JNJ 7777120 and H4 Receptor Antagonism in Asthma

Inflammation and Its Role in Asthma and Allergies

Inflammation is a primary contributing component to the pathophysiology of allergies and asthma (Barbers et al., 2012). Inflammation, along with remodeling, are defining features present in mild to severe asthma. Inflammation due to allergies causes structural and functional changes to blood vessels within the respiratory tract. These changes include increased blood flow, vasodilation, angiogenesis, and higher vascular permeability in the airways of asthmatics (Jang et al., 2012). Remodeling is defined as the structural changes that occur within airways, such as increases in vascularity, increased smooth muscle mass, subepithelial fibrosis, and hyperplasia of goblet cells within the proximal and distal airways (Barbers et al., 2012). Furthermore, remodeling involves a multitude of factors, including complex interactions among cell adhesion molecules, cytokines, and growth factors (Jang et al., 2012). Research has suggested that the structural changes occurring due to remodeling in asthma may affect the recruitment of inflammatory cells, airway hyperresponsiveness, and the degree to which the disease is under control (Jang et al., 2012).

In exacerbators of near-fatal asthma, research has demonstrated the presence of factors such as remodeling of proximal airways accompanied by cellular inflammation (Barbers et al., 2012). In a study by Barbers et al. (2012), findings indicated the presence of remodeling with predominant eosinophilic inflammation. Eosinophils were demonstrated to induce structural changes associated with remodeling through transforming growth factor-β, the production of a fibrogenic cytokine, excessive extracellular matrix expression, and the conversion of fibroblasts to myofibroblasts (Barbers et al., 2012). Furthermore, the predominant features of near-fatal asthma were identified as remodeling and eosinophilic inflammation.

Research has also investigated inflammation and the associated presence of eosinophilic and noneosinophilic phenotypes in individuals exhibiting severe asthma, through comparisons of invasive and noninvasive methods among individuals with moderate and severe asthma (Lemiere et al., 2006). It was also explored whether induced sputum and exhaled nitric oxide could be used to effectively identify eosinophilic and noneosinophilic phenotypes among patients with severe asthma. Results of this study indicated that sputum cell counts and bronchial biopsies could be reliably used for the identification of a subgroup of individuals experiencing severe asthma. Furthermore, these findings indicate that sputum eosinophil counts may be used to identify individuals with the highest disease activity among severe asthmatics (Lemiere et al., 2006).

A central cause of death from asthma has been identified as widespread plugging of airways by mucus (Jang et al., 2012). Research has confirmed this by indicating that fatal asthma is characterized by the occlusion of 98% of airways by mucus. Mucus gland hyperplasia, allergic inflammation, and the upregulation of subsequent T-helper (Th)-2-type inflammatory responses are all induced by the overexpression of vascular endothelial growth factor (VEGF). Moreover, the vascular changes and inflammation that occur in asthma are largely due to VEGF. Research regarding treatments for symptoms of asthma must address the mechanisms underlying inflammation and the structural changes resulting from remodeling.

As discussed above, VEGF plays a key contributing role in the presence of asthma. Significantly higher levels of VEGF have been observed in the biological samples and tissues of individuals with asthma, and these levels have been noted to closely correlate with disease activity and inversely with airway caliber (Jang et al., 2012). Inflammatory responses result from the overexpression of VEGF within airways, which further leads to the upregulation of MUC5AC, a gel-forming mucin. What pharmacological interventions can be used to address these inflammation-related processes in allergies and asthma?

Histamine and the H4 Receptor

Histamine plays a major role in inflammatory processes, and the H4 receptor cells that bind to histamine are present throughout the immune system. Some of these cell types include eosinophils, mast cells, dendritic cells, and T lymphocytes (Seifert et al., 2011). The pro-inflammatory action of H4 receptor cells has been determined to be involved in medical conditions such as asthma, pruritus, and atopic dermatitis, and drugs that target these receptors and provide antagonistic action have demonstrated treatment success (Seifert et al., 2011). Early research by Jablonowski et al. (2003) demonstrated the first prepared potent and selective non-imidazole antagonists to the H4 receptor, paving the way for future research concerning the antagonistic properties of JNJ 7777120.

However, research has demonstrated some conflicting evidence, showing that the H4 receptor may also have an anti-inflammatory role in murine bronchial asthma (Neumann et al., 2010). Neumann et al. (2010) explored data from previous research on the role of H4 receptors in inflammation and noted that the pro-inflammatory function of the H4 receptor had been shown through only one previous study examining bronchial asthma in mice, and that no studies had directly explored the role of the H4 receptor in human asthma. Furthermore, the researchers indicated the necessity for substantially more research in order to fully comprehend the role that the H4 receptor plays in bronchial asthma (Neumann et al., 2010).

Antagonistic Properties of JNJ 7777120

Anti-inflammatory agents are commonly used in the treatment of asthma and allergies. Inflammation in allergic and asthma responses is often caused in part by the presence of histamines. The physiological function of histamine is mediated by its binding to four recognized histamine receptors (Thurmond et al., 2004). Antagonists of histamine receptors may provide anti-inflammatory activity. Research over the past decade has determined JNJ 7777120 to be the standard with regard to antagonistic action against H4 receptor cells (Seifert et al., 2011). Essentially, JNJ 7777120 selectively blocks histamine activity at the H4 receptor.

Cowden et al. (2010) recognized that the characteristic features of asthma — such as airway dysfunction and remodeling — are quite likely due to abnormal production of Th2 cytokines. This cytokine production, along with histamine H4 receptor activity, is involved in the inflammation that occurs in asthma. A study by these researchers explored the processes by which H4 receptor antagonists, such as JNJ 7777120, may effectively modify the effects of Th2 cytokine production. Results of the study showed that H4 receptor antagonists have the ability to significantly improve Th2-driven pathologies that are allergen-induced, such as airway dysfunction and lung remodeling, which provides support for the potential use of these agents in medication for humans (Cowden et al., 2010).

Research by Thurmond et al. (2004) illuminated various attributes of JNJ 7777120 as an effective agent for the treatment of inflammation in humans. This study indicated that JNJ 7777120 is equally potent across the species of mouse, rat, and human, and it shows significant selectivity over the H1, H2, and H3 receptors, with no evident cross-reactivity against 50 other examined targets. In other words, JNJ 7777120 is highly selective for the H4 receptor. With regard to oral bioavailability, JNJ 7777120 exhibited a rate of 30% in rats and 100% in dogs, with a demonstrated half-life in both species of approximately three hours. JNJ 7777120 has been shown to be effective in blocking chemotaxis and calcium influx induced by histamines in mast cells, and it also effectively blocks the migration of mast cells induced by histamines from connective tissue to the epithelium. Additionally, JNJ 7777120 was shown to effectively inhibit neutrophil infiltration. The findings of this study also indicated that the effects of JNJ 7777120 may be mediated in large part by mast cells (Thurmond et al., 2004). There are several conditions among humans that involve mast cells and eosinophils — such as allergic rhinitis, asthma, and rheumatoid arthritis — and JNJ 7777120 may prove to be an effective agent in the treatment of these diseases (Thurmond et al., 2004).