الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Bronchial asthma is a common non-communicable disease, affecting both children and adults. Asthma attacks (exacerbations) can sometimes be fatal and exert a tremendous burden on quality of life and on health care systems. It is an obstructive airway disorder, characterized by variable and recurring symptoms of airflow limitation and hyperresponsiveness due to an underlying inflammation accompanied by structural changes in the bronchioles. The most known, as well as the most common, asthma subtype is the allergic eosinophilic asthma, which is characterized by type 2 airway inflammation. This type results from a complex interplay between the environmental allergen and the tendency of the host’s immune response to be skewed towards the type 2 immune response.
This allergic reaction includes two phases: (I) the sensitization phase, which is associated with an immune response deviated toward a T helper (Th)2-type response. It is enhanced by allergen-specific Th2 cells that release the interleukins (IL)-4, IL-5, and IL-13, and ultimately resulting in the production and accumulation of allergen-specific immunoglobulin E antibodies (IgE). During the next stage, (II) the effector phase, allergen re-exposure causes IgE-sensitized basophils and mast cells to degranulate, resulting in the release of mediators responsible for the acute asthma symptoms. Repeated allergen exposure perpetuates allergic airway inflammation and, consequently, the process of airway tissue damage and repair, which ultimately results in airway structural changes, collectively named airway remodeling.
Limited treatments are available to control symptoms, including corticosteroid therapy; however, they do not influence the underlying dysregulated immune reaction. Thus, they have very little effect on controlling the disease progression, especially in fully remodeled airways. Moreover, long-term high-dose corticosteroids may develop systemic side effects and even resistance. Therefore, it is imperative to target novel mechanisms contributing to the disease’s development and progression. Autophagy is one such developing approach.
Autophagy, a recycling fuel in all eukaryotic cells, has been identified as a crucial mechanism regulating asthma pathogenesis, with contradictory results indicating both deleterious and positive roles in asthma. Previous studies highlighted the possible effect of autophagy on different immune and structural cells involved in airway inflammation and the resultant remodeling changes.
Emerging studies reported that empagliflozin, a selective inhibitor of Na+-glucose cotransporter-2, exerts anti-inflammatory, anti-oxidant, and anti-fibrotic effects on a wide variety of kidney, heart, liver, and lung diseases, in addition to autophagy modulation.
Therefore, in this research, the potential effect of empagliflozin treatment on airway inflammation and remodeling as well as autophagy modulation in a murine model of allergic asthma was investigated. In addition, rapamycin, an autophagy inducer, was used alone or concomitantly with empagliflozin therapy to assess the effect of autophagy induction on disease severity and validate the possibility of autophagy contributing to the potential effects of empagliflozin on asthma.
In the present study, fifty-six male BALB/c were acclimatized for two weeks and underwent pulmonary function assessment using whole body plethysmography. Over a 7 week total period of the work, ovalbumin (OVA) was used to sensitize and challenge the mice to induce allergic asthma model via intraperitoneal injections and aerosol inhalation, respectively . The affected mice were then subdivided into 4 groups of 8 mice each, which either received oral gavage of empagliflozin (10 mg/kg), intraperitoneal injections of rapamycin (4 mg/kg), empagliflozin and rapamycin co-therapy, or only vehicle before every challenge. Three additional control groups were sensitized and challenged with phosphate-buffered saline, and treated with vehicle, empagliflozin, or rapamycin