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Scleroderma
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
The RhoA/ROCK pathway is important in the activation of myofibroblasts leading to matrix stiffening through STAT3 phosphorylation (101, 102). Similarly, the lysophosphatidic acid (LPA) receptor family can also activate the RhoA/ROCK pathway and induce the differentiation of fibroblasts (103). In a bleomycin- induced mouse model of SSc, a novel autotaxin inhibitor, PAT-048, markedly attenuated dermal fibrosis when treatment was initiated before or after the development of fibrosis (104). This study also highlighted the importance of autotaxin playing a major role in the pathogenic loop of SSc fibrogenesis, including LPA and IL-6, to amplify the production of each other.
Disorders of the digestive tract
Published in Judy Bothamley, Maureen Boyle, Medical Conditions Affecting Pregnancy and Childbirth, 2020
It is not clear what causes the itching of ICP. Laboratory studies of nerve fibres have identified that a substance known as lysophosphatidic acid produced by the enzyme autotaxin can mimic an itching effect73. These substances along with certain progesterone sulphates74 have been identified in women with ICP and may offer direction for research into developing strategies to reduce the distress of itching.
Itch and Sensitive Skin
Published in Golara Honari, Rosa M. Andersen, Howard Maibach, Sensitive Skin Syndrome, 2017
Researchers have tried to identify biomarkers for pain and itch for decades. In more recent years, there has been some success as lysophosphatidic acid and its generating enzyme autotaxin have been found to correlate with the severity of pruritus in cholestatic pregnant women (61,62). Interestingly, lysophosphatidic acid has also been linked to the mechanisms of neuropathic pain (63). For neuropathic pain, there is evidence that methylglyoxal, a metabolite in the glucose metabolism, might serve as a biomarker for pain in painful diabetic neuropathy (64). Yet, there are no clinical trials that would use therapeutic approaches based on these two biomarkers. In terms of innovative mechanism-based therapies in the pain field, anti-NGF has proven to be clinically effective against chronic inflammatory pain (42,65). Interestingly, there are also suggestions to use the same approach in chronic itch (44). Antagonists of the neuropeptide SP have failed as a treatment for chronic pain (66) but appear promising as antipruritics (67,68). Thus, there are advances in itch and pain research that have resulted in the identification of first biomarkers and the successful development of therapies. The key question would be how this knowledge can be used for research in sensitive skin.
Emerging drugs for the treatment of scleroderma: a review of recent phase 2 and 3 trials
Published in Expert Opinion on Emerging Drugs, 2020
David Roofeh, Alain Lescoat, Dinesh Khanna
In a preclinical model of SSc, lysophosphatidic acid (LPA-LPA1) signaling participates in myofibroblast accumulation, and TGF-β canonical pathway activation. LPA also impairs anti-inflammatory and pro-resolving properties of macrophages in other pulmonary disorders [102]. In an 8-week double-blind, randomized, placebo-controlled study followed by a 16-week open-label, SAR100842 a selective orally available LPA1 receptor antagonist, was well tolerated in patients with dcSSc and showed a numerically higher reduction of mRSS in the SAR100842 group [103]. The Autotaxin pathway may also play a key role in the fibrotic manifestations of SSc as autotaxin is required for the development and maintenance of dermal fibrosis in pre-clinical models through co-amplification of LPA and IL-6 [104]. Combination therapies both targeting the LPA pathways and the JAK/STAT-dependent IL-6 signaling may constitute a promising therapeutic approach. With this regards, combination of monoclonal antibodies should also be discussed in the future.
Therapeutic targets and early stage clinical trials for pulmonary fibrosis
Published in Expert Opinion on Investigational Drugs, 2019
Seidai Sato, Toyoshi Yanagihara, Martin R. J. Kolb
The oral autotaxin (ATX) inhibitor GLPG1690 (Galapagos NV) is an agent targeting lysophosphatidic acid (LPA). ATX is the enzyme principally responsible for extracellular LPA production, and increased concentrations of ATX have been found in the lungs of patients with IPF and bronchoalveolar lavage fluid (BALF) from mice with experimental fibrosis [21]. LPA is a phospholipid mediator that binds to six receptors (LPA1–6) involved in cell survival, proliferation, migration, differentiation, vascular regulation, and cytokine release [22]. The genetic deletion of LPA1 attenuates bleomycin-induced lung fibrosis in mice via reduced fibroblast recruitment and vascular leak [23]. The genetic deletion of ATX from bronchial epithelial cells or macrophages also attenuates bleomycin-induced lung fibrosis and inhibition of ATX reduced the development of pulmonary fibrosis in mice [24]. One study reported that autotaxin may not be essential for LPA production and fibrosis progression in the lung based on the results that an autotaxin inhibitor, PAT-048, failed to decrease LPA production and inhibit pulmonary fibrosis in bleomycin-induced lung fibrosis in mice [25]. On the contrary, in GLPG1690-treated mice, there is an inverse relationship between LPA and GLPG1690 plasma levels [26], and administration of GLPG1690 reduced disease severity of bleomycin-induced pulmonary fibrosis [27]. The discrepancies between these experiments may be due to the differences of the drugs.
Autotaxin Expression in Hepatocellular Carcinoma
Published in Journal of Investigative Surgery, 2018
Ilker Memet, Evanthia Tsalkidou, Alexandra K Tsaroucha, Maria Lambropoulou, Ekaterini Chatzaki, Gregory Trypsianis, Dimitrios Schizas, Michael Pitiakoudis, Constantinos Simopoulos
For this reason molecular pathogenesis of HCC has been systematically investigated during the last years and preclinical models have focused on upregulating molecular signaling pathways and angiogenesis in tumor evolution [5, 6]. Autotaxin was found to possess lysophospholipase D activity [7, 8], hydrolyzing lysophosphatidylcholine to produce lysophosphatidic acid (LPA), a lipid stimulator of cell migration and angiogenesis. Autotaxin and its role in cancer invasion or metastasis have been intensively studied. Its expression in Hodgkin lymphoma [9], glioblastoma [10], non-small cell lung cancer [11], renal cell carcinoma [12], breast cancer [13], thyroid carcinoma [14] as well as melanoma [15] has been reported. Recently, a limited number of studies report an evidence of autotaxin tissue expression in HCC [16–19].