AssessmentsPulmonary corticosteroids and mast cell inhibitors
Pulmonary corticosteroids and mast cell inhibitors
Content Reviewers:Yifan Xiao, MD
In obstructive lung diseases like asthma, where individuals suffer from reversible narrowing of the airways, medications like bronchodilators are helpful in keeping the airways open.
But, most of the times, narrowing of the airways actually occurs as a result of inflammation and excessive release of various inflammatory chemical mediators like leukotrienes and prostaglandins.
So, to effectively manage the disease, it’s important to give medications that will control the inflammation.
In the bronchioles you’ve got the lumen, the mucosa, which includes the inner lining of epithelial cells, as well as the lamina propria which contains many cells like the type 2 helper cells, B cells, and mast cells.
Surrounding the lamina propria, there is a layer of smooth muscles and submucosa.
The submucosal layer contains mucus-secreting glands and blood vessels.
Now, the molecular pathway that leads to asthma is actually pretty complex, but it is often initiated by an environmental trigger.
These cells then produce cytokines like IL-4 and IL-5 which causes the inflammatory response.
These mast cells use an enzyme called phospholipase A2 to take membrane phospholipids and make a 20 carbon polyunsaturated fatty acid called arachidonic acid.
Arachidonic acid is then metabolized by two important enzymes: one is cyclooxygenase-2 or COX-2, which makes prostaglandins, another one is 5-lipoxygenase or 5-LOX, which makes leukotrienes.
Minutes after exposure to the allergen, phospholipase A2 gets activated inside the mast cells, which results in the synthesis and release of leukotrienes and the prostaglandins.
Leukotrienes bind with the leukotriene receptors on the bronchial smooth muscles and cause them to contract. They also bind to receptors on the mucous glands to increase mucus secretion.
Similarly, prostaglandins also bind to their receptors in the smooth muscles and mucus gland to cause a similar effect.
These mediators also increase the vascular permeability in the airways and attract more immune cells to the area.
The combination of inflammation and bronchospasm cause obstruction of the airway which leads to symptoms like coughing, chest tightness, dyspnea, or difficulty breathing, and wheezing, which is a high-pitched whistling sound during exhalation.
Chronic inflammation also makes the respiratory tract more sensitive to allergens, so these symptoms become easier to trigger.
Now, we have 3 ways to control the inflammation in asthma.
We can decrease the synthesis of the inflammatory mediators, inhibit their release, or prevent mast cell activation.
When these medications reach immune cells, they can pass through the cell membrane because they are steroids, which means they are lipophilic. Once inside, they inhibit the synthesis of all inflammatory cytokines.
In mast cells, they increase the production of annexin-1 proteins that inhibit the enzyme phospholipase A2. This stops the conversion of membrane phospholipid into arachidonic acid and decreases the synthesis of leukotrienes and prostaglandins.
Corticosteroids also downregulate the enzyme cyclooxygenase-2, which reduces the production of prostaglandins. Finally, they also inhibit the proliferation of Th2 cells, which reduces the production of IL-4 and IL-5, further reducing the activity of mast cells and eosinophils.
This way, corticosteroids effectively inhibit the inflammatory process at multiple stages.
Inhaled therapy uses nebulized corticosteroids, which means it’s an aerosolized mist. It’s the first line therapy for chronic asthma because its actions localized in the lungs, so there’s fewer systemic side-effects.
Inhaled corticosteroids are often used alongside a bronchodilator like leukotriene receptor antagonist or a beta-2 agonist to control the disease more effectively.
Among them, dexamethasone and fluticasone are the longer acting and more potent medications.
In general, prednisolone is the medication of choice.
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