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JNJ and Inflammation
Inflammation and its role in disease
Inflammation is a primary contributing component to the pathophysiology of allergies asthma (Barbers et al., 2012). Inflammation along with remodeling are defining features present with 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 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 within the airways, subepithelial fibrosis, and hyperplasia of goblet cells within the proximal and distal airways (Barbers et al., 2012). Furthermore, remodeling is a process involving 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 that occur due to remodeling in asthma may affect the recruitment of inflammatory cells, airway hyperresponsiveness, and level to which the disease is under control (Jang et al., 2012).
In exacerbators of near fatal asthma, research has demonstrated a 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 eosinophilc inflammation. Eosinophils were demonstrated to induce structural changes associated with remodeling through transforming growth factor -- B, 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 eosinophilc inflammation.
Research investigating the inflammation and the associated presence of eosinophilic and noneosinophilc phenotypes in individuals exhibiting severe asthma through comparisons of invasive and noninvasive methods among individuals with moderate and severe asthma (Lemiere et al., 2006). Also, it was 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 finding indicate that sputum eosinophil counts may be used to indicate 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 was characterized by the occlusion of 98% of airways by mucus. Mucus glad 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 due to asthma are largely due to VEGF. Research regarding treatments for symptoms of asthma must address the mechanisms underlying the inflammation and structural changes resulting from remodeling.
As discussed above, VEGF plays a key contributing role to 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 to the activity of the disease inversely with the caliber or airways (Jang et al., 2012). Inflammatory responses result from the overexpression of VEGF within airways, which further lead to the upregulation of MUC5AC, a gel-forming mucin. What pharmacological interventions can be used to address these processes related to inflammation due to 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 in cells throughout the immune system. Some of these cell types include eosinophils, mast cells, dendritic cells, as well as T. lymphocytes (Seifert et al., 2011). The pro-inflammatory action of the H4 receptor cells have 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 a sort of 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 regard to inflammation, and noted that the pro-inflammatory function of the H4 receptor was shown only through one previous study that looked at bronchial asthma in mice, and there have been no studies that have directly explored the role of the H4 receptor in human asthma. Furthermore, the researchers indicate 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).
Antagonisitic 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. By binding to four recognized histamine receptors, the physiological function of histamine is mediated (Thurmond et al., 2004). Antagonists of histamine receptors may provide anti-inflammatory activity. Recent 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.
The researchers 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 are 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 the production of Th2 cytokines. Results of the study showed that H4 receptor antagonists have the ability to significantly improve Th2 driven pathologies that are allergen induced, such as dysfunction in airways 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 in receptors 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 location. In regards 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 3 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 that is induced by histamines from connective tissue to the epithelium. Also, JNJ 7777120 was shown to effectively 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).
What processes underlie the involvement of the H4 receptor in inflammatory functions? Research has demonstrated that the H4 receptor has the ability to mediate the production of cytokine from mast cells (Desai & Thurmond, 2011). This cytokine production is blocked by H4 antagonists and is not observed in cells deficient in H4 receptors. Also, histamine was involved in the production of LPS-induced production of IL-6 when its action was present in conjunction with H4 receptors, and it was demonstrated that the activation of H4 receptors could induce the phosphorylation of ERK, AKT and MEK. These kinases subsequently underwent transient and rapid phosphorylation as a result of the activation of the H4 receptor. All of these findings resulted in the researchers concluding that the H4 receptor could work with other signals associated with inflammation to potentiate the production of cytokine, which further illuminates the role that the H4 receptor plays with regard to inflammation (Desai & Thurmond, 2011). Therefore, antagonists to the actions associated with histamines and H4 receptors, such as JNJ 7777120, counteract resulting inflammation.
Further research regarding the antagonistic effects of JNJ 7777120 at the H4 receptor in a murine model of was asthma that was induced experimentally was conducted by Beermann et al. (2012). Along with the effects of JNJ 7777120, this study also looked at the antagonistic effects that mepyramine has at the H1 receptor site.…[continue]
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