Adrenomedullin as a Potential Therapeutic Agent for Inflammatory Bowel Disease

Abstract

Adrenomedullin (AM) was originally isolated from human pheochromocytoma as a biologically active peptide with potent vasodilating action but is now known to exert a wide range of physiological effects, including cardiovascular protection, neovascularization, and apoptosis suppression. A variety of tissues, including the gastrointestinal tract, have been shown to constitutively produce AM. Pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1, and lipopolysaccharides, induce the production and secretion of AM. Conversely, AM induces the downregulation of inflammatory cytokines in cultured cells. Furthermore, AM downregulates inflammatory processes in a variety of different colitis models, including acetic acid-induced colitis and dextran sulfate sodium-induced colitis. AM exerts antiinflammatory and antibacterial effects and stimulates mucosal regeneration for the maintenance of the colonic epithelial barrier. Here, we describe the first use of AM to treat patients with refractory ulcerative colitis. The results strongly suggest that AM has potential as a new therapeutic agent for the treatment of refractory ulcerative colitis.

<p>Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial</p>

“…12 These data strongly suggest that AM is a novel potent therapeutic agent for IBD. 13 Additionally, AM is an endogenous peptide; thus, it is expected to be safe for patients without the need for excessive immune-suppression and antibody production.…”

Bench-to-bedside pharmacology of adrenomedullin

“…1 (Cooper et al, 1987;Kato and Kitamura, 2013;Roh et al, 2004;Takei et al, 2004). Since the discovery of AM, a substantial number of pharmacological experiments have been performed, revealing that it is involved in mechanisms regulating or modulating biological functions in various types of cell, tissue, or organ through its pleiotropic actions (Ashizuka et al, 2013a;Kato et al, 2005Kato et al, , 2003aKitamura et al, 2002). In that process, basic research was often necessary to interpret phenomena observed clinically in patients, and indeed, these clinical findings have promoted basic pharmacological research on AM.…”

Gene expression analysis of neuropeptides in oral mucosa during periodontal disease in non‐human primates

“…23 Cellular activation by ADM requires its interaction with two different receptors, CALCLR and RAMP2/RAMP3). 23 There is evidence indicating that ADM inhibits inflammation by decreasing pro-inflammatory cytokine production, and T-cell proliferation; however, ADM also has potent vasodilation properties 24 . Hence, increased ADM in gingival tissues during progression of periodontitis could involve an increase in the number of recruited inflammatory cells into the gingival milieu due to its vasodilatory properties.…”

“…23 There is evidence indicating that ADM inhibits inflammation by decreasing pro-inflammatory cytokine production and Tcell proliferation; however, ADM also has potent vasodilation properties. 24 Hence, increased ADM in gingival tissues during progression of periodontitis could involve an increase in the number of recruited inflammatory cells into the gingival milieu due to its vasodilatory properties. However, coincident with this activity, ADM could also block the expression of important inflammatory mediators by these recruited immune cells to control the infection.…”