signaling pathways. Hence, we hypothesized that GSK3ß plays a crucial role in pulmonary vascular remodeling.MethodsAll experiments were done with lung tissue or isolated PASMCs in a well-established monocrotaline (MCT)-induced PAH rat model. The mRNA expression of Wnt ligands (Wnt1, Wnt3a, Wnt5a), upstream Wnt signaling regulator genes (Frizzled Receptors 1, 2 and secreted Frizzled related protein sFRP-1) and canonical Wnt intracellular effectors (GSK3ß, Axin1) were assessed by real-time polymerase chain reaction and protein levels of GSK3ß, phospho-GSK3ß (ser 9) by western blotting and localization by immunohistochemistry. The role of GSK3ß in PASMCs proliferation was assessed by overexpression of wild-type GSK3ß (WT) and constitutively active GSK3ß S9A by [3H]-thymidine incorporation assay.ResultsIncreased levels of total and phosphorylated GSK3ß (inhibitory phosphorylation) were observed in lungs and PASMCs isolated from MCT-induced PAH rats compared to controls. Further, stimulation of MCT-PASMCs with growth factors induced GSK3ß inactivation. Most importantly, treatment with the PDGFR inhibitor, Imatinib, attenuated PDGF-BB and FCS induced GSK3ß phosphorylation. Increased expression of GSK3ß observed in lungs and PASMC isolated from MCT-induced PAH rats was confirmed to be clinically relevant as the same observation was identified in human iPAH lung explants. Overexpression of GSK3ß significantly increased MCT-PASMCs proliferation by regulating ERK phosphorylation. Constitutive activation of GSK3ß (GSK3ß S9A, 9th serine replaced to alanine) inhibited MCT-PASMCs proliferation by decreasing ERK phosphorylation.ConclusionThis study supports a central role for GSK3ß in vascular remodeling processes and suggests a novel therapeutic opportunity for the treatment of PAH.
Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule 3 led to the identification of compound 9 (OATD-01), a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. OATD-01 given orally once daily in a range of doses between 30 and 100 mg/kg showed significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor, currently completed phase 1b of clinical trials, to be a potential treatment for IPF.
Asthma is a chronic inflammatory disease, which is characterized by activation of CD4(+) T helper 2 cells orchestrating an allergic airway response. Whereas the role of Wnt family members in regulating T cell maintenance and maturation is established, their contribution to T cell activation in allergic asthma is not known. We hypothesized that Wnt10b plays a role in the modulation of the allergic airway response and affects T cell activation and polarization. Using an in vivo house dust mite asthma model, Wnt10b-deficient (Wnt10b(-/-)) mice were allergen-sensitized and inflammation, as well as T cell activation, was studied in vivo and in vitro. Wnt10b(-/-) mice exhibited an augmented inflammatory phenotype with an increase in eosinophils in the bronchoalveolar lavage and IL-4 and IL-13 in the lungs when compared with wild-type mice. In vitro studies confirmed an increased T helper type 2 polarization and increased T cell activation of Wnt10b(-/-) cells. Accordingly, the percentage of naive T cells was elevated by the addition of recombinant Wnt10b protein. Finally, Wnt10b(-/-) mice exhibited an increase in the percentage of effector T cells in the lungs after house dust mite sensitization, which indicated a heightened activation state, measured by an increased percentage of CD69(hi)CD11a(hi) cells. These findings suggest that Wnt10b plays an important role in regulating asthmatic airway inflammation through modification of the T cell response and is a prospective target in the disease process.
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