Inhibition of Prostaglandin D Synthase Suppresses Muscular Necrosis

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 D₂. 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 D₂ 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 β1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D₂ 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.Duchenne muscular dystrophy (DMD) is one of the most common types of muscular dystrophy, affecting approximately 1 out of 3500 boys.¹ Progressive muscular dystrophy in DMD is caused by membrane vulnerability,² which results from a defect in the muscle protein dystrophin,^3,4 but the precise pathophysiology of the disease progression is not known. There is still no complete cure for this disastrous disease, albeit gene transfer has been extensively tried in mammalian models. Glucocorticoids^5,6 and their analogs⁷ are effective in suppressing the disease only to some degree. In DMD, these steroids reduce the infiltration of inflammatory cells into the muscle⁸ and down-regulate the expression of genes involved in the immune response.⁹ These data suggest inflammation may play a role in the progression of the disease.Earlier we reported the expression of hematopoietic prostaglandin (PG) D synthase (HPGDS), the enzyme responsible for the production of PGD₂,¹⁰ in necrotic muscle fibers, mainly in the focus of grouped necrosis, in patients with DMD or polymyositis.¹¹ We recently reported that overproduction of PGD₂ produced by HPGDS aggravates inflammation and causes profound tissue damage in twitcher, a genetic demyelinating mouse model.¹² The biosynthesis of PGs was also suppressed by glucocorticoids, via suppression of enzymes in the overall synthesis of PGs including phospholipase A₂ and cyclooxygenase. PGD₂ mediates inflammatory responses through two specific receptors, DP1¹³ and DP2,¹⁴ causing peripheral vasodilatation, augmentation of vascular permeability, and chemotaxis.¹⁵ Based on these findings, we hypothesized that HPGDS augments the inflammation that is followed by the muscle injury, especially in the foci of grouped necrosis. Here, using bupivacaine hydrochloride (BPVC)-induced muscle necrosis, where sequences of muscle necrosis are similar to that of progressive muscular dystrophy,¹⁶ and the mdx mouse as a DMD model, we clarified the role of PGD₂ in the pathogenesis and investigated the therapeutic potentials of blockade of HPGDS/PGD₂/DP signaling on the muscular necrosis.