The newest histamine receptor to be
The newest histamine receptor to be discovered is the H4 receptor, which was identified in humans and cloned in 2000 (Thurmond, 2010). Genetically, the H4 receptor is closely related to the H3 receptor, but is restricted to KPT-335 sale within the spleen, intestines and thymus, and to immune cells such as T cells, mast cells, neutrophils and eosinophils (Thurmond, 2010). In humans, the H4 receptor plays a significant role in regulation of inflammatory responses by inducing inflammatory cell chemotaxis and cytokine release from inflammatory cells (Walter et al., 2011; Thurmond, 2015).
Histamine and histamine receptors have recently become a focus of intense interest in the area of chronic GI disease in people. Many different cell types store and secrete histamine in the GI tract, especially mast cells. Mucosal mast cell accumulation and increased mucosal and luminal concentrations of histamine have been documented in humans with chronic GI diseases such as Crohn’s disease, ulcerative colitis, irritable bowel syndrome and allergic enteropathy (Xie and He, 2005, Thurmond, 2010, Smuda and Bryce, 2011). In the first study to document expression of all histamine receptors in the human GI tract, mRNA associated with H1, H2, and H4 receptors was distributed equally in the mucosa, submucosa and muscular layers, and immunostaining patterns correlated with mRNA expression (Sander et al., 2006). Later studies also confirmed the presence of the H3 receptor in the human GI tract (Breunig et al., 2007). Human patients with irritable bowel syndrome and food allergy have significantly higher expression of H1 and H2 mRNA within the GI tract compared to unaffected individuals (Sander et al., 2006).
Rodent models have also been used to study GI tract histamine receptors. Studies using a commonly employed rodent model, in which the oxidizing hapten TNBS (trinitrobenzenesulfonic acid) induces GI inflammation that mimics Crohn’s disease, have demonstrated increased expression of the H4 receptor in the GI tract and correlation of colitis progression with receptor density (Elson et al., 1995, Coruzzi et al., 2012).
The role of histamine in canine inflammatory bowel disease (IBD) has not been thoroughly investigated, but dogs with IBD have been shown to have increased GI tract mast cell density, and some have high levels of urine N-methylhistamine, a metabolite of histamine (Berghoff et al., 2014). In 2008, the canine H4 receptor was cloned, and PCR techniques were used to identify H4 receptor expression in the canine small intestine (Jiang et al., 2008). More recently, H4 receptor mRNA was identified in the canine colon (Eisenschenk, 2011). To the authors’ knowledge, the specific locations and distribution of all 4 histamine receptors in the entire canine GI tract have never been documented. The purpose of this study was to identify the presence and location of all four histamine receptors in the normal canine GI tract using immunohistochemical techniques. This information will provide additional research opportunities into the pathophysiology and treatment of canine chronic enteropathies.
Material and methods
Discussion Functions of histamine and histamine receptors have been studied for many years, and H1 and H2 receptor antagonists such as diphenhydramine and famotidine are used commonly in both human and veterinary medicine to treat a variety of conditions, including anaphylaxis, allergies, pruritus and GI ulcers. With the discovery of the H3 and H4 receptors, new roles for histamine have been elucidated, and new drug therapies are being explored (Peters and Kovacic, 2009). An understanding of histamine receptor location and function is necessary for the development of novel histamine receptor antagonists and agonists. The current study identified the presence and location of all four histamine receptors in the GI tract of 6 healthy adult dogs. Although no clinical signs of GI disease were noted, mild inflammation was noted in at least one section of the GI tract in all dogs based on WSAVA guidelines. Interpretation of GI inflammation in asymptomatic dogs is challenging for several reasons. A lack of agreement in regards to normal histology exists, despite development of the WSAVA guidelines (Willard and Mansell, 2011). Significant variation in intraepithelial lymphocyte numbers occurs between normal dogs as well (Washabau et al., 2010). Furthermore, in the absence of clinical signs or other clinical criteria for inflammatory bowel disease, the current veterinary literature does not explain the significance of histopathological abnormalities in the GI tract of healthy dogs (Washabau et al., 2010).