Chronic lower respiratory disease, which encompasses conditions such as Chronic Obstructive Pulmonary Disease (COPD) and asthma, ranks just behind heart disease and cancer as the leading cause of death in the United States. According to the CDC, in 2014 these diseases were responsible for approximately 147,101 deaths in the US. Additionally, data from the National Heart, Blood, and Lung Institute contend that aside from costing the United States approximately 64.2 billions of dollars in remedial services, this class of ailments is especially prevalent in modern society –purportedly linked to the escalation of climate change– and is responsible for significant morbidity in the population.
Asthma alone accounts for one of the most prevalent chronic diseases among children and adults in the United States. According to the Center for Disease Control and Prevention, around 25 million Americans suffer from asthma; around eight percent of adults and children alike are affected. Asthma functions to narrow and constrict airways through inflammation, which is often induced by environmental factors.
On a molecular level, divergent activation of Gq protein-dependent signaling pathways is a key element in the manifestation of asthma. These signaling cascades can be defined as chemical reaction sequences in which a Gq protein coupled receptor (GPCRs) receives an initiating stimulus, and this stimulus is consequently transduced into our cells with further amplification. More specifically, the activation of the receptors that work and communicate dynamically with the Gq proteins provokes the distinctive airway inflammation; this causes the disturbance of normal breathing patterns insymptomatic asthma.
Despite the absence of a cure for asthma, current treatments aim to counteract the physiological symptoms that are characteristic of the disease. Medications aim to reduce inflammation of the airway by targeting membrane GPCRs, which transmit information into the cells of eukaryotes. One type of treatment regime includes the use of β2 adrenergic receptor agonists working within the sympathetic nervous system to activate smooth muscle relaxation. However, repeated exposure to drugs similar to the adrenergic agonist commonly produce desensitization to the receptor proteins. In addition, the drug may cause a counterintuitive effect of bronchoconstriction; this consequence limits the efficacy of this type of pharmaceutical.
In an effort to discover a pharmacological improvement, medical faculty under the direction of Michaela Matthey at the University of Bonn in Germany hypothesized that the inhibition of the abnormal Gq protein found in people with asthma would effectively promote bronchorelaxation (which would open the airways and promote regular breathing). The mutation of the Gq protein associated with asthma was targeted in this study to discover if a selective inhibitor could successfully achieve smooth muscle tone reduction in the airways of the three organisms tested.
The compound FR900359 (FR), a pharmacological agent designed to be a Gq inhibitor, was tested for its more indirect role in the regulation of airway tone. In this analysis, FR functions as a potential candidate for clinical treatment due to its membrane permeability and high metabolic stability. In other words, FR could easily enter a cell and was less susceptible to deformation and subsequent ineffectivity once in the environment of the human body.
Polymerase chain reaction (PCR) was utilized to amplify Gq proteins and other functionally homologous proteins in the affected, or murine, tissue of the ex vivo lung and trachea in mice, pig, and human subjects. FR was then introduced using a dose-dependence model in these cells. As a result, it was observed that relaxation of these murine organismal tissues was determined by an optimal dose of the pharmacological agent. The researchers observed reversal of induced construction when airway inflammation was induced with methacholine. Methacholine, a receptor stimulating the parasympathetic nervous system, increases tone in these tissues which effectively constricts the bronchi in the lungs, similarly to the inflammatory effects of asthma. In vivo experiments were then performed to test the capacity of FR to cause bronchorelaxation in live mice. The FR was applied directly to the lungs and lung mechanics were measured; it was demonstrated that there was almost complete reversal of the methacholine-induced constriction of the tissue with the inhalation of the FR in aerosol form. In addition to these procedures, further tests with FR and tissue sensitized with asthma symptoms corroborated the aforementioned results.
This research demonstrates that specific inhibition of the Gq– dependent signal pathway occurring in the airway in mouse, pig, and human airway ex-vivo tissue is effective in inducing airway relaxation in models of allergen-sensitized mice. In these affected mice, the inhalation of FR also protected against hyperreactivity of the airway when house dust mites were allergens that triggered or activated asthma symptoms. This response pattern was also seen in the healthy airways of pigs and human airway tissue ex-vivo in this study. Therefore, FR has promising and positive effects on the airway mechanics of inflamed mice, pig, and human tissue that is analogous to murine tissue in the presence of asthma symptoms. Its local application to the lungs (where the Gq protein play a prominent role) via inhalation suggests its viability as a pharmacological candidate for treatment of asthmatic lung disease. Not only does it improve on current drug strategies that carry drawbacks and limitations, but this provides an outlet for a contemporary therapy to accomplish airway relaxation in humans, optimistically improving the statistics on respiratory disease.
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- Matthey, M., Roberts, R., Seidinger, A., Simon, A., Schröder, R., Kuschak, M., . . . Wenzel, D. (2017, September 13). Targeted inhibition of Gq signaling induces airway relaxation in mouse models of asthma. Retrieved September 29, 2017, from https://www.ncbi.nlm.nih.gov/pubmed/28904224
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