Inhibition of Prostaglandin D Synthase Suppresses Muscular Necrosis

Abstract

Duchenne muscular dystrophy is a fatal muscle wasting disease that is characterized by a deficiency in the protein dystrophin. Previously, we reported that the expression of hematopoietic prostaglandin D synthase (HPGDS) appeared in necrotic muscle fibers from patients with either Duchenne muscular dystrophy or polymyositis. HPGDS is responsible for the production of the inflammatory mediator, prostaglandin D(2). In this paper, we validated the hypothesis that HPGDS has a role in the etiology of muscular necrosis. We investigated the expression of HPGDS/ prostaglandin D(2) signaling using two different mouse models of muscle necrosis, that is, bupivacaine-induced muscle necrosis and the mdx mouse, which has a genetic muscular dystrophy. We treated each mouse model with the HPGDS-specific inhibitor, HQL-79, and measured both necrotic muscle volume and selected cytokine mRNA levels. We confirmed that HPGDS expression was induced in necrotic muscle fibers in both bupivacaine-injected muscle and mdx mice. After administration of HQL-79, necrotic muscle volume was significantly decreased in both mouse models. Additionally, mRNA levels of both CD11b and transforming growth factor beta1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D(2) production and improved muscle strength in the mdx mouse. Our results show that HPGDS augments inflammation, which is followed by muscle injury. Furthermore, the inhibition of HPGDS ameliorates muscle necrosis even in cases of genetic muscular dystrophy.

Novel interactions between mitochondrial superoxide dismutases and the electron transport chain

“…However, reduction in gst‐14 expression lengthened the lifespan of both gas‐1 and sod‐2 ; gas‐1 . The protein GST‐14 is most homologous to the mammalian pro‐inflammatory protein, hematopoetic prostaglandin D2 synthase (HPGDS) (Kanaoka & Urade, ; Mohri et al ., ). Given this homology, we hypothesize that GST‐14 actually is responsible for an inflammatory response in nematodes, rather than ROS scavenging, and are testing this possibility.…”

Macrophages programmed by apoptotic cells inhibit epithelial-mesenchymal transition in lung alveolar epithelial cells via PGE2, PGD2, and HGF

“… 31 , or EP4 antagonist AH-23848 (10 mg/kg, i.p.) 63 , or the selective PGD 2 receptor DP1 antagonist BW-A868C (1 mg/kg, S.C.) 64 or the selective c-Met inhibitor PHA-665752 (25 mg/kg, i.p.) 31 53 was administrated at the same time as instillation of 10 × 10 6 apoptotic Jurkat cells into bleomycin-stimulated lungs (2 days).…”

Enzymes of the Cyclooxygenase Pathways of Prostanoid Biosynthesis

“…Accordingly, human H-PGDS is a promising target for designing drugs to alleviate allergies and inflammation. HQL-79 administration also suppresses the astrogliosis, neuroinflammation, and demyelination seen in the genetic demyelinating twitcher mouse, 178 the expansion of muscular necrosis in mdx mice, 231 an animal model of Duchenne's muscular dystrophy, and secondary tissue damage after spinal cord contusion injury. 232 These results suggest that blockade of H-PGDS/PGD 2 /DP signaling would be an effective therapy for neuroinflammation and muscular dystrophy.…”