Pirfenidone is an orally active small molecule that has recently been evaluated in large clinical trials for the treatment of idiopathic pulmonary fibrosis, a fatal disease in which the uncontrolled deposition of extracellular matrix leads to progressive loss of lung function. This review describes the activity of pirfenidone in several well-characterised animal models of fibrosis in the lung, liver, heart and kidney. In these studies, treatment-related reductions in fibrosis are associated with modulation of cytokines and growth factors, with the most commonly reported effect being reduction of transforming growth factor-b. The consistent antifibrotic activity of pirfenidone in a broad array of animal models provides a strong preclinical rationale for the clinical characterisation of pirfenidone in pulmonary fibrosis and, potentially, other conditions with a significant fibrotic component. KEYWORDS: Animal model, antifibrotic, fibrosis, idiopathic pulmonary fibrosis, pirfenidone F ibrosis, the dysregulated deposition of extracellular matrix (ECM) with progressive destruction of normal tissue, is a primary or contributing factor in chronic disease states in several organs. Pulmonary fibrosis is associated with numerous diffuse parenchymal lung diseases, of which the most common are idiopathic pulmonary fibrosis (IPF) and sarcoidosis [1]. Cardiac fibrosis is associated with chronic heart failure, atrial fibrillation, and cardiac remodelling following acute myocardial infarction [2,3]. Renal fibrosis is associated with multiple forms of chronic kidney disease and correlates with impairment of kidney function [4,5]. Hepatic fibrosis is associated with chronic hepatitis B and C viral infections and nonalcoholic steatohepatitis [6]. Each of these conditions represents a significant unmet medical need, warranting significant research and clinical study into treatment for fibrotic disease.Pirfenidone (Esbriet1, Pirespa1) is an orally active small molecule comprising a modified phenyl pyridone ( fig. 1). The compound exhibits well documented antifibrotic and anti-inflammatory activities in a variety of animal and cellbased models, although its molecular target has not been elucidated. Pirfenidone was initially identified as having anti-inflammatory activity in animal models and evaluated for use as an antiinflammatory drug [7,8]. However, the unexpected identification of antifibrotic effects in animals treated with pirfenidone redefined the interest in the compound [9]. Subsequently, pirfenidone has been shown to attenuate fibrosis in numerous animal models, including fibrosis of the lung, liver, heart and kidney.The most extensive clinical studies of pirfenidone are for treatment of IPF, a chronic interstitial lung disease characterised by the unregulated deposition of ECM leading to the unremitting destruction of normal lung. Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure. The estimated median survival upon diagnosis is approximately ...
Objective. To evaluate the role of the MEK/ERK MAP kinase pathway in murine collagen-induced arthritis (CIA) using the selective MEK inhibitor PD184352. We examined the effects of the inhibitor in cytokine-stimulated synovial fibroblasts and in cytokine-induced arthritis in rabbits to investigate its antiinflammatory mechanisms.Methods. Murine CIA was used to assess the effects of the selective MEK inhibitor on paw edema, clinical scores, weight loss, histopathologic features, and joint levels of p-ERK. Western blotting and immunohistochemistry techniques were used to assess p-ERK in human and rabbit synovial fibroblasts and synovial tissue from rheumatoid arthritis (RA) patients. Interleukin-1␣ (IL-1␣)-stimulated stromelysin production in rabbit synovial fibroblasts was assessed by enzyme-linked immunosorbent assay. A rabbit IL-1␣-induced arthritis model was used to assess the effects of the inhibitor on IL-1␣-induced MEK activity, stromelysin production, and cartilage degradation.Results. In the CIA model, PD184352 inhibited paw edema and clinical arthritis scores in a dosedependent manner. Disease-induced weight loss and histopathologic changes were also significantly improved by treatment. Inhibition of disease-induced p-ERK levels in the joints was seen with the inhibitor. Levels of p-ERK in the synovium were higher in RA patients than in normal individuals. PD184352 reduced IL-1␣-induced p-ERK levels in human RA synovial fibroblasts. The production of p-ERK and stromelysin was also inhibited in IL-1␣-stimulated rabbit synovial fibroblasts. We observed IL-1␣-induced p-ERK in the synovial lining, subsynovial vasculature, and articular chondrocytes. IL-1␣-induced stromelysin production and proteoglycan loss from the articular cartilage were reduced by PD184352.Conclusion. These data demonstrate the inhibition of murine CIA by PD184352, support the hypothesis that antiinflammatory activity contributes to the mechanism of action of the inhibitor, and suggest that a selective inhibitor may effectively treat RA and other inflammatory disorders.
Murine collagen-induced arthritis (CIA) has become a valuable animal model for elucidating pathogenic mechanisms and evaluating therapeutic effects for rheumatoid arthritis. Recent advances in digital imaging and computer technology have enabled gait analysis to develop into a powerful tool for objectively detecting functional deficits in human and animal models. The present study explored the use of non-invasive video-capture gait analysis in the evaluation of a murine CIA model. CIA was induced in 45 female DBA/1LacJ mice (8 to 10 weeks old) by immunization with lyophilized bovine articular type II collagen. Gait parameters were determined by ventral plane videography and were correlated to traditional arthritis clinical scores. Our results showed that increases in clinical scores that measure the severity of CIA corresponded to changes in multiple gait parameters that reflect both morphologic (increases in paw area) and functional (increase in stride frequency, decrease in stride length, hind-limb paw placement angle, as well as stride, stance, and braking times) deficits. Our work indicated that the non-invasive video-capture device may be used as a simple and objective data acquisition system for quantifying gait disturbances in CIA mice for the investigation of mechanisms and the evaluation of therapeutic agents.
Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.
In contrast to classical Ion Mobility Spectrometers (IMS) operating at ambient pressure, the High Kinetic Energy Ion Mobility Spectrometer (HiKE-IMS) is operated at reduced pressures of between 10 and 40 mbar and higher reduced electric field strengths of up to 120 Td. Thus, the ion–molecule reactions occurring in the HiKE-IMS can significantly differ from those in classical ambient pressure IMS. In order to predict the ionization pathways of specific analyte molecules, profound knowledge of the reactant ion species generated in HiKE-IMS and their dependence on the ionization conditions is essential. In this work, the formation of positive reactant ions in HiKE-IMS is investigated in detail. On the basis of kinetic and thermodynamic data from the literature, the ion–molecule reactions are kinetically modeled. To verify the model, we present measurements of the reactant ion population and its dependence on the reduced electric field strength, the operating pressure, and the water concentration in the sample gas. All of these parameters significantly affect the reactant ion population formed in HiKE-IMS.
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